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Malignant Hyperthermia
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Malignant Hyperthermia (MH) is a pharmacogenetic disease of the striated muscle, usually asymptomatic (except in case of myopathy associated with a risk of malignant hyperthermia, see table). Autosomal dominant transmission with incomplete penetrance and variable expressivity. The incidence in childhood (< 18 years) is estimated at 1/10,000 cases in the USA and the mortality in case of crisis is 2.9% versus 18.2% in adults over the same period of time.
Malignant Hyperthermia susceptibility is associated with a mutation of one of the following genes (underlined genes have been validated in 2022):
- MHS1 [MIM 145 600]: RYR1 gene on locus 19q13.1 - 13.2 (> 90 % of cases) of the ryanodine receptor type 1 (Evans myopathy): on more than 300 discovered genetic variants, 35 mutations associated with MH have been identified to date.
- MHS2 [MIM 154 275]: SCN4 gene coding for the Na channel of the skeletal muscle (17q11.24). The positive response to the contracture test could be an artefact due to the channelopathy.
- MHS3 [MIM 154 276]: CACNA2D1 gene (7q21-22): it codes for the unit a2δ of the type-L calcium channel of the dihydropyridine receptor; it is the voltage-dependent receptor for RYR1 at the level of the T-tubules of the muscle membrane (1% of cases)
- MHS4 [MIM 600 467]: unknown gene (3q13.1)
- MHS5 [MIM 601 887]: CACNA1S gene (1q32) (< 1% of cases): this is a subunit a1 of the calcium channel to the skeletal muscle dihydropyridine receptor
- MHS6 [MIM 601 888]: unknown gene (5p)
- STAC3 gene: (< 1 % of cases) responsible for the Native American myopathy (see this term)
- other genes may be involved as the CASQ1 gene that codes for calsequestrin-1, another protein that binds calcium in the sarcoplasmic reticulum.
- TRPV1 gene (Transient Receptor Potential Vanilloid 1) coding for a muscular calcium channel activated by heat (> 42°C), acidosis (pH < 6) and exposure to halogenated anesthetic agents (isoflurane). It could activate indirectly the RYR1 receptor.
- ASPH (8q12.3) gene (aspartate beta hydroxylase) coding for junctin, a protein that interacts with ryanodine 1 and calsequestrin to regulate calcium concentration in muscle. Some variants are also responsible for cases of exercise-induced hyperthermia and heat stroke.
The MH crisis results from the dysfunction of calcium channels at the level of the sarcoplasmic reticulum of the striated muscle. In presence of a halogenated agent (neither NO2 nor Xenon trigger MH) and/or succinylcholine, this dysfunction of calcium channels results, by an unknown mechanism, in an inability to reintegrate the ionized Ca in the sarcoplasmic reticulum and therefore in a massive increase in intracellular ionized Ca level: this leads to an increase in metabolism (mixed acidosis, anaerobic) and massive cellular destruction (rhabdomyolysis). The classical description of MH crisis dates back to the time when halothane was used: the administration of modern halogenated agents often delays the onset of clinical and biological signs of the crisis, of which hyperthermia is now a late sign. This is why some authors propose the term Malignant Hypermetabolism, which better corresponds to the pathogenesis of the crisis, rather than malignant hyperthermia.
Most malignant hyperthermia susceptible subjects do not have a phenotype of myopathy. However, some muscle diseases are associated with an increased risk of malignant hyperthermia: the following table summarizes the current state of knowledge knowing that
(1) the muscular diseases are classified on the basis of their phenotype (presentation, evolutivity, histological picture) but a same phenotype can be caused by different mutations;
(2) contracture tests in presence of halothane and caffeine may be falsely positive in certain myopathies that are not associated with MH;
(3) in some cases (such as Duchenne and Becker dystrophinopathies), there is a high risk of rhabdomyolysis in case of exposure to a halogenated agent and/or succinylcholine: the clinical presentation (hyperkaliemic cardiac arrest) is similar to a fulminant MH but the treatment is radically different (calcium and cardiopulmonary resuscitation, no dantrolene). However, preventive measures are identical: NO halogenated agent NOR succinylcholine.
Cases of malignant hyperthermia without the administration of any triggering anesthetic agent have been described: it seems that these rare cases combine a mutation of the RyR1 gene with another mutation on a different allele, whether MH-related or not. A personal medical history of rhabdomyolysis after a physical exercice and asymptomatic elevation of the CPK level must be considered as a risk factor of malignant hyperthermia until exclusion of another cause.
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Muscle disease |
Risk = similar to that of normal population |
Major risk |
Moderate risk ? |
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Asymptomatic increased CPK level |
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x |
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Becker |
x |
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Brody |
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x (only positive contracture tests) |
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Central core |
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x if RYR1 mutation |
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Deficiency in myoadenilate déaminase |
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x ( positive tests) |
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Deficiency in carnitine-palmitoyl transférase type 2 |
x risk of rhabdomyolysis due to halogenated agents (one case) |
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Duchenne |
x |
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congenital disproportion of fibres I |
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x if RYR1 mutation |
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McArdle
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x |
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King-Denborough |
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x |
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mitochondrial diseases : MERRF, MELAS, Kearns-Sayre etc |
x |
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Minicore ou multicore myopathy |
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x if RYR1 mutation |
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rods myopathy (nemaline rod) |
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x if RYR1 mutation |
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Native American myopathy (Lumbee) |
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x |
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dystrophic I myotony (Steinert) |
x |
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dystrophic II myopathy |
x |
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Noonan |
x |
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Osteogenesis imperfecta |
x |
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hypokaliemic familial periodic paralysis |
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x if RYR1 or CACNA1S mutation |
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Anesthetic implications:
- unexplained heart rhythm disorders,
- hypercarbia that does not respond quickly to a change in the ventilation,
- intraoperative or postoperative hyperthermia, including in infancy: although hyperthermia is a late sign of a crisis, not measuring the temperature of the patient delays the diagnosis of the crisis and doubles the mortality (risk x 13.8 !),
- muscle stiffness or masseter spasm (extremely rare since the halothane-succinylcholine association has fallen into disuse).
In a recent series, the signs of MH appeared 60 to 199 minutes after the beginning of anesthesia and in 23 % of the cases during awakening or in the recovery room.
In a Japanese series (mortality 8.8 %), the most common symptoms and signs were:
- for children under 2 years of age: hyperthermia (46.7 %) and generalized muscle rigidity (26.7 %)
- for children from 2 to 12 years of age: masseteric spasm (35 %), generalized muscle rigidity (19.5 %), dark urine (75 %)
- for children from 13 to 18 years of age: hypercarbia (26.5 %) and tachycardia (22.4 %).
Muscle signs were more common when succinylcholine had been given.
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Chronological stages of treatment |
Details of the therapeutic measures |
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ask for help |
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stop immediately the administration of any halogenated agent |
- hyperventilate / pure oxygen - remove the vaporizer from the circuit (risk of leak !) - replace the soda lime contained in the absorber as well as the breathing circuit (storage effect) - add a activated charcoal filter on the inspiratory and expiratory connections of the anesthesia ventilator circuit (experimental) |
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quickly inject a first dose of dantrolene: 2.5 mg/kg |
- each vial contains 20 mg of dantrolene and 3 g of mannitol and must be diluted with 60 mL of sterile water: a dose of 2.5 mg/kg provides also 0.375 mg/kg of mannitol. - additional doses of 1 mg/kg are administered until the clinical signs of MH (tachycardia, rigidity, hyperthermia) are controlled - it is not uncommon to exceed 10 mg/kg. |
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monitoring |
- monitor the PETCO2 and blood gases (arterial or central venous ) as well as the K+ and Ca++ - check for myoglobinemia, complete hemostasis and blood culture |
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blood gases |
administer NaHCO3 according to the blood gases |
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cool the patient if he is hyperthermic |
- irrigate the stomach, bladder and the operative cavity (except in case of thoracotomy: risk of cardiac arrest) with icy NaCl 0.9% - cover the patient with crushed ice bags - stop as soon as the core temperature reaches 37 °C to avoid hypothermia - cardiopulmonary bypass or EMCO can be used if dantrolene is not immediately available |
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in case of
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- use antiarrhythmic drugs according to the usual algorithms except anticalcic drugs (risk of cardiovascular collapse) |
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in case of
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- administer Ca++ - if the hyperkalemia is progressive try to hyperventilate the patient and administer a mixture of glucose + insulin (10 IU in 50 mL of glucose 30 or 50%); titrate according to thekalemia and the glycemia |
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place
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- to monitor diuresis and diagnose rhabdomyolysis |
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prevent acute
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- ensure that volemia is normalized - mannitol is already administered with dantrolene |
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post-anesthetic monitoring |
- admission to the intensive care unit for 48 hours because there is a risk of recurrence of the crisis in at least 20 % of cases - dantrolene 1 mg/kg IV/6 h until normalization of the clinical and biological signs (K, myoglobinemia) - monitor: CPK, K, Ca, temperature, blood gases, diuresis - notify the patient and his family and sent him to a reference center for possible biopsy |
Treatment of malignant hyperthermia crisis
* prevention: in case of HM risk, use a respirator free of any trace of halogenated agent: the flushingprocedure varies depending on the model of the respirator; the use of special charcoal filters is a fast and effective alternative. Total intravenous anesthesia, NO succinylcholine. Prophylactic dantrolene administration is no longer recommended; in addition, it causes muscle weakness. Monitoring: PETCO2, blood gas (lactates). Any surgical suite must have a quickly available stock of 50 x 20 mg dantrolene.
References :
Updated: November 2023