Materiały źródłowe

• #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. […] Malignant hyperthermia is an autosomal dominantly inherited disorder characterized by skeletal muscle hypermetabolism following exposure to halogenated anesthetics, depolarizing muscle relaxants such as succinylcholine, or, occasionally, physiologic stressors. […] 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.

• #2 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. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. […] 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).

• #3 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 of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. […] The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. […] Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor.

• #4 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. […] Malignant hyperthermia is an autosomal dominantly inherited disorder characterized by skeletal muscle hypermetabolism following exposure to halogenated anesthetics, depolarizing muscle relaxants such as succinylcholine, or, occasionally, physiologic stressors. […] 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.

• #5 Malignant Hyperthermia : Virtual Library

  https://resources.wfsahq.org/atotw/malignant-hyperthermia-tutorial-of-the-week-number-131/

  Malignant hyperthermia (MH) is an uncommon pharmacogenetic disorder of muscle induced by exposure to suxamethonium and all the volatile anaesthetic agents. It is characterized by hypermetabolism, muscle rigidity and muscle injury. […] MH susceptibility is inherited as an autosomal dominant condition with variable penetrance. Administration of triggering agents leads to an uncontrolled release of free calcium from the sarcoplasmic reticulum of skeletal muscle. […] This could be due to an abnormality at any point in the excitation-contraction coupling process, but the most likely site is the junction between the T tubule (involving the dihydropyridine receptor) and the sarcoplasmic reticulum (involving the ryanodine receptor, responsible for calcium efflux). […] In 50-70% of affected families there are links to the ryanodine receptor gene (RYR1) located on chromosome 19. This is a huge gene and many mutations have been identified, but only a small proportion has been shown to have an effect.

• #6 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. […] Malignant hyperthermia is an autosomal dominantly inherited disorder characterized by skeletal muscle hypermetabolism following exposure to halogenated anesthetics, depolarizing muscle relaxants such as succinylcholine, or, occasionally, physiologic stressors. […] 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.

• #7 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. […] Susceptibility can occur due to at least six genetic mutations, with the most common one being of the RYR1 gene. […] In susceptible individuals, the medications induce the release of stored calcium ions within muscle cells. […] The resulting increase in calcium concentrations within the cells cause the muscle fibers to contract. […] This generates excessive heat and results in metabolic acidosis. […] 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.

• #8 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1

  Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. […] A defective or disordered Ca2+ channel located in the SR membrane underlies MH susceptibility. This channel is termed the ryanodine receptor (RyR1). […] 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. […] 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). […] The enhanced intracellular Ca2+ results in abnormal skeletal muscle metabolism manifesting as activation of muscle contraction, increased oxygen consumption and CO2 production, ATP hydrolysis and heat production. […] The normal sequestration of released Ca2+ by the SR/ER Ca2+ -ATPase (SERCA) is inadequate and energy is expended in a futile manner, in an attempt to lower intracellular Ca2+. […] The exact steps in the process have not been definitively demonstrated.

• #9 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. […] Susceptibility can occur due to at least six genetic mutations, with the most common one being of the RYR1 gene. […] In susceptible individuals, the medications induce the release of stored calcium ions within muscle cells. […] The resulting increase in calcium concentrations within the cells cause the muscle fibers to contract. […] This generates excessive heat and results in metabolic acidosis. […] 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.

• #10 Malignant hyperthermia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/malignant-hyperthermia/

  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). An overabundance of calcium ions also causes skeletal muscles to contract, which leads to muscle rigidity. […] 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.

• #11 Malignant hyperthermia – Wikipedia

  https://en.wikipedia.org/wiki/Malignant_hyperthermia

  RYR1 opens in response to conformational changes in the L-type calcium channels following membrane depolarisation, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. […] The process of sequestering this excess Ca2+ consumes large amounts of adenosine triphosphate (ATP), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. […] 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.

• #12 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. […] Malignant hyperthermia is an autosomal dominantly inherited disorder characterized by skeletal muscle hypermetabolism following exposure to halogenated anesthetics, depolarizing muscle relaxants such as succinylcholine, or, occasionally, physiologic stressors. […] 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.

• #13 Malignant Hyperthermia in PICU—From Diagnosis to Treatment in the Light of Up-to-Date Knowledge

  https://www.mdpi.com/2227-9067/9/11/1692

  Malignant Hyperthermia (MH) is a rare, hereditary, life-threatening pharmacogenetic disease triggered by some commonly used anesthetics—specifically all halogenated volatile anesthetics and the depolarizing muscle relaxant succinylcholine. According to the current state of knowledge, an indisputable role in the pathophysiology of MH is played by the ryanodine receptor RYR1 on the sarcoplasmic reticulum membrane and the voltage-dependent calcium channel Cav1.1 located in the T-tubular membrane of myocytes. The genetic disposition to MH is characterized by an autosomal dominant type of transmission in the RYR1 and CACNA1S genes. Recently, a third gene known to be in a causal relationship with MH has been demonstrated. The STAC3 gene encodes one of the proteins involved in Excitation—Contraction Coupling. The genetic background of MH was identified only in approximately 40–60% of MH susceptible patients differing between countries and geographical areas and it is the aim of nowadays scientific research to reveal the underlying genetic cause of MH.

• #14 Malignant hyperthermia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/malignant-hyperthermia/

  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). An overabundance of calcium ions also causes skeletal muscles to contract, which leads to muscle rigidity. […] 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.

• #15 Malignant Hyperthermia in PICU—From Diagnosis to Treatment in the Light of Up-to-Date Knowledge

  https://www.mdpi.com/2227-9067/9/11/1692

  Malignant Hyperthermia (MH) is a rare, hereditary, life-threatening pharmacogenetic disease triggered by some commonly used anesthetics—specifically all halogenated volatile anesthetics and the depolarizing muscle relaxant succinylcholine. According to the current state of knowledge, an indisputable role in the pathophysiology of MH is played by the ryanodine receptor RYR1 on the sarcoplasmic reticulum membrane and the voltage-dependent calcium channel Cav1.1 located in the T-tubular membrane of myocytes. The genetic disposition to MH is characterized by an autosomal dominant type of transmission in the RYR1 and CACNA1S genes. Recently, a third gene known to be in a causal relationship with MH has been demonstrated. The STAC3 gene encodes one of the proteins involved in Excitation—Contraction Coupling. The genetic background of MH was identified only in approximately 40–60% of MH susceptible patients differing between countries and geographical areas and it is the aim of nowadays scientific research to reveal the underlying genetic cause of MH.

• #16 Malignant hyperthermia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/malignant-hyperthermia/

  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). An overabundance of calcium ions also causes skeletal muscles to contract, which leads to muscle rigidity. […] 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.

• #17 Malignant Hyperthermia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2231150-overview

  Malignant hyperthermia (MH) is a life-threatening clinical syndrome of hypermetabolism involving the skeletal muscle. It is triggered in susceptible individuals primarily by the volatile inhalational anesthetic agents and the muscle relaxant succinylcholine, though other drugs have also been implicated as potential triggers. MH is not an allergy but an inherited disorder that is found both in humans and in swine. […] In persons susceptible to MH, the ryanodine receptor in skeletal muscle is abnormal, and this abnormality interferes with regulation of calcium in the muscle. An abnormal ryanodine receptor that controls calcium release causes a buildup of calcium in skeletal muscle, resulting in a massive metabolic reaction. […] MH is a subclinical myopathy that allows large quantities of calcium to be released from the sarcoplasmic reticulum (SR) of skeletal muscle and to cause a hypermetabolic state after exposure to triggering agents. Altered calcium-channel gating kinetics in the SR is the underlying cause. The sustained elevation of calcium allows excessive stimulation of aerobic and anaerobic glycolytic metabolism, which accounts for respiratory and metabolic acidosis, rigidity, altered cell permeability, and hyperkalemia.

• #18 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. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. […] 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).

• #19 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. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. […] 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).

• #20 Malignant Hyperthermia: An Overview

  https://www.uspharmacist.com/article/malignant-hyperthermia-an-overview

  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. […] Evidence suggests that, during an MH reaction, triggering agents produce a change in the patients skeletal-muscle cells, resulting in elevated myoplasmic calcium; dantrolene is thought to prevent or reduce this increase, which activates the acute catabolic processes associated with MH.

• #21 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1

  Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. […] A defective or disordered Ca2+ channel located in the SR membrane underlies MH susceptibility. This channel is termed the ryanodine receptor (RyR1). […] 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. […] 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). […] The enhanced intracellular Ca2+ results in abnormal skeletal muscle metabolism manifesting as activation of muscle contraction, increased oxygen consumption and CO2 production, ATP hydrolysis and heat production. […] The normal sequestration of released Ca2+ by the SR/ER Ca2+ -ATPase (SERCA) is inadequate and energy is expended in a futile manner, in an attempt to lower intracellular Ca2+. […] The exact steps in the process have not been definitively demonstrated.

• #22 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. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. […] 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).

• #23 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 of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. […] The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. […] Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor.

• #24 Aetiology and Pathophysiology of Malignant Hyperthermia | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4613-2079-1_2

  Malignant hyperthermia reactions are initiated by a sudden rise in the concentration of calcium in the muscle cytoplasm. This elevation of myoplasmic calcium appears to be secondary to an increase in calcium induced calcium release from the sarcoplasmic reticulum (SR). This in turn may be a result of either or both: heightened sensitivity of the calcium channels of the SR to normal amounts of trigger calcium; or to increased amounts of trigger calcium. Excessive sensitivity of the SR calcium channels to trigger calcium may be induced by elevated levels of long chain fatty acids. Rises in cytoplasm long chain fatty acid levels in turn may be brought about by heightened phospholipase A2 activity in the mitochondria. Elevated levels of trigger calcium may originate in the mitochondria or the sarcolemma. Accelerated release of calcium from the mitochondria may be precipitated by the increased phospholipase A2 activity. Excessive amounts of calcium entering the cytoplasm from the sarcolemma may be due to: accelerated release of trigger calcium from the sarcolemma, or to increased transport of calcium from the extracellular fluid into the interior of the cell. The rate of calcium release from the SR may also be indirectly stimulated via heightened sensitivity of the skeletal muscle catecholamine receptor to endogenous adrenaline or noradrenaline.

• #25 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1

  Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. […] A defective or disordered Ca2+ channel located in the SR membrane underlies MH susceptibility. This channel is termed the ryanodine receptor (RyR1). […] 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. […] 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). […] The enhanced intracellular Ca2+ results in abnormal skeletal muscle metabolism manifesting as activation of muscle contraction, increased oxygen consumption and CO2 production, ATP hydrolysis and heat production. […] The normal sequestration of released Ca2+ by the SR/ER Ca2+ -ATPase (SERCA) is inadequate and energy is expended in a futile manner, in an attempt to lower intracellular Ca2+. […] The exact steps in the process have not been definitively demonstrated.

• #26 Malignant hyperthermia | PPT

  https://www.slideshare.net/slideshow/malignant-hyperthermia-231452015/231452015

  The molecular basis for these signs and symptoms is an uncontrolled increase in intracellular calcium in skeletal muscle. The sudden release of calcium from the sarcoplasmic reticulum removes the inhibition of troponin, resulting in sustained muscle contraction. […] Malignant hyperthermia (MH) is a rare but serious genetic disorder triggered by certain anesthetic gases and succinylcholine. It results in excessive calcium accumulation in skeletal muscle and causes a hypermetabolic state. […] Treatment involves discontinuing triggers, administering dantrolene to inhibit calcium release, supporting ventilation and organ function, and treating complications like acidosis and kidney damage. Prompt treatment can reduce mortality from over 15% to under 2%. […] Malignant hyperthermia is a pharmacogenetic disorder triggered by volatile anesthetic gases and succinylcholine. It results in an abnormal rise in intracellular calcium in genetically susceptible individuals which leads to rapid increases in body temperature, muscle rigidity, and metabolic acidosis that can be fatal if not treated promptly. […] Treatment involves immediately terminating the triggering agents, active cooling, hyperventilation with 100% oxygen, administration of dantrolene to reduce calcium levels in the muscle, and treating complications like acidosis and hyperkalemia.

• #27 Malignant hyperthermia | PPT

  https://www.slideshare.net/slideshow/malignant-hyperthermia-231452015/231452015

  The molecular basis for these signs and symptoms is an uncontrolled increase in intracellular calcium in skeletal muscle. The sudden release of calcium from the sarcoplasmic reticulum removes the inhibition of troponin, resulting in sustained muscle contraction. […] Malignant hyperthermia (MH) is a rare but serious genetic disorder triggered by certain anesthetic gases and succinylcholine. It results in excessive calcium accumulation in skeletal muscle and causes a hypermetabolic state. […] Treatment involves discontinuing triggers, administering dantrolene to inhibit calcium release, supporting ventilation and organ function, and treating complications like acidosis and kidney damage. Prompt treatment can reduce mortality from over 15% to under 2%. […] Malignant hyperthermia is a pharmacogenetic disorder triggered by volatile anesthetic gases and succinylcholine. It results in an abnormal rise in intracellular calcium in genetically susceptible individuals which leads to rapid increases in body temperature, muscle rigidity, and metabolic acidosis that can be fatal if not treated promptly. […] Treatment involves immediately terminating the triggering agents, active cooling, hyperventilation with 100% oxygen, administration of dantrolene to reduce calcium levels in the muscle, and treating complications like acidosis and hyperkalemia.

• #28

  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 caused by a genetic abnormality of calcium channels within skeletal muscle. Many channels are suspected to be possible locations for this abnormality; however, only the RYR1 and CACNA1S subunits have been demonstrated to have alterations related to MH. […] 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. Next, the patient experiences the actin-myosis-troponin interaction that precipitates muscle contraction, ultimately leading to a hypermetabolic response.

• #29 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1

  Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. […] A defective or disordered Ca2+ channel located in the SR membrane underlies MH susceptibility. This channel is termed the ryanodine receptor (RyR1). […] 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. […] 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). […] The enhanced intracellular Ca2+ results in abnormal skeletal muscle metabolism manifesting as activation of muscle contraction, increased oxygen consumption and CO2 production, ATP hydrolysis and heat production. […] The normal sequestration of released Ca2+ by the SR/ER Ca2+ -ATPase (SERCA) is inadequate and energy is expended in a futile manner, in an attempt to lower intracellular Ca2+. […] The exact steps in the process have not been definitively demonstrated.

• #30

  https://www.nursingcenter.com/cearticle?an=01261775-202104000-00003&Journal_ID=646631&Issue_ID=5834787

  When a muscle is unable to return to a resting state due to the uninhibited release of calcium from the sarcoplasmic reticulum, the physiologic response is for ATP to continue binding to the myosin. This activity results in increased CO2 production as a by-product of ATP generation in the mitochondria, excess heat production from the rapid consumption of ATP, and increased lactate production as the body attempts to produce energy by anaerobic metabolism. All of the consequences of the hypermetabolic response can lead to cellular damage and destruction, resulting in the extrusion of cellular contents such as potassium and creatine kinase into the extracellular space leading to additional complications such as hyperkalemia and cardiac arrhythmias.

• #31 Malignant hyperthermia – Wikipedia

  https://en.wikipedia.org/wiki/Malignant_hyperthermia

  RYR1 opens in response to conformational changes in the L-type calcium channels following membrane depolarisation, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. […] The process of sequestering this excess Ca2+ consumes large amounts of adenosine triphosphate (ATP), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. […] 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.

• #32 Aetiology and Pathophysiology of Malignant Hyperthermia | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4613-2079-1_2

  The elevated cytoplasmic calcium produces contracture of the myofibrils, increased heat, lactic acid and carbon dioxide production and accelerated oxygen consumption. ATP production falls while ATP consumption rises. Without ATP there is no substrate for active pumping of ions and molecules against concentration gradients across cellular and intracellular membranes. Ions and molecules, therefore, simply seep across these membranes in the direction of their natural concentration gradients. This in turn leads to further rises in cytoplasmic calcium. Excessive amounts of sodium and water also enter the muscle cell. In the reverse direction abnormally large amounts of potassium, magnesium, phosphate and at a later time of larger molecules such as myoglobin and enzymes are lost from the muscle cell to the extracellular fluid and from thence to the serum.

• #33 Malignant Hyperthermia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430828/

  The uncontrolled release of calcium from the skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. The sustained muscle contraction produces a depletion of adenosine triphosphate (ATP) and dramatically increases oxygen consumption, carbon dioxide production, and heat. The depletion of ATP stores leads to membrane integrity failure and cell content leakages such as potassium, creatinine kinase, and myoglobin into the circulation. […] Dantrolene works by inhibiting calcium ion release from the sarcoplasmic reticulum. Its mechanism of action is through antagonizing the ryanodine receptors, which lessens the excitation-contraction coupling of muscle cells. […] Dantrolene is currently the only specific medication used for treating a malignant hyperthermia crisis.

• #34 Aetiology and Pathophysiology of Malignant Hyperthermia | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4613-2079-1_2

  The elevated cytoplasmic calcium produces contracture of the myofibrils, increased heat, lactic acid and carbon dioxide production and accelerated oxygen consumption. ATP production falls while ATP consumption rises. Without ATP there is no substrate for active pumping of ions and molecules against concentration gradients across cellular and intracellular membranes. Ions and molecules, therefore, simply seep across these membranes in the direction of their natural concentration gradients. This in turn leads to further rises in cytoplasmic calcium. Excessive amounts of sodium and water also enter the muscle cell. In the reverse direction abnormally large amounts of potassium, magnesium, phosphate and at a later time of larger molecules such as myoglobin and enzymes are lost from the muscle cell to the extracellular fluid and from thence to the serum.

• #35 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. […] Malignant hyperthermia is an autosomal dominantly inherited disorder characterized by skeletal muscle hypermetabolism following exposure to halogenated anesthetics, depolarizing muscle relaxants such as succinylcholine, or, occasionally, physiologic stressors. […] 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.

• #36 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 of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. […] The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. […] Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor.

• #37 Malignant Hyperthermia in Animals – Metabolic Disorders – Merck Veterinary Manual

  https://www.merckvetmanual.com/metabolic-disorders/malignant-hyperthermia/malignant-hyperthermia-in-animals

  Triggering agents include stress (eg, excitement, transportation, and preanesthetic handling), exercise, halogenated inhalation anesthetics (eg, halothane, isoflurane, sevoflurane, and desflurane), and depolarizing neuromuscular blocking drugs (eg, succinylcholine). […] Dantrolene is the only effective specific treatment, with other therapy being symptomatic and supportive. […] Definitive diagnosis of MH is via in vitro contracture test or DNA analysis.

• #38 Malignant hyperthermia | Deranged Physiology

  https://derangedphysiology.com/main/required-reading/environmental-injuries-and-toxicology/Chapter-528/malignant-hyperthermia

  Question 10 from the second paper of 2003 demands that the ICU trainees discuss malignant hyperthermia, a complication of anaesthesia. This demonstrates just how much of this training program was borrowed from the College of Anaesthetists. […] The European Malignant Hyperthermia Group has published some nice guidelines in 2010, which offer an excellent overview of this topic. […] Pathophysiology […] autosomal dominant mutation in the gene coding for the ryanodine receptor […] Excess Ca2+ is released from the sarcolemma during muscle contraction, resulting in increased muscle metabolism, which is exothermic and thus leads to hyperthermia. […] It is triggered by suxamethonium (on the first exposure, frequently) and all volatiles except nitrous oxide (one may experience volatile anaesthesia two or three times before encountering this).

• #39 Malignant hyperthermia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867813/

  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). […] 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.

• #40 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. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. […] 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).

• #41 Malignant hyperthermia: MedlinePlus GeneticsLock

  https://medlineplus.gov/genetics/condition/malignant-hyperthermia/

  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). An overabundance of calcium ions also causes skeletal muscles to contract, which leads to muscle rigidity. […] 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.

• #42 Management of malignant hyperthermia: diagnosis and treatment | TCRM

  https://www.dovepress.com/management-of-malignant-hyperthermia-diagnosis-and-treatment-peer-reviewed-fulltext-article-TCRM

  Malignant hyperthermia is a potentially lethal inherited disorder characterized by disturbance of calcium homeostasis in skeletal muscle. Volatile anesthetics and/or the depolarizing muscle relaxant succinylcholine may induce this hypermetabolic muscular syndrome due to uncontrolled sarcoplasmic calcium release via functionally altered calcium release receptors, resulting in hypoxemia, hypercapnia, tachycardia, muscular rigidity, acidosis, hyperkalemia, and hyperthermia in susceptible individuals. […] Functionally altered calcium release channels cause dysfunction of intracellular calcium homeostasis and uncontrolled calcium release from the sarcoplasmic reticulum, which may lead rapidly to a fatal hypermetabolic state known as MH crisis. […] In an MH crisis, the triggering agent induces prolonged opening of functionally altered ryanodine receptors, resulting in uncontrolled release of calcium from the sarcoplasmic reticulum and ongoing muscle activation presenting as rigidity.

• #43 Malignant hyperthermia: a review | Orphanet Journal of Rare Diseases | Full Text

  https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0310-1

  Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH. […] A defective or disordered Ca2+ channel located in the SR membrane underlies MH susceptibility. This channel is termed the ryanodine receptor (RyR1). […] 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. […] 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). […] The enhanced intracellular Ca2+ results in abnormal skeletal muscle metabolism manifesting as activation of muscle contraction, increased oxygen consumption and CO2 production, ATP hydrolysis and heat production. […] The normal sequestration of released Ca2+ by the SR/ER Ca2+ -ATPase (SERCA) is inadequate and energy is expended in a futile manner, in an attempt to lower intracellular Ca2+. […] The exact steps in the process have not been definitively demonstrated.

• #44 Malignant hyperthermia

  https://pmc.ncbi.nlm.nih.gov/articles/PMC1867813/

  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). […] 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.

• #45

  https://link.springer.com/article/10.1007/s12630-018-1108-0

  The underlying mechanism of MH is the disruption of excitation-contraction coupling and dysregulation of skeletal muscle Ca2+ homeostasis. […] Pathogenic variants, associated with MH susceptibility, have been identified in genes encoding essential proteins involved in the skeletal muscle excitation-contraction coupling process. […] The RYR1 gene has been established as the major gene for MH with MH-associated RYR1 variants found in more than half of the MH families from different populations around the world.

• #46 Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review

  https://www.mdpi.com/2077-0383/12/12/3869

  In MH, the leading abnormality is due to mutations in the gene RYR1, on chromosome 19q13.1, encoding for RyR1: missense mutations alter the receptor with gain-of-function mutations, inducing increased Ca2+ release into the cytoplasm. […] More rarely, mutations in the α1 subunit of DHPR encoded by the gene CACNA1S may be involved: by suppressing the Ca2+ voltage-gated channel’s regulatory effect on RyR1, those variants can also cause an increased Ca2+ flux through the receptor. […] However, the paucity of clinical information surrounding the MH (or MH-like) episodes noted in patients with STAC3 variants, and the lack of robust experimental evidence in in vitro contracture testing, casts some doubt on an association between STAC3 variants and MHS.

• #47 Malignant hyperthermia | MedLink Neurology

  https://www.medlink.com/articles/malignant-hyperthermia

  Malignant hyperthermia is a pharmacogenetic disease that typically manifests during or immediately following general anesthesia. The primary mode of inheritance is autosomal dominant, although malignant hyperthermia does not occur with each anesthetic exposure. Without early identification and treatment, mortality is 70+%; thus, early diagnosis and treatment are lifesaving. Diagnosis of malignant hyperthermia for suspicious episodes may be confirmed only by the caffeine halothane contracture test, which is performed at a limited number of centers in North America and requires fresh muscle tissue. Genetic testing is available at several designated centers. Despite ongoing advances, molecular genetic testing has limited sensitivity; it is used to confirm susceptibility to malignant hyperthermia rather than to clear patients of the diagnosis. The cause of human malignant hyperthermia is not entirely understood, but mutations in different genes have been identified. Anesthesia-induced or, in some patients, heat- or exertion-induced loss of intracellular calcium regulation and consequent grossly elevated myoplasmic calcium are believed to be the turning point in the progression of the syndrome. Control of intracellular calcium is complex. Five proteins have been shown as necessary for conformational coupling of Cav 1.1 to the RYR1 encoded channel in excitation-contraction coupling. There is evidence that deranged intracellular calcium regulation in malignant hyperthermia involves impaired inhibition of RYR1 by intracellular calcium and magnesium as well as excessive extracellular calcium entry and store overload-induced calcium release. In a knock-in mouse model of malignant hyperthermia, excessive calcium accumulation in mitochondria, associated with greatly increased production of reactive oxygen species (ROS), was demonstrated. This was associated with increased sarcoplasmic reticulum calcium release with either caffeine or electrical stimulation. A defect (Cys615 for Arg615) in the RYR1 calcium release channel of skeletal muscle causes autosomal recessive porcine malignant hyperthermia. In malignant hyperthermia susceptible humans, the Cys614 for Arg614 (C1840T Human equivalent) mutation occurs in only 2% of susceptible families, but RYR1 variants may be found in approximately 50% to 75% of patients referred for molecular genetic testing after a malignant hyperthermia episode. More than 700 variants in RYR1 have been described. Through multiple functional studies, 48 have been confirmed to result in a gain in function that could cause malignant hyperthermia. In most families, malignant hyperthermia susceptibility is linked to the RYR1 gene on chromosome 19q13.1, whereas in other families this is not the case. In North America, approximately 25% of malignant hyperthermia-susceptible people have identified mutations in the three hot spots of RYR1 tested.

• #48

  https://link.springer.com/article/10.1007/s12630-018-1108-0

  Malignant hyperthermia is a genetic disorder of skeletal muscle cells affecting myoplasmic calcium homeostasis. […] The underlying mechanism of MH is disruption of excitation-contraction coupling resulting in enhanced calcium ions, Ca2+, release from the sarcoplasmic reticulum via the Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum (RyR1) in response to the triggers. […] The complications of MH include cardiac arrhythmia and cardiac arrest (from acidosis and hyperkalemia), renal failure, compartment syndrome, disseminated intravascular coagulation (DIC), pulmonary edema, and central nervous system injury. […] The risk of dying from MH has increased over the past few years. […] The discovery of genes associated with MH (RYR1, CACNA1S, and STAC3) and availability of the next-generation sequencing technology have allowed fast and cost-efficient screening of large cohorts of MH patients for MH-associated variants and made MH genetic testing a viable diagnostic approach.

• #49 Malignant hyperthermia | MedLink Neurology

  https://www.medlink.com/articles/malignant-hyperthermia

  Malignant hyperthermia is a pharmacogenetic disease that typically manifests during or immediately following general anesthesia. The primary mode of inheritance is autosomal dominant, although malignant hyperthermia does not occur with each anesthetic exposure. Without early identification and treatment, mortality is 70+%; thus, early diagnosis and treatment are lifesaving. Diagnosis of malignant hyperthermia for suspicious episodes may be confirmed only by the caffeine halothane contracture test, which is performed at a limited number of centers in North America and requires fresh muscle tissue. Genetic testing is available at several designated centers. Despite ongoing advances, molecular genetic testing has limited sensitivity; it is used to confirm susceptibility to malignant hyperthermia rather than to clear patients of the diagnosis. The cause of human malignant hyperthermia is not entirely understood, but mutations in different genes have been identified. Anesthesia-induced or, in some patients, heat- or exertion-induced loss of intracellular calcium regulation and consequent grossly elevated myoplasmic calcium are believed to be the turning point in the progression of the syndrome. Control of intracellular calcium is complex. Five proteins have been shown as necessary for conformational coupling of Cav 1.1 to the RYR1 encoded channel in excitation-contraction coupling. There is evidence that deranged intracellular calcium regulation in malignant hyperthermia involves impaired inhibition of RYR1 by intracellular calcium and magnesium as well as excessive extracellular calcium entry and store overload-induced calcium release. In a knock-in mouse model of malignant hyperthermia, excessive calcium accumulation in mitochondria, associated with greatly increased production of reactive oxygen species (ROS), was demonstrated. This was associated with increased sarcoplasmic reticulum calcium release with either caffeine or electrical stimulation. A defect (Cys615 for Arg615) in the RYR1 calcium release channel of skeletal muscle causes autosomal recessive porcine malignant hyperthermia. In malignant hyperthermia susceptible humans, the Cys614 for Arg614 (C1840T Human equivalent) mutation occurs in only 2% of susceptible families, but RYR1 variants may be found in approximately 50% to 75% of patients referred for molecular genetic testing after a malignant hyperthermia episode. More than 700 variants in RYR1 have been described. Through multiple functional studies, 48 have been confirmed to result in a gain in function that could cause malignant hyperthermia. In most families, malignant hyperthermia susceptibility is linked to the RYR1 gene on chromosome 19q13.1, whereas in other families this is not the case. In North America, approximately 25% of malignant hyperthermia-susceptible people have identified mutations in the three hot spots of RYR1 tested.

• #50 Aetiology and Pathophysiology of Malignant Hyperthermia | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4613-2079-1_2

  Malignant hyperthermia reactions are initiated by a sudden rise in the concentration of calcium in the muscle cytoplasm. This elevation of myoplasmic calcium appears to be secondary to an increase in calcium induced calcium release from the sarcoplasmic reticulum (SR). This in turn may be a result of either or both: heightened sensitivity of the calcium channels of the SR to normal amounts of trigger calcium; or to increased amounts of trigger calcium. Excessive sensitivity of the SR calcium channels to trigger calcium may be induced by elevated levels of long chain fatty acids. Rises in cytoplasm long chain fatty acid levels in turn may be brought about by heightened phospholipase A2 activity in the mitochondria. Elevated levels of trigger calcium may originate in the mitochondria or the sarcolemma. Accelerated release of calcium from the mitochondria may be precipitated by the increased phospholipase A2 activity. Excessive amounts of calcium entering the cytoplasm from the sarcolemma may be due to: accelerated release of trigger calcium from the sarcolemma, or to increased transport of calcium from the extracellular fluid into the interior of the cell. The rate of calcium release from the SR may also be indirectly stimulated via heightened sensitivity of the skeletal muscle catecholamine receptor to endogenous adrenaline or noradrenaline.

• #51 Malignant Hyperthermia • LITFL • CCC Toxicology

  https://litfl.com/malignant-hyperthermia-ccc/

  Malignant Hyperthermia = pharmacogenetic disease of skeletal muscle induced by exposure to certain anaesthetic agents. […] mutation in the gene coding for the ryanodine receptor. […] excess Ca2+ release during muscle contraction – increased muscle metabolism + heat production. […] prolonged and intensified interaction between actin and myosin. […] enhanced aerobic metabolism – lactic acidosis – accumulation of intra-mitochondrial calcium – deconjugation of oxidative phosphorylation – cytolysis.

• #52 Malignant Hyperthermia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2231150-overview

  Malignant hyperthermia (MH) is a life-threatening clinical syndrome of hypermetabolism involving the skeletal muscle. It is triggered in susceptible individuals primarily by the volatile inhalational anesthetic agents and the muscle relaxant succinylcholine, though other drugs have also been implicated as potential triggers. MH is not an allergy but an inherited disorder that is found both in humans and in swine. […] In persons susceptible to MH, the ryanodine receptor in skeletal muscle is abnormal, and this abnormality interferes with regulation of calcium in the muscle. An abnormal ryanodine receptor that controls calcium release causes a buildup of calcium in skeletal muscle, resulting in a massive metabolic reaction. […] MH is a subclinical myopathy that allows large quantities of calcium to be released from the sarcoplasmic reticulum (SR) of skeletal muscle and to cause a hypermetabolic state after exposure to triggering agents. Altered calcium-channel gating kinetics in the SR is the underlying cause. The sustained elevation of calcium allows excessive stimulation of aerobic and anaerobic glycolytic metabolism, which accounts for respiratory and metabolic acidosis, rigidity, altered cell permeability, and hyperkalemia.

• #53 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 of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. […] The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. […] Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor.

• #54

  https://journals.lww.com/aenjournal/fulltext/2021/04000/pathophysiology_and_treatment_of_malignant.3.aspx

  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. […] Symptoms of MH include increased carbon dioxide production, hyperthermia, muscle rigidity, tachypnea, tachycardia, acidosis, hyperkalemia, and rhabdomyolysis. […] Hypermetabolic symptoms have a rapid onset; hence, prompt recognition and treatment are vital to prevent morbidity and mortality. […] The first-line treatment agent for an MH response is dantrolene. […] Further treatment includes managing complications related to a hypermetabolic response such as hyperkalemia and arrhythmias.

• #55 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. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. […] 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).

• #56 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. […] When susceptible patients are exposed to triggering agents, calcium accumulates in the myoplasm of skeletal muscle cells. The accumulation of calcium causes sustained muscle contractions and the cells must utilize both aerobic and anaerobic metabolism in order to maintain the contraction. The result is ATP depletion, oxygen depletion, carbon dioxide production, and the development of acidosis. This pathological process is responsible for the early signs of malignant hyperthermia, which are tachycardia, hypercapnia and muscle rigidity. […] While in this hypermetabolic state, the body generates more heat than it is able to dissipate. This leads to hyperthermia which can occur early or later as the condition progresses. Studies show that in some cases, body temperature can increase by as much as 1 to 2 degrees Celsius every five minutes. Organ dysfunction sets in once the temperature reaches dangerously high levels above 41.5-degree Celsius (106.7-degrees Fahrenheit).

• #57 Malignant Hyperthermia (MH) – EMCrit Project

  https://emcrit.org/ibcc/mh/

  Malignant hyperthermia (MH) can be caused by any inhalational anesthetic, other than nitrous oxide. MH usually occurs intraoperatively or in the very early postoperative period (up to an hour after finishing anesthesia). Patients with central core myopathy are predisposed to develop malignant hyperthermia. […] Increased metabolic rate usually manifests with an increased end-tidal CO2 and/or minute ventilation. Increased volumetric CO2 production is the best index, if this is available. The volumetric CO2 should increase substantially in MH, regardless of whether the patient becomes tachypneic or how the ventilator settings are changed. […] Muscle rigidity may be an early finding. Rigidity may occur despite neuromuscular blockade. […] The key initial finding is the rate of temperature rise, which can be as rapid as 1-2 C every five minutes.

• #58 Malignant Hyperthermia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430828/

  The uncontrolled release of calcium from the skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. The sustained muscle contraction produces a depletion of adenosine triphosphate (ATP) and dramatically increases oxygen consumption, carbon dioxide production, and heat. The depletion of ATP stores leads to membrane integrity failure and cell content leakages such as potassium, creatinine kinase, and myoglobin into the circulation. […] Dantrolene works by inhibiting calcium ion release from the sarcoplasmic reticulum. Its mechanism of action is through antagonizing the ryanodine receptors, which lessens the excitation-contraction coupling of muscle cells. […] Dantrolene is currently the only specific medication used for treating a malignant hyperthermia crisis.

• #59 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 of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. […] The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. […] Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor.

• #60 Malignant Hyperthermia (MH) – EMCrit Project

  https://emcrit.org/ibcc/mh/

  Malignant hyperthermia (MH) can be caused by any inhalational anesthetic, other than nitrous oxide. MH usually occurs intraoperatively or in the very early postoperative period (up to an hour after finishing anesthesia). Patients with central core myopathy are predisposed to develop malignant hyperthermia. […] Increased metabolic rate usually manifests with an increased end-tidal CO2 and/or minute ventilation. Increased volumetric CO2 production is the best index, if this is available. The volumetric CO2 should increase substantially in MH, regardless of whether the patient becomes tachypneic or how the ventilator settings are changed. […] Muscle rigidity may be an early finding. Rigidity may occur despite neuromuscular blockade. […] The key initial finding is the rate of temperature rise, which can be as rapid as 1-2 C every five minutes.

• #61 ‘It’s Getting Hot in Here’: A Discussion on Malignant Hyperthermia – AACN

  https://www.aacn.org/blog/its-getting-hot-in-here-a-discussion-on-malignant-hyperthermia

  Malignant hyperthermia (MH) is a rare but life-threatening condition triggered by certain medications. […] MH is a disorder due to an acceleration of the metabolism in the skeletal muscle. […] MH is triggered by many common anesthetic gases that typically end in -flurane. […] An MH crisis usually occurs within one hour of administration of one of these medications. […] Identifying MH early is a crucial component of MH management and prevention of complications. […] The primary way to manage acidosis with an MH crisis is through hyperventilation. […] Although calcium is usually a first-line treatment for hyperkalemia, it is not the case with MH, as there is some evidence that an influx of extracellular calcium contributes to calcium overload of the myoplasm and can lead to muscle rigidity. […] CK levels may not peak for up to 24 hours after an MH event.

• #62

  https://www.nursingcenter.com/cearticle?an=01261775-202104000-00003&Journal_ID=646631&Issue_ID=5834787

  When a muscle is unable to return to a resting state due to the uninhibited release of calcium from the sarcoplasmic reticulum, the physiologic response is for ATP to continue binding to the myosin. This activity results in increased CO2 production as a by-product of ATP generation in the mitochondria, excess heat production from the rapid consumption of ATP, and increased lactate production as the body attempts to produce energy by anaerobic metabolism. All of the consequences of the hypermetabolic response can lead to cellular damage and destruction, resulting in the extrusion of cellular contents such as potassium and creatine kinase into the extracellular space leading to additional complications such as hyperkalemia and cardiac arrhythmias.

• #63 Aetiology and Pathophysiology of Malignant Hyperthermia | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-4613-2079-1_2

  The elevated cytoplasmic calcium produces contracture of the myofibrils, increased heat, lactic acid and carbon dioxide production and accelerated oxygen consumption. ATP production falls while ATP consumption rises. Without ATP there is no substrate for active pumping of ions and molecules against concentration gradients across cellular and intracellular membranes. Ions and molecules, therefore, simply seep across these membranes in the direction of their natural concentration gradients. This in turn leads to further rises in cytoplasmic calcium. Excessive amounts of sodium and water also enter the muscle cell. In the reverse direction abnormally large amounts of potassium, magnesium, phosphate and at a later time of larger molecules such as myoglobin and enzymes are lost from the muscle cell to the extracellular fluid and from thence to the serum.

• #64 Malignant Hyperthermia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2231150-overview

  The large ischemic demands imposed by the hypermetabolic state prevailing during acute MH can severely impair myocardial function. The extreme temperature elevation, hyperkalemia, acidosis, and cerebral edema can affect the central nervous system (CNS), causing coma, areflexia, and dilated pupils. […] DIC can occur as a consequence of the release of tissue thromboplastin. Pulmonary changes are secondary to systemic effects. Eventually, metabolic exhaustion ensues, leading to increased cellular permeability, whole-body edema, compartment syndrome in the extremities, cerebral edema, and death.

• #65 Malignant Hyperthermia: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/2231150-overview

  The large ischemic demands imposed by the hypermetabolic state prevailing during acute MH can severely impair myocardial function. The extreme temperature elevation, hyperkalemia, acidosis, and cerebral edema can affect the central nervous system (CNS), causing coma, areflexia, and dilated pupils. […] DIC can occur as a consequence of the release of tissue thromboplastin. Pulmonary changes are secondary to systemic effects. Eventually, metabolic exhaustion ensues, leading to increased cellular permeability, whole-body edema, compartment syndrome in the extremities, cerebral edema, and death.

• #66 Nursing Guide to Malignant Hyperthermia – Straight A Nursing

  https://straightanursingstudent.com/malignant-hyperthermia/

  Hyperthermia leads to DIC, which causes widespread coagulopathy and, ultimately, hemorrhage. If the patient gets to this point, the outcome is dire and the patient will not survive. […] The hypermetabolic state causes body temperature to increase which leads to widespread organ dysfunction and DIC.

• #67 Malignant Hyperthermia in PICU—From Diagnosis to Treatment in the Light of Up-to-Date Knowledge

  https://www.mdpi.com/2227-9067/9/11/1692

  MH crisis is a severe hypermetabolic whole-body reaction to the pathologically increased level of calcium in muscle cells released by the triggering agents. Increased cell metabolism results in higher oxygen consumption, excessive CO2 production, heat production, acidosis, muscle generalized rigidity, etc. All lead to rhabdomyolysis causing hyperkalemia, myoglobinuria, and acute kidney injury (AKI), and if untreated further, it leads to disseminated intravascular coagulation (DIC), cardiovascular failure and death. The incidence of MH crisis is approximately 1:10,000–1:250,000 anesthesia depending on the population and the chosen anesthetic management, but the prevalence of genetic abnormality associated with MH is several times higher. The combined prevalence of all MH causal diagnostic variants in total is 1:2750. Even though MH crisis mortality is currently significantly lower thanks to the availability of dantrolene, MH is still considered to be a very serious and life-threatening complication. As MH crisis is well preventable by not administering triggers to MH susceptible individuals, that is why the detection and diagnosis of at-risk patients are so crucial.

• #68 Malignant hyperthermia susceptibility: Evaluation and management – UpToDate

  https://www.uptodate.com/contents/susceptibility-to-malignant-hyperthermia-evaluation-and-management

  Malignant hyperthermia (MH) is a complex genetic disorder of skeletal muscle typically manifesting clinically as a hypermetabolic crisis when a susceptible individual receives a halogenated inhalational anesthetic agent and/or succinylcholine. Patients who are susceptible to MH have skeletal muscle excitation-contraction receptor or adaptor protein (eg, STAC3) abnormalities that allow excessive myoplasmic calcium to accumulate in the presence of the anesthetic triggering agents. Very little is known about the specific mechanisms by which anesthetics interact with these abnormal receptors to trigger an MH crisis. […] Malignant hyperthermia susceptibility (MHS) may arise de novo, though it is most often inherited in an autosomal dominant fashion. MHS is suspected in individuals with a history of a clinical event indicative of an acute MH crisis or with a family history of susceptibility. The mainstay of prevention is the identification of these genetically susceptible individuals. Avoidance of anesthetic triggers in MHS patients and prompt administration of dantrolene when an acute event occurs have reduced the mortality associated with MH from historic rates of 70 percent to <10 percent. [...] This topic will review the genetic basis and testing for MHS and the safe administration of anesthesia to MHS patients. The pathophysiology, clinical manifestations, diagnosis, and management of an acute MH crisis are discussed separately.

• #69 Malignant Hyperthermia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430828/

  The uncontrolled release of calcium from the skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. The sustained muscle contraction produces a depletion of adenosine triphosphate (ATP) and dramatically increases oxygen consumption, carbon dioxide production, and heat. The depletion of ATP stores leads to membrane integrity failure and cell content leakages such as potassium, creatinine kinase, and myoglobin into the circulation. […] Dantrolene works by inhibiting calcium ion release from the sarcoplasmic reticulum. Its mechanism of action is through antagonizing the ryanodine receptors, which lessens the excitation-contraction coupling of muscle cells. […] Dantrolene is currently the only specific medication used for treating a malignant hyperthermia crisis.

• #70 Malignant Hyperthermia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430828/

  The uncontrolled release of calcium from the skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. The sustained muscle contraction produces a depletion of adenosine triphosphate (ATP) and dramatically increases oxygen consumption, carbon dioxide production, and heat. The depletion of ATP stores leads to membrane integrity failure and cell content leakages such as potassium, creatinine kinase, and myoglobin into the circulation. […] Dantrolene works by inhibiting calcium ion release from the sarcoplasmic reticulum. Its mechanism of action is through antagonizing the ryanodine receptors, which lessens the excitation-contraction coupling of muscle cells. […] Dantrolene is currently the only specific medication used for treating a malignant hyperthermia crisis.

• #71 Malignant Hyperthermia : Virtual Library

  https://resources.wfsahq.org/atotw/malignant-hyperthermia-tutorial-of-the-week-number-131/

  The clinical features are a direct consequence of loss of skeletal muscle calcium homeostasis, resulting in increased intracellular calcium ion concentration, which causes muscle rigidity, hypermetabolism, and rhabdomyolysis. […] Dantrolene is a hydantoin derivative which acts within the muscle cell to reduce calcium release by the sarcoplasmic reticulum. During an MH episode, dantrolene reduces intracellular calcium levels. It can be dramatically effective when given in time. The average dose required is 3 mg/kg. […] The only condition definitely associated with MH is central core disease, an inherited disorder of peripheral muscle weakness. Patients with this condition should be considered as potentially, but not invariably, susceptible to MH and referred for screening.

• #72 RYANODEX® | What is malignant hyperthermia (MH)?

  https://www.ryanodex.com/about-mh/

  Malignant hyperthermia (MH) is a pharmacogenetic disease that causes hypermetabolism, a fast rise in body temperature and severe muscle contractions when an affected person receives general anesthesia using volatile anesthetics or the paralytic succinylcholine. […] The disorder is due to an acceleration of the metabolism in skeletal muscle. […] The underlying defect is abnormally increased levels of cellular calcium in the skeletal muscle. […] Stopping the triggering agents and administering dantrolene sodium to the patient as quickly as possible are the greatest priorities in an MH crisis. […] Every delay in treatment increases the risk of further complication during an MH crisis. […] The risk of complications may increase to 30% with a 20-minute delay in treating MH from its first symptom.

• #73 RYANODEX® | What is malignant hyperthermia (MH)?

  https://www.ryanodex.com/about-mh/

  Malignant hyperthermia (MH) is a pharmacogenetic disease that causes hypermetabolism, a fast rise in body temperature and severe muscle contractions when an affected person receives general anesthesia using volatile anesthetics or the paralytic succinylcholine. […] The disorder is due to an acceleration of the metabolism in skeletal muscle. […] The underlying defect is abnormally increased levels of cellular calcium in the skeletal muscle. […] Stopping the triggering agents and administering dantrolene sodium to the patient as quickly as possible are the greatest priorities in an MH crisis. […] Every delay in treatment increases the risk of further complication during an MH crisis. […] The risk of complications may increase to 30% with a 20-minute delay in treating MH from its first symptom.

• #74 Malignant Hyperthermia (MH) – EMCrit Project

  https://emcrit.org/ibcc/mh/

  Treatment must be initiated empirically, when the MH diagnosis is considered probable. […] Hyperventilate with 100% oxygen at 2-3 times the normal minute ventilation, to clear any residual volatile anesthetic. […] Dantrolene 2.5 mg/kg IV immediately, then administer an additional 1-2.5 mg/kg IV q5min until symptoms subside. […] Continuous monitoring of the core temperature is essential. […] Severe MH can cause disseminated intravascular coagulation (DIC).

• #75 Malignant Hyperthermia : Virtual Library

  https://resources.wfsahq.org/atotw/malignant-hyperthermia-tutorial-of-the-week-number-131/

  The clinical features are a direct consequence of loss of skeletal muscle calcium homeostasis, resulting in increased intracellular calcium ion concentration, which causes muscle rigidity, hypermetabolism, and rhabdomyolysis. […] Dantrolene is a hydantoin derivative which acts within the muscle cell to reduce calcium release by the sarcoplasmic reticulum. During an MH episode, dantrolene reduces intracellular calcium levels. It can be dramatically effective when given in time. The average dose required is 3 mg/kg. […] The only condition definitely associated with MH is central core disease, an inherited disorder of peripheral muscle weakness. Patients with this condition should be considered as potentially, but not invariably, susceptible to MH and referred for screening.

• #76

  https://journals.lww.com/aenjournal/fulltext/2021/04000/pathophysiology_and_treatment_of_malignant.3.aspx

  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. […] Symptoms of MH include increased carbon dioxide production, hyperthermia, muscle rigidity, tachypnea, tachycardia, acidosis, hyperkalemia, and rhabdomyolysis. […] Hypermetabolic symptoms have a rapid onset; hence, prompt recognition and treatment are vital to prevent morbidity and mortality. […] The first-line treatment agent for an MH response is dantrolene. […] Further treatment includes managing complications related to a hypermetabolic response such as hyperkalemia and arrhythmias.

• #77 Malignant Hyperthermia in PICU—From Diagnosis to Treatment in the Light of Up-to-Date Knowledge

  https://www.mdpi.com/2227-9067/9/11/1692

  The clinical presentation reflects disturbed calcium homeostasis due to genetic defects and MH triggers. The most typical symptoms of MH are hypercapnia, tachycardia, hyperthermia, and muscle rigidity. Hypercapnia, due to inappropriately elevated CO2 production (raised end-tidal CO2 on capnography, tachypnoea if breathing spontaneously), is known to be the earliest sign of the MH crisis. […] The cornerstone of successful treatment is to start as soon as possible, the sooner, the better patient outcomes. Eliminate the triggers, administer dantrolene, commence cooling and treat adverse consequences.

• #78 Successful management of malignant hyperthermia without dantrolene – A case report – IJCA

  https://www.ijca.in/html-article/21388

  Dantrolene Sodium is an antidote for MH and it binds to the RYR1 receptor thereby inhibits the release of calcium from the sarcoplasmic reticulum and reverses the negative cascade of effects. […] The prognosis of an MH crisis depends on early detection and how rapidly appropriate treatment is initiated. The principles of treatment are firstly to reverse the reaction and secondly to treat the consequences of the reaction. There are three approaches to reversing the MH process: (1) eliminate the triggering agent; (2) give i.v. dantrolene; and (3) start active body cooling. […] The successful management of MH without dantrolene emphasizes the need for stringent monitoring, early detection and immediate and effective treatment. Essential monitoring especially temperature and ETCO2 should be used so that early warning signs can be detected in all cases where volatile anesthetic agents and other triggering agents are used.

• #79 ‘It’s Getting Hot in Here’: A Discussion on Malignant Hyperthermia – AACN

  https://www.aacn.org/blog/its-getting-hot-in-here-a-discussion-on-malignant-hyperthermia

  Malignant hyperthermia (MH) is a rare but life-threatening condition triggered by certain medications. […] MH is a disorder due to an acceleration of the metabolism in the skeletal muscle. […] MH is triggered by many common anesthetic gases that typically end in -flurane. […] An MH crisis usually occurs within one hour of administration of one of these medications. […] Identifying MH early is a crucial component of MH management and prevention of complications. […] The primary way to manage acidosis with an MH crisis is through hyperventilation. […] Although calcium is usually a first-line treatment for hyperkalemia, it is not the case with MH, as there is some evidence that an influx of extracellular calcium contributes to calcium overload of the myoplasm and can lead to muscle rigidity. […] CK levels may not peak for up to 24 hours after an MH event.

• #80 Malignant hyperthermia susceptibility: Evaluation and management – UpToDate

  https://www.uptodate.com/contents/susceptibility-to-malignant-hyperthermia-evaluation-and-management

  Malignant hyperthermia (MH) is a complex genetic disorder of skeletal muscle typically manifesting clinically as a hypermetabolic crisis when a susceptible individual receives a halogenated inhalational anesthetic agent and/or succinylcholine. Patients who are susceptible to MH have skeletal muscle excitation-contraction receptor or adaptor protein (eg, STAC3) abnormalities that allow excessive myoplasmic calcium to accumulate in the presence of the anesthetic triggering agents. Very little is known about the specific mechanisms by which anesthetics interact with these abnormal receptors to trigger an MH crisis. […] Malignant hyperthermia susceptibility (MHS) may arise de novo, though it is most often inherited in an autosomal dominant fashion. MHS is suspected in individuals with a history of a clinical event indicative of an acute MH crisis or with a family history of susceptibility. The mainstay of prevention is the identification of these genetically susceptible individuals. Avoidance of anesthetic triggers in MHS patients and prompt administration of dantrolene when an acute event occurs have reduced the mortality associated with MH from historic rates of 70 percent to <10 percent. [...] This topic will review the genetic basis and testing for MHS and the safe administration of anesthesia to MHS patients. The pathophysiology, clinical manifestations, diagnosis, and management of an acute MH crisis are discussed separately.

• #81

  https://link.springer.com/article/10.1007/s12630-018-1108-0

  Malignant hyperthermia is a genetic disorder of skeletal muscle cells affecting myoplasmic calcium homeostasis. […] The underlying mechanism of MH is disruption of excitation-contraction coupling resulting in enhanced calcium ions, Ca2+, release from the sarcoplasmic reticulum via the Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum (RyR1) in response to the triggers. […] The complications of MH include cardiac arrhythmia and cardiac arrest (from acidosis and hyperkalemia), renal failure, compartment syndrome, disseminated intravascular coagulation (DIC), pulmonary edema, and central nervous system injury. […] The risk of dying from MH has increased over the past few years. […] The discovery of genes associated with MH (RYR1, CACNA1S, and STAC3) and availability of the next-generation sequencing technology have allowed fast and cost-efficient screening of large cohorts of MH patients for MH-associated variants and made MH genetic testing a viable diagnostic approach.

• #82 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 of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. […] The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response. […] Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. […] In most cases, the syndrome is caused by a defect in the ryanodine receptor.

• #83 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. Due to ATP depletion, the muscle membrane integrity is compromised leading to hyperkalemia and rhabdomyolysis. In most cases, the syndrome is caused by a defect in the ryanodine receptor. Over 90 mutations have been identified in the RYR-1 gene located on chromosome 19q13.1, and at least 25 are causal for MH. […] 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).

• #84 Management of malignant hyperthermia: diagnosis and treatment | TCRM

  https://www.dovepress.com/management-of-malignant-hyperthermia-diagnosis-and-treatment-peer-reviewed-fulltext-article-TCRM

  Malignant hyperthermia is a potentially lethal inherited disorder characterized by disturbance of calcium homeostasis in skeletal muscle. Volatile anesthetics and/or the depolarizing muscle relaxant succinylcholine may induce this hypermetabolic muscular syndrome due to uncontrolled sarcoplasmic calcium release via functionally altered calcium release receptors, resulting in hypoxemia, hypercapnia, tachycardia, muscular rigidity, acidosis, hyperkalemia, and hyperthermia in susceptible individuals. […] Functionally altered calcium release channels cause dysfunction of intracellular calcium homeostasis and uncontrolled calcium release from the sarcoplasmic reticulum, which may lead rapidly to a fatal hypermetabolic state known as MH crisis. […] In an MH crisis, the triggering agent induces prolonged opening of functionally altered ryanodine receptors, resulting in uncontrolled release of calcium from the sarcoplasmic reticulum and ongoing muscle activation presenting as rigidity.

• #85 Pathophysiology and Treatment of Malignant Hyperthermia: Ingenta Connect

  https://www.ingentaconnect.com/content/10.1097/TME.0000000000000344

  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. […] Hypermetabolic symptoms have a rapid onset; hence, prompt recognition and treatment are vital to prevent morbidity and mortality. […] The first-line treatment agent for an MH response is dantrolene. Further treatment includes managing complications related to a hypermetabolic response such as hyperkalemia and arrhythmias.

• #86 Malignant Hyperthermia – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK430828/

  The uncontrolled release of calcium from the skeletal muscle sarcoplasmic reticulum leads to sustained muscle contraction. The sustained muscle contraction produces a depletion of adenosine triphosphate (ATP) and dramatically increases oxygen consumption, carbon dioxide production, and heat. The depletion of ATP stores leads to membrane integrity failure and cell content leakages such as potassium, creatinine kinase, and myoglobin into the circulation. […] Dantrolene works by inhibiting calcium ion release from the sarcoplasmic reticulum. Its mechanism of action is through antagonizing the ryanodine receptors, which lessens the excitation-contraction coupling of muscle cells. […] Dantrolene is currently the only specific medication used for treating a malignant hyperthermia crisis.

• #87 Malignant hyperthermia susceptibility: Evaluation and management – UpToDate

  https://www.uptodate.com/contents/susceptibility-to-malignant-hyperthermia-evaluation-and-management

  Malignant hyperthermia (MH) is a complex genetic disorder of skeletal muscle typically manifesting clinically as a hypermetabolic crisis when a susceptible individual receives a halogenated inhalational anesthetic agent and/or succinylcholine. Patients who are susceptible to MH have skeletal muscle excitation-contraction receptor or adaptor protein (eg, STAC3) abnormalities that allow excessive myoplasmic calcium to accumulate in the presence of the anesthetic triggering agents. Very little is known about the specific mechanisms by which anesthetics interact with these abnormal receptors to trigger an MH crisis. […] Malignant hyperthermia susceptibility (MHS) may arise de novo, though it is most often inherited in an autosomal dominant fashion. MHS is suspected in individuals with a history of a clinical event indicative of an acute MH crisis or with a family history of susceptibility. The mainstay of prevention is the identification of these genetically susceptible individuals. Avoidance of anesthetic triggers in MHS patients and prompt administration of dantrolene when an acute event occurs have reduced the mortality associated with MH from historic rates of 70 percent to <10 percent. [...] This topic will review the genetic basis and testing for MHS and the safe administration of anesthesia to MHS patients. The pathophysiology, clinical manifestations, diagnosis, and management of an acute MH crisis are discussed separately.

• #88

  https://ronlitman.substack.com/p/a-new-era-in-malignant-hyperthermia

  I am sure that you are all aware that MH is inherited in an autosomal dominant manner in humans, what medications trigger MH, how preparation and steps in treatment have reduced the mortality of MH from about 70% to about 10% (still too high). […] However, over the past ten years, work on the genetics of MH has shown that three genes contain DNA variants that are causal for the disorder(RYR 1, CACNA1S and STAC 3). […] There are several hundred variants in the genes that are pathogenic or likely pathogenic for MH, but to date, only about 50 have been so identified, other variants still remain to be classified. […] It is important to remember that MH is an inherited disorder like many others and advances in care depend on collaboration between clinicians and geneticists, genetic counselors and pharmacogeneticists. […] There is a lot more to the story since a variety of myopathies and other disorders such as heat stroke are sometimes associated with MH pathogenic variants.

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