Good topic -- I needed the review -- from Goldfrank's Toxicologic Emergencies
Malignant hyperthermia is a heterogeneous syndrome that typically affects individuals who are otherwise healthy, although there is an association with certain myopathic diseases. Malignant hyperthermia usually occurs in the operating room shortly after initial exposure to anesthetic agents, but it can also occur after many hours of anesthesia, and as long as 12 hours after surgery. In addition, recurrence can occur 24-36 hours after an initial episode.
Malignant hyperthermia is caused inconsistently by exposure to certain anesthetic agents that trigger abnormal calcium release from the sarcoplasmic reticulum (SR) into the cytoplasm. The disorder is associated with a defect of a skeletal muscle regulatory/ receptor protein, and inheritance is autosomal dominant with variable penetrance.101 The incidence of malignant hyperthermia is about 1:15,000 in children and 1:50,000 in adults. Drugs typically associated with triggering an attack of malignant hyperthermia are succinylcholine and the potent volatile inhalational anesthetics (the prototype agent is halothane). Diseases associated with malignant hyperthermia include Duchenne muscular dystrophy, central core disease, King-Denborough syndrome, myotonia, and osteogenesis imperfecta. Drugs that may be safely administered to individuals considered susceptible to malignant hyperthermia include NDNMBs, nitrous oxide, propofol, ketamine, etomidate, benzodiazepines, barbiturates, opioids, and local anesthetics.
The immediate systemic manifestations of malignant hyperthermia are a result of hypermetabolism following uncontrolled calcium release from the terminal cisternae of the sarcoplasmic reticulum. Calcium release produces skeletal muscle contractions. Continuous calcium reuptake by sarcoplasmic Ca2+ATPase causes depletion of cellular ATP, hypermetabolism, excess heat production, hyperthermia, increased O2 consumption and CO2 production, venous O2 desaturation and hypercarbia, anaerobic metabolism, and lactic acid generation, and can cause cardiac dysrhythmias, hyperkalemia, rhabdomyolysis, and disseminated intravascular coagulopathy. Tachycardia and initial hypertension or labile blood pressure are common. Elevation of venous, arterial, and exhaled CO2 is among the earliest findings. The extreme elevation of metabolic rate causes severe mixed venous oxygen desaturation (far below the normal of 75%). Early septic shock is also associated with hypermetabolism, increased cardiac output, and fever, but typically the mixed venous O2 saturation is >75%. The differential diagnosis of malignant hyperthermia also includes neuroleptic malignant syndrome, thyroid storm, baclofen withdrawal, drug overdose (eg, salicylate, amphetamine, cocaine and antimuscarinic), unintentional intraoperative patient overheating, heat stroke, transfusion reaction, and serotonin syndrome. Rare malignant hyperthermia-triggering agents/events include IV potassium salts (which depolarize the muscle membrane), severe exercise in a hot climate, antipsychotic drugs (eg, phenothiazines), and infection. It is unlikely that these three cause true malignant hyperthermia. However, there are cases in which patients with hypermetabolism and rhabdomyolysis respond to dantrolene; this does not mean that these patients have malignant hyperthermia.
Potassium release from muscle cells may also cause life-threatening hyperkalemia during the acute reaction. Subsequently, rhabdomyolysis can occur, causing renal damage. Signs of malignant hyperthermia include tachycardia, tachypnea, skeletal muscle and jaw muscle rigidity, fever, and increased CO2 production. In contrast to what its name suggests, although hyperthermia is a typical finding, it is not a universal finding; moreover, when it occurs, it is often a late finding.
In humans, several different chromosomal and protein defects have been causally associated with malignant hyperthermia, which may account for the heterogeneity of the inheritance and clinical presentation. Of practical importance, the existence of multiple mutations means that genetic testing is unlikely to prove useful in detecting all susceptible individuals. One possible defect involves an abnormal ryanodine-1 receptor (RYR-1, chromosome 19q13.1) that regulates intracellular calcium release in both fast- and slow-twitch skeletal muscle. According to this theory, a malignant hyperthermia-triggering agent keeps the RYR-1 channel open, leading to accelerated sarcoplasmic calcium release. A mutation of the ryanodine receptor may be necessary in some cases, but it may not be sufficient, and ryanodine receptor defects are observed in less than 50% of malignant hyperthermia-susceptible persons.The association of defects in skeletal muscle sodium channels with certain myotonic disorders has led to research into the role of this channel in the genesis of malignant hyperthermia. Also, malignant hyperthermia-susceptible persons and swine manifest increased skeletal muscle fatty acid production, and fatty acids augment halothane-induced sarcoplasmic calcium release. Although it is not yet possible to define one pathogenic mechanism, any unitary hypothesis must account for the above observations.
By partially blocking the release of calcium from skeletal muscle sarcoplasmic reticulum, dantrolene rapidly reverses the signs and symptoms of hypermetabolism: fever, mottled skin, dysrhythmias, muscle rigidity, tachycardia, metabolic acidosis, and hypercapnia. Before the discovery of dantrolene, the mortality rate from malignant hyperthermia was 70%. Death from malignant hyperthermia resulted from cardiac arrest, dysrhythmias, brain damage, hemorrhage, or multiple organ failure. When acute malignant hyperthermia is treated immediately with dantrolene, volume resuscitation, active cooling, control of hyperkalemia, and supportive care, the mortality from acute malignant hyperthermia is under 5%. Therefore, the most important aspects of therapy are rapid initial diagnosis and immediate therapy (within minutes) with dantrolene. Even if delayed for hours or days, dantrolene may still improve survival following acute malignant hyperthermia. In acute malignant hyperthermia, significant dysrhythmias may be treated with standard antidysrhythmic agents; however, calcium entry blockers should not be given with dantrolene as they may precipitate hyperkalemia and severe cardiac depression.
Persons who have had a possible episode of malignant hyperthermia, or who have a positive family history, may be considered for muscle biopsy and muscle testing; the fresh tissue specimen is placed in a tissue bath perfused with Krebs solution and then halothane or caffeine is added. According to the North America Malignant Hyperthermia Group, a positive muscle contraction in response to either halothane or caffeine is considered an indication of malignant hyperthermia susceptibility
