الفهرس 
Pathophysiology of Malignant HyperthermiaOnly 14 pages are availabe for public view
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Abstract
Malignant Hyperthermia (MH) is a pharmacogenetic clinical syndrome that in its classic form is one of the most devastating anesthesia related complications. It occurs during anesthesia with a volatile halogenated alkane such as halothane and/or the administration of the depolarizing muscle relaxant succinylcholine. MH is truly an example of the interaction of genes and the environment. At the physiological and biochemical level, MH predisposes susceptible individuals to an acute increase in cytosolic Ca2+ during general anesthesia with volatile anesthetics or depolarizing muscle relaxants. In addition, several studies suggest that MH susceptibility is commonly associated with increased resting cytosolic Ca2+. Mutations have been identified in MH-susceptible (MHS) individuals in two key proteins of EC coupling, the Ca2+ release channel of the SR, ryanodine receptor type 1 (RyR1) and the α1 subunit of the dihydropyridine receptor causing dysregulation of EC coupling. This dysfunctional Ca2+ release causes increase in the intracellular myoplasmic calcium which leads to increase in the activity of pumps and exchangers trying to correct the increase in sarcoplasmic Ca2+ increases the need for ATP. All of these events leads to muscle contracture especially of the masseter, with generalized rigidity, and heat production. Hypermetabolism associated to the sarcoplasmic calcium elevation causing tachycardia which may be observed as an early sign along with the masseter rigid contraction. This hypercatabolic state leads to ATP depletion, high oxygen consumption and carbon dioxide production resulting in hypoxemia and hypercapnia. The current treatment of choice is the intravenous administration of dantrolene, the only known antidote. 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 5%. Dantrolene should be given as 2.5 mg/kg rapidly through large-bore IV, if possible. This may be repeated as frequently as needed until the patient responds with a decrease in ETCO2, decreased muscle rigidity, and/or lowered heart rate. Large doses (>10mg/kg) may be required for patients with persistent contractures or rigidity. Discontinuation of triggering agents is a must, 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. Once the patient is stablizied, he should be transferred to a MH specialist center according to the guidelines established by Larach MG and others in 2012. Those specialist centers are scattered across North America and Europe. There is also a center in South Africa. These centers provide the essential registry of MH cases helping to provide essential data for the research in MH. The current gold standard for diagnosis of MH susceptibility is the halothane and caffeine muscle contracture test, also known as the in-vitro contracure test (IVCT) by the protocol of the European Malignant Hyperthermia group (EMHG) or the caffeine halothane contracture test (CHCT) by the protocol of the North American Malignant Hyperthermia group (NAMHG). In both IVCT and CHCT a muscle biopsy is performed. The biopsy is taken using regional anesthesia (avoiding local infilteration) or under general anesthesia using a non-triggering agent. The muscle samples can be dissected in-vivo or removed as a block for dissection in the laboratory within 15 min. The diagnostic criteria for (MH) according to the protocol of IVCT and the CHCT is divided into three groups MHS, MHN and MHE according contracture results from the different concentrations of caffeine and halothane used in the tests. As both of the contracture tests are invasive and requires an open muscle biopsy sample, the need for a fast, safe and non-invasive test is always high. Some researchers had done a study with intramuscular caffeine and halothane application and studying the metabolic changes in different known groups of MHN and MHS. These studies shows that intramuscular injection of caffeine and halothane induces a temporary and abnormal increase of local carbon dioxide pressure pCO2 and local lactate in MHS individual. But due to the non-reliability of these metabolic studies, they’re still not standardized and not recognized by (EMHG) or (NAMHG). This results makes the contracture tests (IVCT & CHCT) still the gold standard for detecting MH susceptibility. Since 1990, when the first gene associated with MH susceptibility was identified, the major goal has been to discover the ability to replace these physiological contracture tests with a simple DNA test. The advent of the polymerase chain reaction and the availability of data from various global human genome projects should make it possible, DNA testing can be performed on an individual of any age including the newborn by using cord blood for DNA extraction. The DNA sample isolated from white blood cells, to diagnose rapidly and accurately almost any monogenic condition resulting from single nucleotide changes. So, a DNA-based diagnosis for malignant hyperthermia (MH) is an attractive proposition, because it could replace the invasive caffeine-halothane in vitro contracture tests of skeletal muscle biopsy tissue. Moreover, MH is preventable if an accurate diagnosis of susceptibility can be made before general anesthesia. While we are still some way from the dream of eliminating the CHCT/IVCT, tremendous progress has been made in variant screening with at least a small number of mutations being accepted as diagnostic. Even though currently limited to an MHS diagnosis, this is still very valuable in cost to health care providers as well as patient comfort and safety. There is much work to be done, however, first in the functional characterization of the myriad known RYR1 variants linked to MH but not yet shown to be causative. Completion of this task would significantly increase the number of families worldwide who could be offered DNA-based testing. The quest for new “hot” genes must continue, and fortunately, NGS provides the technology and instrumentation to achieve this knowledge.