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

Malignant hyperthermia (MH or MHS for "malignant hyperthermia syndrome", or "malignant hyperpyrexia due to anaesthesia") is a rare life-threatening condition that is triggered by exposure to certain drugs used for general anaesthesia (specifically all volatile anaesthetics), nearly all gas anaesthetics, 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 untreated. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) is a coding of diseases and signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or diseases, as classified by the World Health Organization (WHO). ... // S00-T98 - Injury, poisoning and certain other consequences of external causes (S00-S09) Injuries to the head (S00) Superficial injury of head (S01) Open wound of head (S02) Fracture of skull and facial bones (S03) Dislocation, sprain and strain of joints and ligaments of head (S04) Injury of cranial nerves... The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... In medicine, hyperpyrexia is an excessive and unusual elevation of body temperature above 107. ... In modern medical practice, general anaesthesia (AmE: anesthesia) is a state of total unconsciousness resulting from general anaesthetic drugs. ... The volatile anaesthetics are a class of general anaesthetic drugs. ... Suxamethonium chloride (also known as succinylcholine, or scoline) is a white crystalline substance, it is odourless and highly soluble in water. ... A top-down view of skeletal muscle Skeletal muscle is a type of striated muscle, usually attached to the skeleton. ... Cellular respiration is the process in which the chemical bonds of energy-rich molecules such as glucose are converted into energy usable for life processes. ... This article is about the chemical element and its most stable form, or dioxygen. ... Carbon dioxide (chemical formula: ) is a chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom. ... Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when temperature surrounding is very different. ... The circulatory system or cardiovascular system is the organ system which circulates blood around the body of most animals. ...

Susceptibility to MH is often inherited as an autosomal dominant disorder, for which there are at least 6 genetic loci of interest,^[1] most prominently the ryanodine receptor gene (RYR1). MH susceptibility is phenotypically and genetically related to central core disease (CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy. MH is usually unmasked by anesthesia, or when a family member develops the symptoms. There is no simple, straightforward test to diagnose the condition. When MH develops during a procedure, treatment with dantrolene sodium is usually initiated; dantrolene and the avoidance of anesthesia in susceptible people have markedly reduced the mortality from this condition. It has been suggested that this article or section be merged into Dominance relationship. ... Ryanodine receptors (RyRs) form a class of calcium channels in various forms of muscle and other excitable animal tissue. ... In medicine, a myopathy is a neuromuscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. ... Dantrolene sodium is a muscle relaxant that is currently the only specific and effective treatment for malignant hyperthermia. ...

Signs and symptoms

Malignant hyperthermia develops during or after receiving a general anaesthetic, and symptoms are generally identified by operating department staff. Characteristic signs are muscular rigidity, followed by a hypermetabolic state with increased oxygen consumption, increased carbon dioxide production (hypercapnia, usually measured by capnography), tachycardia (fast heart rate), and an increase in body temperature (hyperthermia) at a rate of up to ~2°C per hour; temperatures up to 42°C are not uncommon. Rhabdomyolysis (breakdown of muscle tissue) may develop, as evidenced by red-brown decoloration of the urine and cardiological or neurological evidence of electrolyte disturbances.^{[citation needed]} A general anaesthetic drug is an anaesthetic (or anesthetic AE) drug that brings about a reversible loss of consciousness. ... A top-down view of skeletal muscle Skeletal muscle is a type of striated muscle, usually attached to the skeleton. ... This article is about the chemical element and its most stable form, or dioxygen. ... Carbon dioxide (chemical formula: ) is a chemical compound composed of two oxygen atoms covalently bonded to a single carbon atom. ... // Hypercapnia (from the Greek hyper = above and kapnos = smoke), also known as CO2 Poisoning, is a condition where there is too much carbon dioxide (CO2) in the blood. ... Capnography is the indirect monitoring of carbon dioxide (CO2) concentrations in a patients blood. ... This article or section does not cite any references or sources. ... Hyperthermia in its advanced state referred to as heat stroke or sunstroke, is an acute condition which occurs when the body produces or absorbs more heat than it can dissipate. ... Rhabdomyolysis is the rapid breakdown of skeletal muscle tissue due to traumatic injury, either mechanical, physical or chemical. ... This article is about the urine of animals generally. ... An electrolyte is any substance containing free ions that behaves as an electrically conductive medium. ...

Halothane, a once popular but now rarely used volatile anaesthetic, has been linked to a large proportion of cases, however, all halogenated volatile anaesthetics are potential triggers of malignant hyperthermia. Succinylcholine, a neuromuscular blocking agent, is also a trigger for MH. MH does not occur with every exposure to triggering agents, and susceptible patients may undergo multiple uneventful episodes of anesthesia before developing an episode of MH. The symptoms usually develop within one hour after exposure to trigger substances, but may even occur several hours later in rare instances. Halothane vapour is an inhalational general anaesthetic. ... The volatile anaesthetics are a class of general anaesthetic drugs. ... Suxamethonium chloride (also known as succinylcholine, or scoline) is a white crystalline substance, it is odourless and highly soluble in water. ...

A proportion of people susceptible to malignant hyperthermia may have particular characteristics. A 1972 report on a family with MH also described myopathy (muscle weakness due to muscle cell abnormality), short stature, cryptorchidism (undescended testicles), pectus carinatum (a chest wall deformity), lumbar lordosis and thoracic kyphosis (reversed curvature of the spine), and unusual facial characteristics.^[2] Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report. In medicine, a myopathy is a neuromuscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. ... People who are shorter have short stature. ... Cryptorchidism is a medical term referring to absence from the scrotum of one or both testes. ... Pectus carinatum, also called pigeon chest, is a deformity of the chest characterized by a protrusion of the sternum. ... Lordosis is a term used to describe the direction of the curvature of the five lumbar and seven cervical vertebrae of the vertebral column. ... Kyphosis (Greek - kyphos, a hump), in general terms, is a curvature of the upper spine. ...

Diagnosis

During an attack

Malignant hyperthermia is diagnosed on clinical grounds, but various investigations are generally performed. This includes blood tests, 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.^{[citation needed]} Blood tests are laboratory tests done on blood to gain an appreciation of disease states and the function of organs. ... Creatine Kinase Creatine kinase (CK), also known as phosphocreatine kinase or creatine phosphokinase (CPK) is an enzyme (EC 2. ... General Name, symbol, number potassium, K, 19 Chemical series alkali metals Group, period, block 1, 4, s Appearance silvery white Standard atomic weight 39. ... A phosphate, in inorganic chemistry, is a salt of phosphoric acid. ... Calcium (Ca2+) plays a vital role in the anatomy, physiology and biochemistry of organisms and of the cell, particularly in signal transduction pathways. ... An X-ray diffraction image for the protein myoglobin. ... In medicine, metabolic acidosis is a state in which the blood pH is low (under 7. ... Respiratory acidosis is acidosis (abnormal acidity of the blood) due to decreased ventilation of the pulmonary alveoli, leading to elevated arterial carbon dioxide concentration. ... In medicine (nephrology) renal function is an indication of the state of the kidney and its role in physiology. ...

Susceptibility testing

In patients who have suffered an episode of MH, further tests are usually not performed as even a normal test would not mean that the patient is not at further risk of further episodes on future occasions. The exception would be if it is unclear whether the initial attack was due to a different medical problem, such as sepsis (severe infection).^{[citation needed]} Sepsis (in Greek Σήψις, putrefaction) is a serious medical condition, resulting from the immune response to a severe infection. ...

The main candidates for testing are those with a close relative who has suffered an episode of MH or has been shown to be susceptible. The standard procedure is the "caffeine-halothane contracture test", CHCT. A muscle biopsy is carried out at an approved research center, under local anesthesia. The fresh biopsy is bathed in solutions containing caffeine or halothane and observed for contraction; under good conditions, the sensitivity is 97% and the specificity 78%.^[3] Negative biopsies are not definitive, so any patient who is suspected of MH by their medical history or that of blood relatives is generally treated with non-triggering anesthetics even if the biopsy was negative. Some researchers advocate the use of the "calcium-induced calcium release" test in addition to the CHCT to make the test more specific.^{[citation needed]} Brain biopsy A biopsy (in Greek: bios = life and opsy = look/appearance) is a medical test involving the removal of cells or tissues for examination. ... Caffeine is a xanthine alkaloid compound that acts as a stimulant in humans. ... Halothane vapour is an inhalational general anaesthetic. ... The sensitivity of a binary classification test or algorithm, such as a blood test to determine if a person has a certain disease, or an automated system to detect faulty products in a factory, is a parameter that expresses something about the tests performance. ... The specificity is a statistical measure of how well a binary classification test correctly identifies the negative cases, or those cases that do not meet the condition under study. ... Calcium (Ca2+) plays a vital role in the anatomy, physiology and biochemistry of organisms and of the cell, particularly in signal transduction pathways. ...

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.^[4] 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.^[5] Halothane vapour is an inhalational general anaesthetic. ... The sensitivity of a binary classification test or algorithm, such as a blood test to determine if a person has a certain disease, or an automated system to detect faulty products in a factory, is a parameter that expresses something about the tests performance. ... The specificity is a statistical measure of how well a binary classification test correctly identifies the negative cases, or those cases that do not meet the condition under study. ... The positive predictive value is the proportion of patients with positive test results who are correctly diagnosed. ... Binary classification is the task of classifying the members of a given set of objects into two groups on the basis of whether they have some property or not. ...

A 2005 paper proposes a protocol for investigating people with a family history of MH, where first-line genetic screening of RYR1 mutations is one of the options.^[1]

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:^[6]

• Respiratory acidosis (end-tidal CO₂ above 55 mmHg or arterial pCO₂ above 60 mgHg)
• Heart involvement (unexplained sinus tachycardia, ventricular tachycardia or ventricular fibrillation)
• Metabolic acidosis (base excess lower than -8, pH<7.25)
• Muscle rigidity (generalized rigidity including severe masseter muscle rigidity)
• Muscle breakdown (CK >20,000/L units, cola colored urine or excess myoglobin in urine or serum, potassium above 6 mmol/l)
• Temperature increase (rapidly increasing temperature, T >38.8°C)
• Other (rapid reversal of MH signs with dantrolene, elevated resting serum CK levels)
• Family history (autosomal dominant pattern)

Respiratory acidosis is acidosis (abnormal acidity of the blood) due to decreased ventilation of the pulmonary alveoli, leading to elevated arterial carbon dioxide concentration. ... Sinus tachycardia is a rhythm with elevated rate of impulses originating from the SA node, defined as a rate greater than 100 beats/min in an average adult. ... Ventricular tachycardia (V-tach or VT) is a fast rhythm that originates in one of the ventricles of the heart. ... Ventricular fibrillation (V-fib or VF) is a cardiac condition which consists of a lack of coordination of the contraction of the muscle tissue of the large chambers of the heart that eventually leads to the heart stopping altogether. ... In medicine, metabolic acidosis is a state in which the blood pH is low (under 7. ... It has been suggested that this article or section be merged into Dominance relationship. ...

Pathophysiology

Disease mechanism

The potential for malignant hyperthermia is caused in a large proportion (50-70%) of cases by a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium.^[7][8] RYR1 opens in response to increases in intracellular Ca²⁺ level mediated by L-type calcium channels, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing Ca²⁺ concentrations: the A-site and the I-site. 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 or these site is greatly reduced. The end result of these alterations is greatly increased Ca²⁺ release due to a lowered activation and heightened deactivation threshold.^[9][10] The process of reabsorbing this excess Ca²⁺ consumes large amounts of ATP (adenosine triphosphate), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium, myoglobin, creatine, phosphate and creatine kinase. For linguistic mutation, see Apophony. ... Ryanodine receptors (RyRs) form a class of calcium channels in various forms of muscle and other excitable animal tissue. ... The endoplasmic reticulum or ER is an organelle found in all eukaryotic cells that is an interconnected network of tubules, vesicles and cisternae that is responsible for several specialized functions: Protein translation, folding, and transport of proteins to be used in the cell membrane (e. ... Schematic of typical animal cell, showing subcellular components. ... A top-down view of skeletal muscle Skeletal muscle is a type of striated muscle, usually attached to the skeleton. ... Drawing of the structure of cork as it appeared under the microscope to Robert Hooke from Micrographia which is the origin of the word cell being used to describe the smallest unit of a living organism Cells in culture, stained for keratin (red) and DNA (green) The cell is the... Calcium (Ca2+) plays a vital role in the anatomy, physiology and biochemistry of organisms and of the cell, particularly in signal transduction pathways. ... For other uses, see Calcium (disambiguation). ... Ion channels are present in the membranes that surround all biological cells. ... Look up affinity in Wiktionary, the free dictionary. ... Caffeine is a xanthine alkaloid compound that acts as a stimulant in humans. ... Halothane vapour is an inhalational general anaesthetic. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... General Name, symbol, number potassium, K, 19 Chemical series alkali metals Group, period, block 1, 4, s Appearance silvery white Standard atomic weight 39. ... An X-ray diffraction image for the protein myoglobin. ... For the use of creatine to enhance athletic performance, please see Creatine supplements. ... A phosphate, in inorganic chemistry, is a salt of phosphoric acid. ... Creatine Kinase Creatine kinase (CK), also known as phosphocreatine kinase or creatine phosphokinase (CPK) is an enzyme (EC 2. ...

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.^[11][12] This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in HEK 293 (human embryonic kidney) cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5-10mV more hyperpolarized. Furthermore, cells expressing these channels have an increased basal cytosolic Ca²⁺ concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular Ca²⁺, and, thereby, muscle excitability.^[13] The L-type calcium channel is a type of voltage-dependent calcium channel. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Human Embryonic Kidney cells, also known as HEK cells, HEK 293 or just 293 cells, are an epithelial cell line originally derived, as their name indicates, from embryonic human kidney. ...

Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.^[1]

Animal model

Research into malignant hyperthermia was limited until the discovery of "porcine stress syndrome" in Landrace pigs, a condition in which stressed pigs develop "pale, soft, exudative" flesh (a manifestation of the effects of malignant hyperthermia) rendering their meat unmarketable at slaughter. This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently susceptible humans were discovered to "awake trigger" (develop malignant hyperthermia) in stressful situations. This supported the use of the pig model for research. Pig farmers use halothane cones in swine yards to expose piglets to halothane. Those that die were MH-susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market.^{[citation needed]} Landrace refers to a race of animals or plants ideally suited for the land (environment) in which they live and, in some cases, work; they often develop naturally with minimal assistance or guidance from humans (or from humans using traditional rather than modern breeding methods), hence are usually older, less... For other uses, see Pig (disambiguation). ...

Gillard et al discovered the causative mutation in humans only after similar mutations had first been described in pigs.^[7]

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. ^[14]

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.^[15] Dantrolene sodium is a muscle relaxant that is currently the only specific and effective treatment for malignant hyperthermia. ... Halothane vapour is an inhalational general anaesthetic. ...

Genetics

At least 70 mutations in the ryanodine receptor have been described, which are transmitted in an autosomal dominant fashion. The gene is located on the long arm of the nineteenth chromosome (19q13.1). These mutations tend to cluster in one of three domains within the protein, designated MH1-3. MH1 and MH2 are located in the N-terminus of the protein, which interacts with L-type calcium channels and Ca²⁺. MH3 is located in the transmembrane forming C-terminus. This region is important for allowing Ca²⁺ passage through the protein following opening.^{[citation needed]} It has been suggested that this article or section be merged into Dominance relationship. ... For other uses, see Gene (disambiguation). ... A scheme of a condensed (metaphase) chromosome. ...

Treatment

Dantrolene sodium, the only known medical treatment for malignant hyperthermia.

The current treatment of choice is the intravenous administration of dantrolene, the only known antidote, discontinuation of triggering agents, and supportive therapy directed at correcting hyperthermia, acidosis, and organ dysfunction. Treatment must be instituted rapidly on clinical suspicion of the onset of malignant hyperthermia.^{[citation needed]} Image File history File links This is a lossless scalable vector image. ... Image File history File links This is a lossless scalable vector image. ... Dantrolene sodium is a muscle relaxant that is currently the only specific and effective treatment for 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.^[16] Dantrolene sodium is a muscle relaxant that is currently the only specific and effective treatment for malignant hyperthermia. ...

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.^[17] It has yet to be studied in vivo in humans, but may present a suitable alternative to dantrolene in the treatment of MH. Water is a bent, polar compound and possesses the ability to Hydrogen bond. ... For the Analog Science Fiction and Science Fact publication, see Astounding Magazine. ...

Prevention

In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia.^[16] However, multiple retrospective studies, have demonstrated the safety of trigger-free general anesthesia in these patients in the absence of prophylactic dantrolene administration. The largest of these studies looked at the charts of 2214 patients who underwent general or regional anesthesia for an elective muscle biopsy. 1082 of the patients were muscle biopsy positive for MH. Only five of these patients exhibited symptoms consistent with MH, four of which were treated successfully with parenteral dantrolene, and the remaining one recovered with only symptomatic therapy.^[18] After weighing its questionable benefits against its possible adverse effects, experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients.^[16] This page is a candidate to be moved to Wiktionary. ... Dantrolene sodium is a muscle relaxant that is currently the only specific and effective treatment for malignant hyperthermia. ... This article or section may be confusing for some readers, and should be edited to be clearer. ... Regional anaesthesia includes epidural anaesthesia, spinal anaesthesia and blocks to specific nerves to block sensation in the parts of the body served. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body 1. ...

The only sure way to prevent MH is avoid the use of triggering agents in patients known or suspected of being susceptible to MH.^{[citation needed]}

Epidemiology

The incidence has been reported to be between 1:4,500 to 1:60,000 procedures involving general anaesthesia. This disorder occurs worldwide and affects all racial groups. Most cases however occur in children and young adults, which might be related to the fact that many older people will have already had surgeries and thus would know about and be able to avoid this condition.^{[citation needed]} Incidence is a measure of the risk of developing some new condition within a specified period of time. ... In modern medical practice, general anaesthesia (AmE: anesthesia) is a state of total unconsciousness resulting from general anaesthetic drugs. ...

History

The syndrome was first recognized in Australia in an affected family by Denborough et al in 1962.^[19] Similar reactions were found in pigs.^[20] After animal studies indicated possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.^[21]

References

A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... PubMed Central grew from the online Entrez PubMed biomedical literature search system. ... PubMed Central grew from the online Entrez PubMed biomedical literature search system. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... A digital object identifier (or DOI) is a standard for persistently identifying a piece of intellectual property on a digital network and associating it with related data, the metadata, in a structured extensible way. ... PubMed Central grew from the online Entrez PubMed biomedical literature search system. ...

External links

• Malignant Hyperthermia Association of the United States
• Making Anesthesia Safer - Unraveling the Malignant Hyperthermia Puzzle by Marilyn Green Larach, FASEB "Breakthroughs in Bioscience"