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Malignant hyperthermia

This is part of Rare diseases.

Diagnosis: Malignant hyperthermia

Synonyms: --

Innehåll


Date of publication: 2007-05-31
Version: 1.2

The disease

Malignant hyperthermia is an inherited muscle disease. People with this disease have no symptoms except during exposure to certain drugs used for general anaesthesia. In susceptible individuals these drugs trigger an acute reaction, which can be fatal if left untreated. The reaction is caused by an uncontrolled increase in metabolism, leading to temperature elevation (hyperthermia).

The first case report, published in 1961, described one Australian family in which 10 members had died unexpectedly during general anaesthesia.

The current mortality rate is less than 5 per cent, to be compared with over 70 per cent in the 1960s. Three main factors lie behind this dramatic decrease. The first is the introduction of the antidote drug dantrolene, followed by diagnostic testing for family members of affected individuals. The third is related to growing awareness about the condition. Increased knowledge, in combination with advancements in patient monitoring during anaesthesia, facilitates early detection of a hyperthermic reaction.

Triggering anaesthetic agents should not be used in individuals susceptible to malignant hyperthermia. Safe alternatives are available.

Occurrence

The incidence of malignant hyperthermia is unknown. In Sweden, 10-20 suspected reactions occur every year.

The condition has been identified in approximately 200 Swedish families (2006).

Cause

In the majority of families with malignant hyperthermia the condition is caused by a mutation (structural defect) in a gene known as RYR1, coding for ryanodine receptor 1.

The ryadonine receptor is a protein residing within the membranes of the sarcoplasmic reticulum, the organelle in muscle cells that stores calcium. The ryanodine receptor acts as an ion channel that adjusts calcium concentrations, thereby regulating muscle contractions. In a malignant hyperthermic reaction, the channel is opened and calcium is released uncontrollably. The rising calcium concentration in the cell markedly increases the rate of metabolism, and the muscle contracts.

Other genes than RYR1 have also been associated with malignant hyperthermia. In some families, it is very likely that the condition is caused by a different gene mutation.

Central core disease is genotypically related to malignant hyperthermia as both disorders are caused by a RYR1 mutation. People with this rare inherited muscle disease also have an elevated risk of being affected by a hyperthermic reaction during anaesthesia. Separate information about central core disease is available in the Swedish Rare Disease Database.

Heredity

In most families with malignant hyperthermia the pattern of inheritance is autosomal dominant, meaning that if one of the parents has the disease, the risk of his or her passing it down to sons or daughters is 50 per cent. Children who do not inherit the genetic trait for malignant hyperthermia will neither be born with it nor pass it down.

Autosomal dominant inheritance of genetic traits

The inheritance pattern may also be more complex. In some families, both parents may be carriers of the RYR1 mutation.

The disorder may also be caused by a new mutation, meaning that the defective gene has not been inherited and is not present in the affected individual’s family. However, the new mutation is hereditary and there is a risk that a person with a new mutation will pass it down to his or her children.

Symptoms

Symptoms of malignant hyperthermia only present in susceptible individuals who are exposed to triggering anaesthetic drugs.

The reaction varies considerably among individuals, but some muscle and hypermetabolic symptoms are always involved.

Muscle symptoms

  • Pronounced muscle stiffness

    and/or
  • Pronounced jaw stiffness (triggered by the anaesthetic drug suxamethonium/ succinylcholine)
  • Signs of degenerating muscle tissue

Hypermetabolic symptoms

  • The level of exhaled carbon dioxide (end-tidal CO2) rises rapidly (hypercarbia). The carbon dioxide concentration is a measure of oxidative metabolism, and is always monitored during anaesthesia
  • Rapidly increasing oxygen consumption
  • Increased heart rate, perspiration and escalating fever (the temperature may rise by up to 1 degree per 5 minutes)

Left untreated, malignant hyperthermia can give rise to life-threatening complications by impairing blood coagulation and kidney function. Brain function may also be affected. In severe cases, damage may be irreversible.

Although malignant hyperthermia reactions can occur at all ages, they usually affect individuals between the ages of 1 and 40. Neonates and elderly people are rarely affected.

Malignant hyperthermia may not occur with every exposure to triggering agents, and having undergone surgery and general anaesthesia without complications is no guarantee against future reactions. Cases have been reported in which patients have had severe reactions, even causing death, despite previous uneventful exposure to known triggers. The underlying cause of this unpredictability is still unknown.

As symptoms only arise in conjunction with anaesthesia, the disorder imposes no limitations on everyday life. Procedures such as vaccinations and dental anaesthesia are no cause for concern.

Diagnosis

Patients who have had a suspected episode of malignant hyperthermia undergo a diagnostic investigation that always begins with an in vitro contracture test (IVCT). In Sweden, this muscle test is only performed in Lund. The muscle should be fully grown, which means that the patient should preferably have reached puberty. In the test a muscle sample is extracted from the vastus lateralis muscle on the side of the upper leg. After preparation, the sample is placed in a special container filled with a tepid solution, of the same temperature as the fluids surrounding cells in the body (37° C). The muscle strip is then exposed to halothane and caffeine and the reaction measured. In individuals susceptible to malignant hyperthermia the muscle fibres will contract in response to low concentrations of these substances. However, people with the disorder may still be coffee drinkers, as the caffeine concentrations used in an IVCT test are far higher than doses ingested through caffeinated beverages.

Genetic testing is performed in an attempt to detect the underlying mutation. In Scandinavia it has only been possible to identify the mutation in 20 per cent of the families in which one member has had a malignant hyperthermic reaction. When the diagnosis has been established, first-degree relatives are offered diagnostic investigation, usually in the form of an IVCT test.

If the underlying mutation is identified, other blood relatives should also be offered DNA-based diagnostic testing. If a person is found to be a carrier of the mutation, the IVCT test is unnecessary. However, if the mutation is not found the investigation must also include a muscle biopsy. The experience of the European Malignant Hyperthermia Group (EMGH, see under R&D) suggests that the mode of inheritance is complex and that a negative DNA test does not exclude susceptibility to malignant hyperthermia.

Treatment/interventions

The following anaesthetic agents should never be administered to individuals with established or suspected malignant hyperthermia:

  • Desflurane
  • Enflurane
  • Isoflurane
  • Sevoflurane
  • Suxamethonium/succinylcholine (a muscle relaxant)
  • Halothane

Although halothane is a triggering agent no longer used by European anaesthetists, it is still in use in other parts of the world. Ether is another known trigger, which may be used in some non-Western countries.

The triggering agents on the list are widely used because they are effective and well tolerated by the majority of patients.

Preventive measures

The most important preventive measure is to inform medical staff about the diagnosis in advance of scheduled general anaesthesia. This simple measure enables the anaesthetics to make a choice of alternative anaesthetic regimens. Individuals susceptible to malignant hyperthermia should also carry this information on them, for example in the form of medical alert jewellery or a wallet card, in case of an emergency. A warning should be added to the patient’s medical record file. School and preschool staff and sports and recreation leaders must all be informed about the condition.

Relatives should be informed about the potential risks.

Malignant hyperthermia treatment

  • Rapid discontinuation of the triggering agents
  • Dantrolene treatment is the most important intervention. Dantrolene binds to the ryanodin receptor, thereby inhibiting the uncontrolled release of calcium into the muscle cells. The calcium equilibrium is restored, and the hyperthermic reaction is stopped. Dantrolene is a drug requiring a license in Sweden, and is not listed in FASS (the Swedish system of approved drugs).
  • Aggressive efforts to support functioning of the heart, respiration, kidneys, blood coagulation and brain. All interventions must be adapted to individual signs and symptoms.

Travelling abroad

Malignant hyperthermia is a well recognized disorder and as a rule safe treatment protocols and patient monitoring can be expected. Dantrolene is normally available. In poor countries, however, or in war zones, the choice of anaesthetic drugs may be restricted, depending on the resources of the local hospital. Safe anaesthetics may not be available and public hospitals may not have access to dantrolene, which is a very expensive drug.

Ultimately, risk assessment is the responsibility of the individual. If, for example, travel plans include backpacking or travel in third world countries, one cannot expect all hospitals to provide safe anaesthesia or dantrolene treatment in emergencies.

Practical advice

The Malignant Hyperthermia Investigation Unit in Lund (see under “National and regional resources”) offers practical advice on ways for susceptible individuals of providing information about the disorder. Internet: www.malignhypertermi.se.

National and regional resources in Sweden

Diagnostic investigation and IVCT (see under “Diagnosis”) are performed at The Malignant Hyperthermia Unit, Department of Intensive and Perioperative Care, Lund, Skåne University Hospital, Sweden. Tel +46 17 10 00, Internet: www.malignhypertermi.se.

Resource personnel

Senior physician Gunilla Islander, The Malignant Hyperthermia Unit, Department of Intensive and Perioperative Care, Lund, Skåne University Hospital, Sweden. Tel +46 17 10 00 or +46 17 19 49, email: gunilla.islander@skane.se.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

There is currently no Swedish patient association.

The British Malignant Hyperthermia Association (BMHA), www.bmha.co.uk.

Malignant Hyperthermia Association of the United States (MHAUS), email: info@mhaus.org, www.mhaus.org.

Courses, exchanges of experience for personnel

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Research and development (R&D)

The European Malignant Hyperthermia Group (EMHG) is a forum for cooperation between physicians and researchers with an interest in the disorder. The group has a website: www.emhg.org.

Current research is directed at identifying the mutations underlying malignant hyperthermia. The aim is to be able to offer all patients about to undergo anaesthesia a blood test that would reveal susceptibility to hyperthermic reactions. Research is also ongoing to determine which proteins are involved in the various mechanisms involved in an episode of malignant hyperthermia.

Information material

Short summaries of all the information texts in the Rare Disease Database of the National Board of Health and Welfare are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version of each text, and then clicking on the leaflet icon which will appear under “Mer hos oss” in the column on the right-hand side.

Information from The Malignant Hyperthermia Unit, Department of Intensive and Perioperative Care, Lund, Skåne University Hospital, Sweden, is available at: www.malignhypertermi.se.

Information in English is available at the website of the Malignant Hyperthermia Association of the United States: www.mhaus.org.

Literature

Denborough MA, Forster JF, Lovell RR, Maplestone PA, Villiers JD. Anaesthetic deaths in a family. Br J Anaesth 1962; 34: 395-396.

Hopkins PM. Malignant hyperthermia: advances in clinical management and diagnosis. Br J Anaesth 2000; 85: 118-128.

Islander G, Bendixen D, Ranklev-Twetman E, Oring H. Results of in vitro contracture testing of both parents of malignant hyperthermia susceptible probands. Acta Anaesthesiol Scand 1996; 40: 579-584.

Islander G, Jungner M. ABC om anestesi vid ärftlig perifer muskelsjukdom. Läkartidningen 2005; 102: 566-571.

Ording H, Brancadoro V, Cozzolino S, Ellis FR, Glauber V, Gonano EF et al. In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group. Acta Anaesthesiol Scand 1997; 41: 955-966.

Robinson R, Hopkins P, Carsana A, Gilly H, Halsall J, Heytens L et al. Several interacting genes influence the malignant hyperthermia phenotype. Hum Genet 2003; 112: 217-218.

Rueffert H, Olthoff D, Deutrich C. Spontaneous occurrence of the disposition to malignant hyperthermia. Anesthesiology 2004; 100: 731-733.

Urwyler A, Deufel T, McCarthy T, West W. Guidelines for molecular genetic detection of susceptibility to malignant hyperthermia. Br J Anaesth 2001; 86: 283-287.

Database references

OMIM (Online Mendelian Inheritance in Man).
www.ncbi.nlm.nih.gov/omim
search: malignant hyperthermia

GeneReviews (University of Washington)
www.genetests.org (select Genereviews)
search: malignant hyperthermia susceptibility

Orphanet
www.ojrd.com/content/2/1/21/

Document information

The Swedish Information Centre for Rare Diseases, produced and edited this information material.

The medical expert who wrote the draft of this information material is senior physician Gunilla Islander, Lund University Hospital, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

The expert group on rare diseases of the Swedish National Board of Health and Welfare approved the material prior to publication.

Date of publication: 2007-05-31
Version: 1.2
Publication date of the original Swedish version:
2006-11-28

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.