Malignant hyperthermia
Encyclopedia
Malignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent
, succinylcholine. In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in skeletal muscle
oxidative metabolism, which overwhelms the body's capacity to supply oxygen
, remove carbon dioxide
, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly.
Susceptibility to MH is often inherited as an autosomal dominant disorder, for which there are at least 6 genetic loci of interest, most prominently the ryanodine receptor
gene (RYR1). MH susceptibility is phenotypically and genetically related to central core disease
(CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy
. MH is usually revealed by anesthesia, or when a family member develops the symptoms. There is no simple, straightforward test to diagnose the condition. When MH develops during a procedure, treatment with dantrolene sodium
is usually initiated; dantrolene and the avoidance of anesthesia in susceptible people have markedly reduced the mortality from this condition.
and breathing rate
, increased carbon dioxide production, increased oxygen consumption, acidosis
, rigid muscles, and rhabdomyolysis
.
The symptoms usually develop within one hour after exposure to trigger substances, but may even occur several hours later in rare instances.
, sevoflurane
, desflurane
or the depolarizing muscle relaxant succinylcholine used primarily in general anesthesia. In rare cases, the biological stresses of physical exercise or heat may be the trigger.
Other anesthetic drugs are considered safe. These include local anesthetics (lidocaine
, bupivicaine, mepivacaine
), opiates (morphine
, fentanyl), ketamine
, barbiturates, nitrous oxide
, propofol
, etomidate
, benzodiazepines.
The nondepolarizing muscle relaxants pancuronium
, cisatracurium
, atracurium
, mivacurium
, vecuronium
and rocuronium
also do not cause MH.
(19q13.1) involving the ryanodine receptor
. More than 25 different mutations are in this gene are linked with malignant hyperthermia. These mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the protein, which interacts with L-type calcium channels and Ca2+. MH3 is located in the transmembrane forming C-terminus. This region is important for allowing Ca2+ passage through the protein following opening.
of the ryanodine receptor
(type 1), located on the sarcoplasmic reticulum (SR), the organelle
within skeletal muscle
cells that stores calcium
. RYR1 opens in response to increases in intracellular Ca2+
level mediated by L-type calcium channel
s, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing Ca2+ concentrations: the A-site and the I-site. The A-site is a high affinity Ca2+ binding site that mediates RYR1 opening. The I-site is a lower affinity site that mediates the protein's closing. Caffeine
, halothane, and other triggering agents act by drastically increasing the affinity of the A-site for Ca2+ and concomitantly decreasing the affinity of the I-site in mutant proteins. Mg2+ also affect RYR1 activity, causing the protein to close by acting at either the A- or I-sites. In MH mutant proteins, the affinity for Mg2+ at either one of these sites is greatly reduced. The end result of these alterations is greatly increased Ca2+ release due to a lowered activation and heightened deactivation threshold. The process of reabsorbing 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 muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium
, myoglobin
, creatine
, phosphate
and creatine kinase
.
The other known causative gene for MH is CACNA1S, which encodes and L-type
voltage-gated calcium channel α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086. This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in human embryonic kidney (HEK 293
) cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5-10mV more hyperpolarized. Furthermore, cells expressing these channels have an increased basal cytosolic Ca2+ concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Ca2+, and, thereby, muscle excitability.
Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.
and other pig
breeds selected for muscling, a condition in which stressed pigs develop "pale, soft, exudative" flesh
(a manifestation of the effects of malignant hyperthermia) rendering their meat less marketable at slaughter. This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently, susceptible humans were discovered to "awake trigger" (develop malignant hyperthermia) in stressful situations. This supported the use of the pig model for research. Pig farmers use halothane cones in swine yards to expose piglets to halothane. Those that die were MH-susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market. This also reduced the use of breeding stock carrying the genes for PSS. The condition in swine is also due to a defect in ryanodine receptors.
Gillard et al. discovered the causative mutation in humans only after similar mutations had first been described in pigs.
Horses also suffer from malignant hyperthermia. It is the Thoroughbred breed that was found to have susceptibility. It can be caused by overwork, anesthesia, or stress. An inheritable genetic mutation is found in susceptible animals. In dogs, its inheritance is autosomal recessive.
An MH mouse has been constructed, bearing the R163C mutation prevalent in humans. These mice display symptoms similar to human MH patients, including sensitivity to halothane (increased respiration, body temperature, and death). Blockade of RYR1 by dantrolene
prevents adverse reaction to halothane in these mice, as with humans. Muscle from these mice also shows increased K+-induced depolarization and an increased caffeine sensitivity.
(despite increased minute ventilation), tachycardia, and muscle rigidity. Despite the name, elevation of body temperature is often a late sign. Other signs may include acidosis, tachypnea
(in a spontaneously breathing patient), and hyperkalemia
. Core body temperatures should be measured in any patient undergoing general anesthesia longer than 20 minutes.
Malignant hyperthermia is diagnosed on clinical grounds, but various investigations are generally performed. This includes blood test
s, which may show a raised creatine kinase level, elevated potassium, increased phosphate (leading to decreased calcium) and—if determined—raised myoglobin; this is the result of damage to muscle cells. Metabolic acidosis
and respiratory acidosis
(raised acidity of the blood) may both occur. Severe rhabdomyolysis may lead to acute renal failure
, so kidney function
is generally measured on a frequent basis. Patients may also get cardiac arrythmias (PVCs) due to the increased levels of potassium released from the muscles during episodes.
.
is carried out at an approved research center, under local anesthesia. The fresh biopsy is bathed in solutions containing caffeine or halothane and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78%. Negative biopsies are not definitive, so any patient who is suspected of MH by their medical history or that of blood relatives is generally treated with nontriggering anesthetics, even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.
Less invasive diagnostic techniques have been proposed. Intramuscular injection of halothane 6 vol% has been shown to result in higher than normal increases in local pCO2 among patients with known malignant hyperthermia susceptibility. The sensitivity was 100% and specificity was 75%. For patients at similar risk to those in this study, this leads to a positive predictive value
of 80% and negative predictive value
of 100%. This method may provide a suitable alternative to more invasive techniques.
A 2002 study examined another possible metabolic test. In this test, intramuscular injection of caffeine was followed by local measurement of the pCO2; those with known MH susceptibility had a significantly higher pCO2 (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.
is being performed in a limited fashion to determine susceptibility to MH. In people with a family history of MH, analysis for RYR1 mutations maybe useful.
dantrolene, and the remaining one recovered with only symptomatic therapy. After weighing its questionable benefits against its possible adverse effects (including nausea, vomiting, muscle weakness and prolonged duration of action of nondepolarising neuromuscular blocking agents), experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients.
Anaesthesia for known MH susceptible patients requires avoidance of triggering agents (all volatile anaesthetic agents and succinylcholine). All other drugs are safe (including nitrous oxide), as are regional anaesthetic techniques. Where general anaesthesia is planned, it can be provided safely by removing vaporisers from the anaesthetic machine, placing a new breathing circuit on the machine, flushing the machine and ventilator with 100% oxygen at maximal gas flows for 20–30 minutes, and inducing and maintaining anaesthesia with nontriggering agents (e.g.: propofol).
The current treatment of choice is the intravenous administration of dantrolene, the only known antidote, discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction. Treatment must be instituted rapidly on clinical suspicion of the onset of malignant hyperthermia.
Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium.
After the widespread introduction of treatment with dantrolene, the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%. Dantrolene remains as the only drug known to be effective in the treatment of MH.
Its clinical use has been limited by its low water solubility
, leading to requirements of large fluid volumes, which may complicate clinical management. Azumolene is a 30-fold more water-soluble analogue
of dantrolene that also works to decrease the release of intracellular calcium by its action on the ryanodine receptor. In MH susceptible swine, azumolene was as potent as dantrolene. It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH.
Research in mouse models suggests that azumolene "is likely uncoupling the efficiency of a Ca2+-dependent RyR1 signal coupled directly or indirectly to the [store-operated calcium entry] machinery." There may be two different pathways of store-operated calcium entry: one, RyR1-reliant and the other, RyR1-non-reliant (see Deisease Mechanism section above for RyR1 description). Furthermore, elucidating earlier ideas on the pathogenesis of malignant hyperthermia, researchers point out that it may be "as much a syndrome of exaggerated Ca2+ entry as it is of exaggerated Ca2+ release."
Azumolene has also been shown to be as effective as dantrolene at preventing and reversing contracture in in vitro experiments with human skeletal muscle.
is between 1:5,000 to 1:50,000–100,000 procedures involving general anaesthesia. This disorder occurs worldwide and affects all racial groups. Most cases, however, occur in children and young adults, which might be related to the fact many older people will have already had surgeries and thus would know about and be able to avoid this condition.
. Similar reactions were found in pigs. The efficacy of dantrolene as a treatment was discovered by South African anesthesiologist Gaisford Harrison and reported in a 1975 article published in the British Journal of Anaesthesia
. After further animal studies corroborated the possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.
Neuromuscular-blocking drug
Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished either by acting presynaptically via the inhibition of acetylcholine synthesis or release or by acting postsynaptically at the...
, succinylcholine. In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
oxidative metabolism, which overwhelms the body's capacity to supply oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
, remove carbon dioxide
Carbon dioxide
Carbon dioxide is a naturally occurring chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom...
, and regulate body temperature, eventually leading to circulatory collapse and death if not treated quickly.
Susceptibility to MH is often inherited as an autosomal dominant disorder, for which there are at least 6 genetic loci of interest, most prominently the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
gene (RYR1). MH susceptibility is phenotypically and genetically related to central core disease
Central core disease
Central core disease , also known as central core myopathy, is an autosomal dominant congenital myopathy . It was first described by Shy and Magee in 1956...
(CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
. MH is usually revealed by anesthesia, or when a family member develops the symptoms. There is no simple, straightforward test to diagnose the condition. When MH develops during a procedure, treatment with dantrolene sodium
Dantrolene
Dantrolene sodium is a muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells, probably by action on the ryanodine receptor. It is the only specific and effective treatment for malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia...
is usually initiated; dantrolene and the avoidance of anesthesia in susceptible people have markedly reduced the mortality from this condition.
Classification
This condition is known by a number of names, including malignant hyperthermia (MH), malignant hyperthermia syndrome (MHS), and malignant hyperpyrexia.Signs and symptoms
The typical symptoms of malignant hyperthermia are due to a hypercatabolic state, which presents as a very high temperature, an increased heart rateTachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
and breathing rate
Tachypnea
Tachypnea means rapid breathing. Any rate between 12-20 breaths per minute is normal. Tachypnea is a respiration rate greater than 20 breaths per minute. - Distinction from other breathing terms :...
, increased carbon dioxide production, increased oxygen consumption, acidosis
Acidosis
Acidosis is an increased acidity in the blood and other body tissue . If not further qualified, it usually refers to acidity of the blood plasma....
, rigid muscles, and rhabdomyolysis
Rhabdomyolysis
Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...
.
The symptoms usually develop within one hour after exposure to trigger substances, but may even occur several hours later in rare instances.
Causes
Malignant hyperthermia is most commonly due to volatile anesthetic gases, such as halothaneHalothane
Halothane is an inhalational general anesthetic. Its IUPAC name is 2-bromo-2-chloro-1,1,1-trifluoroethane. It is the only inhalational anesthetic agent containing a bromine atom; there are several other halogenated anesthesia agents which lack the bromine atom and do contain the fluorine and...
, sevoflurane
Sevoflurane
Sevoflurane , also called fluoromethyl hexafluoroisopropyl ether, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used for induction and maintenance of general anesthesia. Together with desflurane, it is replacing isoflurane and halothane in modern anesthesiology...
, desflurane
Desflurane
Desflurane is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane and isoflurane, it is a racemic mixture of and optical isomers...
or the depolarizing muscle relaxant succinylcholine used primarily in general anesthesia. In rare cases, the biological stresses of physical exercise or heat may be the trigger.
Other anesthetic drugs are considered safe. These include local anesthetics (lidocaine
Lidocaine
Lidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
, bupivicaine, mepivacaine
Mepivacaine
Mepivacaine is a local anesthetic of the amide type. Mepivacaine has a reasonably rapid onset and medium duration of action and is marketed under various trade names including Carbocaine and Polocaine.Mepivacaine became available in the United States in the 1960s.Mepivacaine is used in any...
), opiates (morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
, fentanyl), ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
, barbiturates, nitrous oxide
Nitrous oxide
Nitrous oxide, commonly known as laughing gas or sweet air, is a chemical compound with the formula . It is an oxide of nitrogen. At room temperature, it is a colorless non-flammable gas, with a slightly sweet odor and taste. It is used in surgery and dentistry for its anesthetic and analgesic...
, propofol
Propofol
Propofol is a short-acting, intravenously administered hypnotic agent. Its uses include the induction and maintenance of general anesthesia, sedation for mechanically ventilated adults, and procedural sedation. Propofol is also commonly used in veterinary medicine...
, etomidate
Etomidate
Etomidate is a short acting intravenous anaesthetic agent used for the induction of general anaesthesia and for sedation for short procedures such as reduction of dislocated joints, tracheal intubation and cardioversion...
, benzodiazepines.
The nondepolarizing muscle relaxants pancuronium
Pancuronium
Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...
, cisatracurium
Cisatracurium
Cisatracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
, atracurium
Atracurium
Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...
, mivacurium
Mivacurium
Mivacurium chloride is a short-duration non-depolarizing neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during...
, vecuronium
Vecuronium
Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...
and rocuronium
Rocuronium
Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...
also do not cause MH.
Genetics
Malignant hyperthermia's inheritance is autosomal dominant. The defect is typically located on the long arm of the nineteenth chromosomeChromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
(19q13.1) involving the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
. More than 25 different mutations are in this gene are linked with malignant hyperthermia. These mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the protein, which interacts with L-type calcium channels and Ca2+. MH3 is located in the transmembrane forming C-terminus. This region is important for allowing Ca2+ passage through the protein following opening.
Disease mechanism
In a large proportion (50–70%) of cases, the propensity for malignant hyperthermia is due to a mutationMutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
of the ryanodine receptor
Ryanodine receptor
Ryanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
(type 1), located on the sarcoplasmic reticulum (SR), the organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
within skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
cells that stores calcium
Calcium in biology
Calcium plays a pivotal role in the physiology and biochemistry of organisms and the cell. It plays an important role in signal transduction pathways, where it acts as a second messenger, in neurotransmitter release from neurons, contraction of all muscle cell types, and fertilization...
. RYR1 opens in response to increases in intracellular Ca2+
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
level mediated by L-type calcium channel
Calcium channel
A Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
s, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing Ca2+ concentrations: the A-site and the I-site. The A-site is a high affinity Ca2+ binding site that mediates RYR1 opening. The I-site is a lower affinity site that mediates the protein's closing. Caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
, halothane, and other triggering agents act by drastically increasing the affinity of the A-site for Ca2+ and concomitantly decreasing the affinity of the I-site in mutant proteins. Mg2+ also affect RYR1 activity, causing the protein to close by acting at either the A- or I-sites. In MH mutant proteins, the affinity for Mg2+ at either one of these sites is greatly reduced. The end result of these alterations is greatly increased Ca2+ release due to a lowered activation and heightened deactivation threshold. The process of reabsorbing this excess Ca2+ consumes large amounts of adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
(ATP), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
, myoglobin
Myoglobin
Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals. It is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells. The only time myoglobin is found in the...
, creatine
Creatine
Creatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...
, phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
and creatine kinase
Creatine kinase
Creatine kinase , also known as creatine phosphokinase or phospho-creatine kinase , is an enzyme expressed by various tissues and cell types. CK catalyses the conversion of creatine and consumes adenosine triphosphate to create phosphocreatine and adenosine diphosphate...
.
The other known causative gene for MH is CACNA1S, which encodes and L-type
L-type calcium channel
The L-type calcium channel is a type of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. Like the others of this class, the α1 subunit is the one that determines most of the channel's properties....
voltage-gated calcium channel α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086. This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in human embryonic kidney (HEK 293
HEK cell
Human Embryonic Kidney 293 cells, also often referred to as HEK 293, 293 cells, or less precisely as HEK cells are a specific cell line originally derived from human embryonic kidney cells grown in tissue culture. HEK 293 cells are very easy to grow and transfect very readily and have been...
) cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5-10mV more hyperpolarized. Furthermore, cells expressing these channels have an increased basal cytosolic Ca2+ concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Ca2+, and, thereby, muscle excitability.
Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.
Animal model
Research into malignant hyperthermia was limited until the discovery of "porcine stress syndrome" (PSS) in Danish LandraceDanish Landrace
The Danish Landrace is a medium to large breed of pig, white in colour with long bodies, fine hair, long snouts, and heavy drooping ears. They are bred for pork production....
and other pig
Pig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
breeds selected for muscling, a condition in which stressed pigs develop "pale, soft, exudative" flesh
PSE meat
Pale, soft, exudative meat or PSE meat or PSE pork is pork generally regarded as being of inferior quality, characterised by its pallor, softness and low water binding capacity. It is more common in pigs sensitive to the anaesthetic halothane. In most cases it appears to be the result of...
(a manifestation of the effects of malignant hyperthermia) rendering their meat less marketable at slaughter. This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently, susceptible humans were discovered to "awake trigger" (develop malignant hyperthermia) in stressful situations. This supported the use of the pig model for research. Pig farmers use halothane cones in swine yards to expose piglets to halothane. Those that die were MH-susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market. This also reduced the use of breeding stock carrying the genes for PSS. The condition in swine is also due to a defect in ryanodine receptors.
Gillard et al. discovered the causative mutation in humans only after similar mutations had first been described in pigs.
Horses also suffer from malignant hyperthermia. It is the Thoroughbred breed that was found to have susceptibility. It can be caused by overwork, anesthesia, or stress. An inheritable genetic mutation is found in susceptible animals. In dogs, its inheritance is autosomal recessive.
An MH mouse has been constructed, bearing the R163C mutation prevalent in humans. These mice display symptoms similar to human MH patients, including sensitivity to halothane (increased respiration, body temperature, and death). Blockade of RYR1 by dantrolene
Dantrolene
Dantrolene sodium is a muscle relaxant that acts by abolishing excitation-contraction coupling in muscle cells, probably by action on the ryanodine receptor. It is the only specific and effective treatment for malignant hyperthermia, a rare, life-threatening disorder triggered by general anesthesia...
prevents adverse reaction to halothane in these mice, as with humans. Muscle from these mice also shows increased K+-induced depolarization and an increased caffeine sensitivity.
During an attack
The earliest signs are a rise in end-tidal carbon dioxide concentrationHypercapnia
Hypercapnia or hypercapnea , also known as hypercarbia, is a condition where there is too much carbon dioxide in the blood...
(despite increased minute ventilation), tachycardia, and muscle rigidity. Despite the name, elevation of body temperature is often a late sign. Other signs may include acidosis, tachypnea
Tachypnea
Tachypnea means rapid breathing. Any rate between 12-20 breaths per minute is normal. Tachypnea is a respiration rate greater than 20 breaths per minute. - Distinction from other breathing terms :...
(in a spontaneously breathing patient), and hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
. Core body temperatures should be measured in any patient undergoing general anesthesia longer than 20 minutes.
Malignant hyperthermia is diagnosed on clinical grounds, but various investigations are generally performed. This includes blood test
Blood test
A blood test is a laboratory analysis performed on a blood sample that is usually extracted from a vein in the arm using a needle, or via fingerprick....
s, which may show a raised creatine kinase level, elevated potassium, increased phosphate (leading to decreased calcium) and—if determined—raised myoglobin; this is the result of damage to muscle cells. Metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
and respiratory acidosis
Respiratory acidosis
Respiratory acidosis is a medical condition in which decreased ventilation causes increased blood carbon dioxide concentration and decreased pH ....
(raised acidity of the blood) may both occur. Severe rhabdomyolysis may lead to acute renal failure
Acute renal failure
Acute kidney injury , previously called acute renal failure , is a rapid loss of kidney function. Its causes are numerous and include low blood volume from any cause, exposure to substances harmful to the kidney, and obstruction of the urinary tract...
, so kidney function
Renal function
Renal function, in nephrology, is an indication of the state of the kidney and its role in renal physiology. Glomerular filtration rate describes the flow rate of filtered fluid through the kidney...
is generally measured on a frequent basis. Patients may also get cardiac arrythmias (PVCs) due to the increased levels of potassium released from the muscles during episodes.
Susceptibility testing
In those who have experienced an episode of MH, further testing is not usually useful, as even a normal test does not mean there is no risk of recurrence. The exception would be if it is unclear whether the initial attack was due to a different medical problem, such as sepsisSepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
.
Muscle testing
The main candidates for testing are those with a close relative who has suffered an episode of MH or has been shown to be susceptible. The standard procedure is the "caffeine-halothane contracture test", CHCT. A muscle biopsyBiopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
is carried out at an approved research center, under local anesthesia. The fresh biopsy is bathed in solutions containing caffeine or halothane and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78%. Negative biopsies are not definitive, so any patient who is suspected of MH by their medical history or that of blood relatives is generally treated with nontriggering anesthetics, even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.
Less invasive diagnostic techniques have been proposed. Intramuscular injection of halothane 6 vol% has been shown to result in higher than normal increases in local pCO2 among patients with known malignant hyperthermia susceptibility. The sensitivity was 100% and specificity was 75%. For patients at similar risk to those in this study, this leads to a positive predictive value
Positive predictive value
In statistics and diagnostic testing, the positive predictive value, or precision rate is the proportion of subjects with positive test results who are correctly diagnosed. It is a critical measure of the performance of a diagnostic method, as it reflects the probability that a positive test...
of 80% and negative predictive value
Negative predictive value
In statistics and diagnostic testing, the negative predictive value is a summary statistic used to describe the performance of a diagnostic testing procedure. It is defined as the proportion of subjects with a negative test result who are correctly diagnosed. A high NPV means that when the test...
of 100%. This method may provide a suitable alternative to more invasive techniques.
A 2002 study examined another possible metabolic test. In this test, intramuscular injection of caffeine was followed by local measurement of the pCO2; those with known MH susceptibility had a significantly higher pCO2 (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.
Genetic testing
Genetic testingGenetic testing
Genetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
is being performed in a limited fashion to determine susceptibility to MH. In people with a family history of MH, analysis for RYR1 mutations maybe useful.
Criteria
A 1994 consensus conference led to the formulation of a set of diagnostic criteria. The higher the score (above 6), the more likely a reaction constituted MH:- Respiratory acidosis (end-tidal CO2 above 55 mmHg/7.32 kPa or arterial pCO2 above 60 mmHg/7.98 kPa)
- Heart involvement (unexplained sinus tachycardiaSinus tachycardiaSinus tachycardia is a heart rhythm with elevated rate of impulses originating from the sinoatrial node, defined as a rate greater than 100 beats/min in an average adult. The normal heart rate in the average adult ranges from 60–100 beats/min...
, ventricular tachycardiaVentricular tachycardiaVentricular tachycardia is a tachycardia, or fast heart rhythm, that originates in one of the ventricles of the heart...
or ventricular fibrillationVentricular fibrillationVentricular fibrillation is a condition in which there is uncoordinated contraction of the cardiac muscle of the ventricles in the heart, making them quiver rather than contract properly. Ventricular fibrillation is a medical emergency and most commonly identified arrythmia in cardiac arrest...
) - Metabolic acidosis (base excess lower than -8, pH <7.25)
- Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
- Muscle breakdown (CK >20,000/L units, cola colored urine or excess myoglobin in urine or serum, potassium above 6 mmol/l)
- Temperature increase (rapidly increasing temperature, T >38.8°C)
- Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
- Family history (autosomal dominant pattern)
Prevention
In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia. However, multiple retrospective studies have demonstrated the safety of trigger-free general anesthesia in these patients in the absence of prophylactic dantrolene administration. The largest of these studies looked at the charts of 2214 patients who underwent general or regional anesthesia for an elective muscle biopsy. About half (1082) of the patients were muscle biopsy positive for MH. Only five of these patients exhibited symptoms consistent with MH, four of which were treated successfully with parenteralParenteral
Parenteral is a route of administration that involves piercing the skin or mucous membrane. Parenteral nutrition refers to providing nutrition via the veins.-Etymology:...
dantrolene, and the remaining one recovered with only symptomatic therapy. After weighing its questionable benefits against its possible adverse effects (including nausea, vomiting, muscle weakness and prolonged duration of action of nondepolarising neuromuscular blocking agents), experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients.
Anaesthesia for known MH susceptible patients requires avoidance of triggering agents (all volatile anaesthetic agents and succinylcholine). All other drugs are safe (including nitrous oxide), as are regional anaesthetic techniques. Where general anaesthesia is planned, it can be provided safely by removing vaporisers from the anaesthetic machine, placing a new breathing circuit on the machine, flushing the machine and ventilator with 100% oxygen at maximal gas flows for 20–30 minutes, and inducing and maintaining anaesthesia with nontriggering agents (e.g.: propofol).
Treatment
Dantrolene is a muscle relaxant that appears to work directly on the ryanodine receptor to prevent the release of calcium.
After the widespread introduction of treatment with dantrolene, the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%. Dantrolene remains as the only drug known to be effective in the treatment of MH.
Its clinical use has been limited by its low water solubility
Water solubility
Water is a bent, polar compound and possesses the ability to Hydrogen bond. As a result, it has unique solubility characteristics as a solvent and functions differently at different temperatures.-Sources:...
, leading to requirements of large fluid volumes, which may complicate clinical management. Azumolene is a 30-fold more water-soluble analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of dantrolene that also works to decrease the release of intracellular calcium by its action on the ryanodine receptor. In MH susceptible swine, azumolene was as potent as dantrolene. It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH.
Research in mouse models suggests that azumolene "is likely uncoupling the efficiency of a Ca2+-dependent RyR1 signal coupled directly or indirectly to the [store-operated calcium entry] machinery." There may be two different pathways of store-operated calcium entry: one, RyR1-reliant and the other, RyR1-non-reliant (see Deisease Mechanism section above for RyR1 description). Furthermore, elucidating earlier ideas on the pathogenesis of malignant hyperthermia, researchers point out that it may be "as much a syndrome of exaggerated Ca2+ entry as it is of exaggerated Ca2+ release."
Azumolene has also been shown to be as effective as dantrolene at preventing and reversing contracture in in vitro experiments with human skeletal muscle.
Prognosis
Prognosis is poor if this condition is not aggressively treated. In the 1970s, mortality was greater than 80%; with the current management, however, mortality is now less than 5%.Epidemiology
The incidenceIncidence (epidemiology)
Incidence is a measure of the risk of developing some new condition within a specified period of time. Although sometimes loosely expressed simply as the number of new cases during some time period, it is better expressed as a proportion or a rate with a denominator.Incidence proportion is the...
is between 1:5,000 to 1:50,000–100,000 procedures involving general anaesthesia. This disorder occurs worldwide and affects all racial groups. Most cases, however, occur in children and young adults, which might be related to the fact many older people will have already had surgeries and thus would know about and be able to avoid this condition.
History
The syndrome was first recognized in Australia in an affected family by Denborough et al. in 1962. Denborough did much of his subsequent work on the condition at the Royal Canberra HospitalRoyal Canberra Hospital
Royal Canberra Hospital was the first hospital in Canberra, the capital of Australia. It opened in 1914 on the Acton Peninsula, as the Canberra Community Hospital. It grew to become the major hospital in Canberra before being closed in 1991 and later demolished in 1997.- Early Years 1912–1939 :In...
. Similar reactions were found in pigs. The efficacy of dantrolene as a treatment was discovered by South African anesthesiologist Gaisford Harrison and reported in a 1975 article published in the British Journal of Anaesthesia
British Journal of Anaesthesia
BJA: British Journal of Anaesthesia is a monthly peer-reviewed medical journal published by Oxford University Press on behalf of the Royal College of Anaesthetists, of which it is the official journal. It was established in 1923 and covers all aspects of anaesthesia. The current editor-in-chief is...
. After further animal studies corroborated the possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.
In other animals
Other animal including certain pig breeds, dogs, and horses are susceptible to malignant hyperthermia. In dogs its inheritance is autosomal recessive.External links
- GeneReview/NIH/UW entry on Malignant Hyperthermia Susceptibility
- Malignant Hyperthermia Association of the United States
- Making Anesthesia Safer - Unraveling the Malignant Hyperthermia Puzzle by Marilyn Green Larach, FASEBFederation of American Societies for Experimental BiologyThe Federation of American Societies for Experimental Biology, abbreviated FASEB, is a non-profit organization that is the principal umbrella organization of U.S. societies in the field of biological and medical research. FASEB organizes academic conferences and publishes scientific literature...
"Breakthroughs in Bioscience"