Malignant hyperthermia

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 drugs used for general anaesthesia, such as volatile anaesthetics or the depolarizing muscle relaxant suxamethonium chloride. 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. MH is often inherited as an autosomal dominant disorder, for which there are at least 6 loci of interest. MH is phenotypically and genetically related to central core disease (CCD), an autosomal dominant disorder characterized both by MH symptoms and myopathy.

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Signs, symptoms and diagnosis

The phenomenon presents with muscular rigidity, followed by a hypermetabolic state with increased oxygen consumption, increased carbon dioxide production (hypercarbia), metabolic acidosis, tachycardia, and an increase in body temperature (hyperthermia) at a rate of up to ~2°C per hour. This is followed by a breakdown of muscle cells (rhabdomyolysis), which release their contents such as myoglobin, creatine kinase (CK/CPK) and potassium, into the bloodstream.

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.

A proportion of people with malignant hyperthermia may have particular characteristics. A 1972 report on a family with MH also described myopathy, short stature, cryptorchidism (undescended testicles), pectus carinatum (a chest wall deformity), lumbar lordosis and thoracic kyphosis (deformity of the spine), and unusual facial characteristics.^[1] Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report.

Diagnosis

The standard procedure to test persons suspected of being susceptible 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%.^[2] 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.

There is also a protocol for investigating people with a family history of MH, where first-line genetic screening of RYR1 mutations is one of the options.^[3]

Pathophysiology

Disease mechanism

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.^[4][5] 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.^[6][7] 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 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.^[8][9] 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 cells, the resulting channels are 5x 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.^[10]

Other chromosomal mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.^[3]

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.

Gillard et al discovered the causative mutation in humans only after similar mutations had first been described in pigs.^[4]

Horses also suffer from malignant hyperthermia. It is the Thoroughbred breed that was found to have this etiology. It can be caused by overwork, anesthesia, or stress. An inheritable genetic mutation is found in susceptible animals. ^[11]

An MH mouse has been constructed, bearing the R163C prevalent in many 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.^[12]

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]}

Treatment

The current treatment of choice is the intravenous administration of dantrolene, 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 works directly on the ryanodine receptor to prevent the release of calcium. Pretreatment with dantrolene has been advocated in the past to prevent MH, but this is probably unreliable, and the long half-life of the drug may leave patients weak for extended periods. The only sure way to prevent MH is avoid the use of triggering agents in patients known or suspected of being susceptible to MH.

After the widespread introduction of treatment with dantrolene the mortality of malignant hyperthermia fell from 80% in the 1960s to less than 10%. The substance azumolene, chemically related to dantrolene, is under investigation for use in MH.

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]}

History

The syndrome was first recognized in one affected family by Denborough et al in 1962.^[13]

One of the second descriptions of MHS was in Wausau, Wisconsin. There is still a high prevalence of malignant hyperthermia in this area today.^{[citation needed]}

References