Malignant hyperthermia Totally Explained

Everything about Malignant Hyperthermia totally explained

Malignant hyperthermia (MH or MHS for "malignant hyperthermia syndrome", or "malignant hyperpyrexia due to anaesthesia") is a rare life-threatening condition that's 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 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, Later reports have termed this combinations the King-Denborough syndrome, after the authors of the report.

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.

Susceptibility testing

In patients who have suffered an episode of MH, further tests are usually not performed as even a normal test wouldn't mean that the patient isn't at further risk of further episodes on future occasions. The exception would be if it's unclear whether the initial attack was due to a different medical problem, such as sepsis (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%. 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 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.
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.

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 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)

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. 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. 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's 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 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.
   Other mutations causing MH have been identified, although in most cases the relevant gene remains to be identified.
   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.

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.

Treatment

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.

Prevention

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, experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients. Similar reactions were found in pigs. After animal studies indicated possible benefit from dantrolene, a 1982 study confirmed its usefulness in humans.

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