Злокачественная гипертермия: генетика, триггеры и механизмы развития.

In susceptible individuals, the medications induce the release of stored calcium ions within muscle cells. The condition affects one in 5,000 to 50,000 cases where people are given anesthetic gases. Males are more often affected than females. These signs can develop any time during the administration of the anesthetic triggering agents. Rarely, signs may develop up to 40 minutes after the end of anaesthesia.

Malignant hyperthermia is a disorder that can be considered a gene–environment interaction. In most people with malignant hyperthermia susceptibility, they have few or no symptoms unless they are exposed to a triggering agent. The most common triggering agents are volatile anesthetic gases, such as halothane, sevoflurane, desflurane, isoflurane, enflurane or the depolarizing muscle relaxants suxamethonium and decamethonium used primarily in general anesthesia. In fact, malignant hyperthermia susceptibility (MHS), predisposed by mutations in the skeletal muscle calcium release channel (RYR1), is one of the most severe heat related illnesses. The MHS associated heat susceptibilities predominantly affect children and metabolically active young adults, often leading to life threatening hypermetabolic responses to heat. Other anesthetic drugs do not trigger malignant hyperthermia. Some examples of drugs that don't cause MH include local anesthetics (lidocaine, bupivacaine, mepivacaine), opiates (morphine, fentanyl), ketamine, barbiturates, nitrous oxide, propofol, etomidate, and benzodiazepines. The nondepolarizing muscle relaxants pancuronium, cisatracurium, atracurium, mivacurium, vecuronium and rocuronium also do not cause MH. There is mounting evidence that some individuals with malignant hyperthermia susceptibility may develop MH with exercise and/or on exposure to hot environments.

Malignant hyperthermia's inheritance is autosomal dominant with variable penetrance.) involving the ryanodine receptor. 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. RYR1 has two sites believed to be important for reacting to changing concentrations: the A site and the I site. The A site is a high affinity 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 and concomitantly decreasing the affinity of the I site in mutant proteins. 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 at either one of these sites is greatly reduced. The result of these alterations is greatly increased release due to a lowered activation and heightened deactivation threshold. The process of sequestering this excess 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 an 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 concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular , and, thereby, muscle excitability. Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified. Gillard et al. discovered the causative mutation in humans only after similar mutations had first been described in pigs. has been identified in the American Quarter Horse and breeds with Quarter Horse ancestry, inherited as an autosomal dominant. It can be caused by overwork, anesthesia, or stress. In dogs, its inheritance is autosomal recessive.

The earliest signs may include: masseter muscle contracture following administration of succinylcholine, a rise in end tidal carbon dioxide concentration (despite increased minute ventilation), unexplained tachycardia, and muscle rigidity. 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. 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 link=pCO2pCO2 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 ; those with known MH susceptibility had a significantly higher (63 versus 44 mmHg). The authors propose larger studies to assess the test's suitability for determining MH risk.

Genetic testing is being performed in a limited fashion to determine susceptibility to MH.

In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia. After weighing its questionable benefits against its possible adverse effects (including nausea, vomiting, muscle weakness and prolonged duration of action of nondepolarizing neuromuscular blocking agents

Charcoal filters can be used to prepare an anesthesia machine in less than 60 seconds for people at risk of malignant hyperthermia. These filters prevent residual anesthetic from triggering malignant hyperthermia for up to 12 hours, even at low fresh gas flows. Prior to placing the charcoal filters, the machine should be flushed with fresh gas flows greater than 10 L/min for 90 seconds.

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 5%. The recommended dose of dantrolene is 2.5 mg/kg, repeated as necessary.

Fast recognition and treatment of MH utilizes skills and procedures that are utilized with a low frequency and high risk. Conducting MH crisis training for perioperative teams can identify system failures as well as improve response to these events. Simulation techniques to include the use of cognitive aids have also been shown to improve communication in clinical treatment of MH.

Prognosis is poor if this condition is not aggressively treated.

The syndrome was first recognized in Royal Melbourne Hospital, 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 Hospital. 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. In 1981, the Malignant Hyperthermia Association of the United States (MHAUS) hotline was established to provide telephone support to clinical teams treating patients with suspected malignant hyperthermia. The hotline became active in 1982 and since that time MHAUS has provided continuous access to board certified anesthesiologists to assist teams in treatment.

Other animals, including certain pig breeds, dogs, and horses, are susceptible to malignant hyperthermia. The syndrome has been reported in Pointers, Greyhounds, Labrador Retrievers, Saint Bernards, Springer Spaniels, Bichon Frises, Golden Retrievers, and Border Collies. In pigs its inheritance is autosomal recessive.

Azumolene is a 30 fold more water soluble analog 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.