Key Points
Disease sum mary:
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered by potent halogenated volatile anesthetics and depolarizing muscle relaxants and in rare case by strenuous exercise and/or heat exposure, too.
Susceptible individuals have an inherited abnormality of muscle metabolism that is compensated under everyday life conditions (no clinical symptoms). However, patients with central core disease (CCD) who are at risk for MH may display muscle weakness.
Upon exposure to triggering agents muscle cell metabolism is massively accelerated with potentially fatal consequences. The resulting hypermetabolic syndrome is characterized by typical clinical signs such as tachycardia, hypercapnia, acidosis, muscle rigidity, and breakdown as well as hyperthermia.
The underlying abnormality relates to an uncontrolled release of calcium from the sarcoplasmic reticulum (SR) resulting in elevation of intracellular calcium. This in turn leads to activation of muscle contractile elements, and elevated anaerobic and aerobic metabolism.
The ryanodine receptor subtype 1 (RYR1; fast calcium-releasing channel) is considered to play a key role in the pathogenesis of MH. It controls the calcium release from the SR into the cytoplasm in normal skeletal muscle cells.
The response of the RYR1 to MH triggering substances is functionally affected in MH patients. This results in an uncontrolled calcium release via the SR membrane.
Early recognition of MH and its immediate treatment is essential for the patient’s survival. Besides symptomatic therapy dantrolene sodium is the only effective and specific treatment drug for MH (RYR1 antagonist).
MH susceptibility may reliably be detected by standardized in vitro contracture testing of biopsied skeletal muscle. Upon exposure to compounds such as halothane, caffeine, ryanodine, and other calcium release agents, marked contracture of the muscle is noted.
DNA analysis can be used in up to 30% of MH families, mainly for the screening of family members that carry a MH-associated mutation in the RYR1 gene.
A patient advocacy organization exists in the United States, Malignant Hyperthermia Association of the United States (MHAUS) (www.mhaus.org). A registry of patients with MH in North America is sponsored by MHAUS.
In Europe, the European MH Group (www.emhg.org) sponsors meetings and research into the syndrome.
Hereditary basis:
The disposition to MH is inherited in humans in an autosomal dominant fashion with variable penetrance and expressivity.
The majority of MH cases (>70%) is linked to the ryanodine receptor 1 gene (RYR1) located on chromosome 19q13.1 (MHS-1). Another gene locus is the DHPR gene. Other gene loci (MHS 2-6) are of minor importance.
There is a considerable allelic heterogeneity in the RYR1 gene with over 200 mutations which were detected in MH patients. About 30 RYR1 mutations were proven causal for MH.
Differential diagnosis:
Malignant neuroleptic syndrome, sepsis, serotonergic syndrome, heat stroke, thyroid crisis, drug intoxication (ecstasy, cocaine), hyperkalemic cardiac arrest during anesthesia in patients with occult myopathy
Iatrogenic: rapid uptake of carbon dioxide incident to laparoscopic surgery, overheating, hypoventilation, anesthesia machine malfunction
Neuromuscular disorders
CCD: causal relationship to MH (same gene locus)
Multiminicore disease (MmD): MmD patients with mutations in the RYR1 gene (minority)
Other: for example muscle dystrophies (Duchenne, Becker), myotonias
System | Manifestation | Incidence |
|---|---|---|
Skeletal muscle | Masseter spasm, general muscle rigidity | up to 80% |
Rhabdomyolysis, myoglobinemia myoglobinuria | ∼50% | |
Cardiovascular | Tachycardia, arrhythmia | up to 80% |
Severe hyper or hypotension, cardiac arrest | <1% | |
(Hyper) metabolism | Hypercapnea,a hyperthermia,b acidosisc | ∼80%,a ∼30%,b ∼70%c |
Electrolytes | Hyperkalemia (secondary to acidosis and muscle breakdown) | ∼30% |
Renal | Acute renal failure (secondary to myoglobinuria) | <5% |
Respiratory | Hyperventilation; respiratory acidosis | ∼50% |
Hematologic | Disseminated intravascular coagulation syndrome | <1% |
Diagnostic Criteria and Clinical Characteristics
To make an accurate diagnosis can be difficult because clinical signs associated with MH are not unique. Each sign allows a number of differential diagnoses, so the provider must be able to recognize a pattern of signs.
In the presence of potent volatile anesthetics and/or succinylcholine
Early signs:
Tachycardia, arrhythmia, hypertension or hypotension
Masseter spasm, generalized muscle rigidity
Tachypnea (if breathing spontaneously), raised end-tidal CO2
Mixed acidosis
Cyanosis, skin mottling
Later signs
Hyperkalemia
Rapid increase of core body temperature (up to >40°C)
Muscle breakdown: creatinine kinase (CK) elevation, myoglobinemia, myoglobinuria
Disseminated intravascular coagulation particularly with marked hyperthermia
Cardiac arrest, multiorgan failure
A clinical grading scale may retrospectively help determine the likelihood that the incident was really attributable to MH. However, this scoring system depends on the manifestation of the clinical signs in the grading scale. Multiple organ systems may be affected, see Table 156-1.
Onset of signs of MH is variable and may occur on induction, during maintenance of anesthesia, and within 1 hour of termination of anesthesia.
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