Malignant Hyperthermia

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 2017):

-         MHS1 [MIM 145 600]: RYR1 gene on locus 19q13.1 - 13.2 (50-70% of cases) of the ryanodine receptor type 1: on more than 300 discovered genetic variants, 35 mutations associated with MH have been identified to date

-         MHS2 [MIM 154 275]: SCN4 gene of the sodium channel 'a' in the skeletal muscle (17q11.24)

-         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: 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. 

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).

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 administration of 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, MH-related or not. 



Muscle disease

Risk = similar to that of normal population

Major risk

Moderate risk ?

Asymptomatic increased CPK level



x

Becker

x



Brody



x

(only positive contracture tests)

Central core


x if RYR1 mutation


Deficiency in myoadenilate déaminase



x

( positive tests)

Deficiency in carnitine-palmitoyl transférase type 2

x risk of rhabdomyolysis due to halogenated agents (one case)



Duchenne

x



congenital disproportion of fibres I


x if RYR1 mutation


McArdle
glycogenosis 

x



King-Denborough


x


mitochondrial diseases : MERRF, MELAS, Kearns-Sayre etc

x



Minicore ou multicore myopathy


x if RYR1 mutation 


rods myopathy

(nemaline rod)


x if RYR1 mutation 


Native American myopathy (Lumbee)


x


dystrophic I myotony (Steinert)

x



dystrophic II myopathy

x



Noonan

x



Osteogenesis imperfecta

x



hypokaliemic familial periodic paralysis


x if RYR1 or CACNA1S mutation



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.



Chronological stages

of treatment 

Details of the therapeutic measures

ask for help


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)

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.

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

blood gases

       administer NaHCO3 according to the blood gases

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

in case of 
cardiac rhythm disorders

-        use antiarrhythmic drugs according to the usual algorithms except anticalcic drugs (risk of cardiovascular collapse)

in case of 
acute hyperkalemia

-         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 the results

place 
an urinary catheter

-        to monitor diuresis and diagnose rhabdomyolysis

prevent acute
renal failure 

-         ensure that volemia is normalized

-         mannitol is already administered with dantrolene

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: January 2018