Malignant hyperthermia




Malignant hyperthermia (MH, malignant hyperpyrexia) is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia — specifically the volatile anesthetic agents and succinylcholine, a neuromuscular blocking agent. In susceptible individuals, these drugs can induce a drastic and uncontrolled increase in oxidative metabolism in skeletal muscle, 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 immediately treated.


The typical signs of malignant hyperthermia are due to a hypercatabolic state, which presents as a very high temperature, an increased heart rate and abnormally rapid breathing, increased carbon dioxide production, increased oxygen consumption, mixed acidosis, rigid muscles, and rhabdomyolysis. These signs can develop any time during the administration of the anesthetic triggering agents. It is difficult to find confirmed cases in the postoperative period more than several minutes after discontinuation of anesthetic agents.


Malignant hyperthermia is a disorder that can be considered a gene-environment interaction. In most people with malignant hyperthermia susceptibility, they have few or no symptoms unless they are exposed to a triggering agent. The most common triggering agents are volatile anesthetic gases, such as halothane, sevoflurane, desflurane, isoflurane, enflurane or the depolarizing muscle relaxants suxamethonium and decamethonium used primarily in general anesthesia. In rare cases, the biological stresses of physical exercise or heat may be the trigger.

Other anesthetic drugs are considered safe.These include local anesthetics (lidocaine, bupivacaine, mepivacaine), opiates (morphine, fentanyl), ketamine, barbiturates, nitrous oxide, propofol, etomidate, and benzodiazepines.

The nondepolarizing muscle relaxants pancuronium, cisatracurium, atracurium, mivacurium, vecuronium and rocuronium also do not cause MH.

There is mounting evidence that some individuals with malignant hyperthermia susceptibility may develop MH with exercise and/or on exposure to hot Environments.


Malignant hyperthermia's inheritance is autosomal dominant with variable penetrance.The defect is typically located on the long arm of chromosome 19 (19q13.1) involving the ryanodine receptor. More than 25 different mutations in this gene are linked with malignant hyperthermia. 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.

Chromosome 7q and chromosome 17 have also been implicated. It has also been postulated that MH and central core disease may be allelic and thus can be co-inherited.


In the past, the prophylactic use of dantrolene was recommended for MH susceptible patients undergoing general anesthesia. However, multiple retrospective studies have demonstrated the safety of trigger-free general anesthesia in these patients in the absence of prophylactic dantrolene administration. The largest of these studies looked at the charts of 2214 patients who underwent general or regional anesthesia for an elective muscle biopsy. About half (1082) of the patients were muscle biopsy positive for MH. Only five of these patients exhibited signs consistent with MH, four of which were treated successfully with parenteral dantrolene, and the remaining one recovered with only symptomatic therapy. After weighing its questionable benefits against its possible adverse effects (including nausea, vomiting, muscle weakness and prolonged duration of action of nondepolarising neuromuscular blocking agents), experts no longer recommend the use of prophylactic dantrolene prior to trigger-free general anesthesia in MH susceptible patients.

Anaesthesia for known MH susceptible patients requires avoidance of triggering agents (all volatile anaesthetic agents and succinylcholine). All other drugs are safe (including nitrous oxide), as are regional anaesthetic techniques. Where general anaesthesia is planned, it can be provided safely by removing vaporisers from the anaesthetic machine, placing a new breathing circuit on the machine, flushing the machine and ventilator with 100% oxygen at maximal gas flows for 20–30 minutes, and inducing and maintaining anaesthesia with nontriggering agents (e.g.: propofol). Modern anaesthetic machines have more rubber and plastic components which provide a reservoir for volatile anaesthetics, and should be flushed for 60 minutes.

Charcoal filters can be used to prepare an anesthesia machine for malignant hyperthermia patients in less than 60 seconds. These filters prevent residual anesthetic from triggering malignant hyperthermia for up to 12 hours, even at low fresh gas flows


During an attack

The earliest signs may include: masseter muscle contracture following administration of succinylcholine, a rise in end-tidal carbon dioxide concentration (despite increased minute ventilation), unexplained tachycardia, and muscle rigidity. Despite the name, elevation of body temperature is often a late sign, but may appear early in severe cases. Respiratory acidosis is universally present and many patients have developed metabolic acidosis at the time of diagnosis. A fast rate of breathing (in a spontaneously breathing patient), cyanosis, hypertension, abnormal heart rhythms, and high blood potassium may also be seen. Core body temperatures should be measured in any patient undergoing general anesthesia longer than 30 minutes.

Malignant hyperthermia is diagnosed on clinical grounds, but various laboratory investigations may prove confirmatory. These include 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. Severe rhabdomyolysis may lead to acute kidney failure, so kidney function is generally measured on a frequent basis. Patients may also get premature ventricular contractions due to the increased levels of potassium released from the muscles during episodes.

Susceptibility testing

Muscle testing

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 nontriggering 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.

Genetic testing

Genetic testing is being performed in a limited fashion to determine susceptibility to MH. In people with a family history of MH, analysis for RYR1 mutations may be useful


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/7.32 kPa or arterial pCO2 above 60 mmHg/7.98 kPa)
  • 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)


Prognosis is poor if this condition is not aggressively treated. In the 1970s, mortality was greater than 80%; with the current management, however, mortality is now less than 5%.


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 5%. Dantrolene remains the only drug known to be effective in the treatment of MH. It is recommended that each hospital keeps a minimum stock of 36 dantrolene vials (720 mg) sufficient for a 70-kg person.

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.

Research in mouse models suggests that azumolene "is likely uncoupling the efficiency of a Ca2+-dependent RyR1 signal coupled directly or indirectly to the [store-operated calcium entry] machinery." There may be two different pathways of store-operated calcium entry: one, RyR1-reliant and the other, RyR1-non-reliant (see Disease Mechanism section above for RyR1 description). Furthermore, elucidating earlier ideas on the pathogenesis of malignant hyperthermia, researchers point out that it may be "as much a syndrome of exaggerated Ca2+
entry as it is of exaggerated Ca2+ release."

Azumolene has also been shown to be as effective as dantrolene at preventing and reversing contracture in in vitro experiments with human skeletal muscle.