Approach

There are two aspects to the diagnosis: the recognition of an acute episode of malignant hyperthermia (MH), and the identification of patients with susceptibility to MH.

Recognition of an acute episode of MH

MH usually occurs during the intraoperative or, less commonly, in the postoperative period. Recognition of an acute episode is dependent on appropriate intra- and postoperative monitoring:

  • Minute ventilation, exhaled carbon dioxide (ETCO₂), and inspired and expired oxygen concentrations should be assessed. Minute ventilation (to maintain a normal end tidal carbon dioxide), carbon dioxide production, and oxygen consumption are all increased in an MH event. An unexplained and unexpected progressive increase in carbon dioxide production as evidenced in ETCO₂ should lead to a high index of suspicion for MH.[1]

  • Core temperature should be monitored during all anesthetics. A marked increase in core temperature (>104°F [40°C]) can be seen in MH.[54][55] Emphasis on temperature monitoring is stressed in every patient receiving an anesthetic, specifically when changes in body temperature are possible. An increase in deaths due to MH from 2007 to 2012 was reported to be likely associated with inadequate and inaccurate temperature monitoring.[55]

  • Unless the sympathetic nervous system response is obtunded, for example by the use of beta-blockers or remifentanil, increased carbon dioxide production accompanied by an otherwise unexplained and unexpected increase in heart rate is a diagnostic feature of MH. It is the upward trend in heart rate that is more useful than attainment of a specific value.[1]

  • Muscle tone and the degree of neuromuscular blockade should be noted. Masseter muscle rigidity may be an early sign of an episode of MH.[2][6]

  • Patient’s body habitus and age should also be taken into consideration when suspecting acute MH. A review of pediatric patients found that there are differences in clinical characteristics of acute MH episodes among different-aged cohorts in childhood.[56] Younger patients are likely to present with greater degree of lactic acidosis, while older children may demonstrate higher temperatures and potassium levels.

Any inhalation anesthetic should be stopped and the fresh gas flow rate increased above minute ventilation if MH is suspected. Adding activated charcoal filters to the breathing circuit is an effective way to immediately eliminate any further volatile agent exposure.[57][58]​​ Venous blood is obtained to measure venous blood gases and serum electrolytes, especially potassium. This should ideally be taken from a central venous catheter if feasible. Findings suggestive of MH include pCO₂ >55 mmHg (>7.33 kPa), pH <7.25, base excess more negative than -8 mEq/L, and potassium >6 mEq/L.[59]

Hypercapnia, tachycardia, and muscle stiffness may abate after the inhalation anesthetic is removed, a therapeutic trial of dantrolene is given, and the patient is cooled to 100.4ºF (38ºC); this is supportive evidence that the patient has had an episode of MH. However, dantrolene can also decrease metabolism, temperature, heart rate, and acidosis in patients who are not susceptible to MH, so this response is not by itself diagnostic.

Rarely, MH may be triggered without exposure to anesthetics. Triggers include intense physical activity, exercise-induced rhabdomyolysis, febrile illness, or repeated episodes of heat-related illness.[8][10][11][13] Patients present with a spontaneous episode of severe muscle stiffness.[7] MH should be considered in the differential diagnosis of any patient presenting with muscle stiffness associated with any of these triggers.[3][12]

Confirmatory testing

Genetic testing or a muscle contracture test can provide a definitive diagnosis (see below). In settings where the clinical evidence very strongly supports a diagnosis of MH and a muscle contracture test is contraindicated (i.e., patient weighs <20 kg) genetic testing could precede muscle contracture testing.[60] In these patients, a known MH-causative mutation may be found at loci RYR1, CACNA1S, or STAC3 (a skeletal muscle-specific T-tubule protein involved in calcium regulation). Further diagnostic mutations are being sought.

Exclusion of other diagnoses

Most of the signs of MH are nonspecific, so it is important to exclude other diagnoses. If the results of ventilation and routine blood tests are normal, the anesthetic complication is unlikely to be due to MH and other causes should be considered. The most important diagnoses to exclude depend on the abnormalities that are noted.

If hypercapnia is present, consider:

  • Changes in compliance of the ventilator system (leaks, faulty valves)

  • Changes in compliance of the patient's respiratory system (compromise of the upper airway, stiff lungs, elevated diaphragm, retraction against the lungs, mucus plugs)

  • Administration of drugs that increase the apneic threshold (narcotics, sedatives, anesthetics)

  • Absorption of carbon dioxide from insufflation

  • Increased metabolism due to other medical illnesses (sepsis, stimulant drugs, drug withdrawal, allergy, endocrinopathy).

If fever is present, consider:[61]

  • Iatrogenic overheating

  • Inability to lose heat due to occlusive dressing, high humidity and temperature, or vasoconstriction

  • Diseases that increase the set point for thermoregulation

  • Presence of recently ingested illicit or designer drugs, also known as “new psychoactive substances”. These can alter neurotransmitter levels and result in hyperactivity leading to elevated temperatures.[62]

If evidence of muscle injury is present (including high potassium), consider:

  • Conditions producing muscle ischemia

  • Possible history of inheritable muscular disease, such as dystrophinopathy

  • Concomitant myopathic drugs such as HMG-CoA reductase inhibitors (i.e., statins)

  • If there is evidence that rhabdomyolysis persists, this may be an indication of enzyme defects in the muscle (consider carnitine palmitoyltransferase [CPT] II deficiency and myophosphorylase deficiency [McArdle disease]).

Monitoring for complications

Rhabdomyolysis

  • Urinalysis and urine myoglobin: should be performed as an initial test in all patients to detect rhabdomyolysis. If there is a positive finding on dipstick for blood, urine should be sent for microscopic and chemical analysis to differentiate between red blood cells, myoglobin, and hemoglobin.

  • Urine output should be monitored during the acute episode. A decrease in urine output accompanied by myoglobinemia indicates impending acute kidney injury.

  • Creatine kinase should be measured at the time of an episode of MH and daily until it is normal. If creatine kinase is markedly elevated and there have been minimal signs of increased metabolism, structural myopathies, such as dystrophinopathy, or enzyme defects, such as CPT deficiency, should be considered as causes.[37]

Acute kidney injury

  • Serum creatinine: this is measured to document renal function, which can be impaired secondary to rhabdomyolysis.

Coagulopathy

  • Measures of coagulation function such as platelet count, prothrombin time, partial thromboplastin time, and fibrinogen should be performed as an initial test in all patients suspected of having an MH episode. MH susceptible people may be at increased risk of bleeding without exposure to pharmacologic MH triggers.[63] Consider thromboelastography if feasible.

  • Disseminated intravascular coagulation, leading to excessive bleeding, may be a complicating feature as MH progresses.[1]

Identification of patients with susceptibility to MH

Susceptibility to MH is a subclinical condition, although patients may describe feeling uncomfortable exercising in the heat, and some patients may complain of muscle cramps.[12]

Testing for susceptibility to MH by muscle contracture testing and/or genetic screening is part of basic health maintenance for families affected by MH. There can be discordance between genetic testing and muscle contracture testing results.[7][64] For diagnostic purposes the results of muscle contracture testing should be relied upon. However, when a causative genetic variant is identified, a diagnosis of MH susceptibility should be applied and additional muscle contracture testing is not required.[60]

[Figure caption and citation for the preceding image starts]: Diagnostic pathway for investigation of MH susceptibility. IVCT, in vitro contracture test; MH, malignant hyperthermia; MHN (MH negative or normal), classification applied when all contracture tests are negative; MHShc, MHSh, and MHSc, classifications are applied when contracture responses to both halothane and caffeine are abnormal, response to halothane alone is abnormal, or response to caffeine alone is abnormal, respectively. MHShc, MHSh, and MHSc patients should be asked to take part in research studies of the genetic basis of malignant hyperthermiaHopkins PM et al. Br J Anaesth. 2015 Oct;115(4):531-9. Used with permission [Citation ends].com.bmj.content.model.Caption@31e02243

Genetic testing

The role of genetic testing in MH is complex, and expanding.[65][66]​​ Such testing is performed by a number of academic institutions and private companies. The Malignant Hyperthermia Association of the United States (MHAUS), the European Malignant Hyperthermia Group (EMHG) and clinical geneticists can help to identify the options for genetic testing in specific localities. Malignant Hyperthermia Association of the United States Opens in new window The European Malignant Hyperthermia Group Opens in new window​​​

Individuals who are suspected to have had a clinical MH event should undergo genetic testing focused on the RYR1, CACNA1S, and STAC3 genes. If such patients are found to have a genetic variant classified as pathogenic or likely pathogenic for MH, they can be considered MH susceptible without the need for invasive contracture testing. If no such diagnostic MH variant is identified, the risk profile for developing MH under anesthesia remains unclear, and contracture testing should be considered.[60]

Separately, there is an increase in MH genetic testing in patients without a personal or family history of an adverse anesthetic event.[67]​ As these patients have a substantially lower pre-test probability of being MH susceptible, any identified variants (especially variants of unknown significance) should be evaluated in that context. Genetic counseling is indicated in all patients with mutations suspected to cause susceptibility to MH, including those of unknown significance.[10]

If MH is suspected as the cause of a death, genetic testing should be undertaken as part of the autopsy.[24][65]

Muscle contracture testing

Muscle contracture testing is the most sensitive test for determining MH susceptibility. This is an in vitro test that must be performed on fresh muscle, obtained by muscle biopsy. The patient must have recovered from the MH episode for this test to be valid. The patient must travel to the laboratory where the muscle test will be performed. The muscle biopsy and contracture test must be planned as any outpatient surgery. The in vitro administration of a bolus of halothane, or incremental exposure to caffeine, to the fresh muscle sample produces characteristic mechanical responses to stimulation in muscle susceptible to MH, which are diagnostic.[68][Figure caption and citation for the preceding image starts]: The mechanical response of normal and MH-susceptible muscle (positive) to direct stimulation in the presence of 3% halothaneFrom the collection of Dr Sheila Muldoon [Citation ends].com.bmj.content.model.Caption@b0bd1f6[Figure caption and citation for the preceding image starts]: The mechanical response of normal and MH-susceptible muscle (positive) to direct stimulation in the presence of incremental administration of caffeineFrom the collection of Dr Sheila Muldoon [Citation ends].com.bmj.content.model.Caption@2ada758e

The caffeine halothane contracture test (CHCT) and the in vitro contracture test (IVCT) are the standardized bioassays used.[69] These tests are designed to be very sensitive and are the only tests that can definitively exclude the diagnosis of MH or verify the susceptibility to MH. The characteristic response is quantified as an increase in the contracture threshold. The diagnostic criteria differ depending on which test is used:

  • CHCT: patients with an increased contracture threshold in response to either caffeine or halothane are considered susceptible to MH.

  • IVCT: patients with an increased contracture threshold in response to caffeine and halothane, or either agent alone, are diagnosed as being susceptible to MH.[60]

The positive and negative predictive values of both of these contracture tests depend on the prior probability of the patient being susceptible to MH, which is established by a thorough review of the personal and family anesthetic and medical history.[7]

These tests require minor surgery and must be performed at an MH testing center, of which there are several worldwide. Malignant Hyperthermia Association of the United States Opens in new window The European Malignant Hyperthermia Group Opens in new window These tests have not been standardized for the pediatric population and because they require a large piece of muscle they are not suitable in children <20 kg.

Screening of relatives

If a patient is diagnosed as susceptible to MH, close blood relatives should be screened once the assessment of the patient is complete.[24] If the patient has an identifiable mutation, genetic studies on relatives can be focused on the particular exon.

If the same mutation is identified in a relative, that individual should be considered to be susceptible to MH, and muscle contracture testing is not required. If a mutation is not identified, then muscle contracture testing is required to definitively exclude the diagnosis.[70]

Many families have novel mutations in RYR1.[11][13][15]​​[18][19][25][26]​​[71]​ These are suspected to cause MH but are not biologically confirmed.[34][72]​ Given the variable penetrance and prevalence of malignant hyperthermia-susceptible (MHS) individuals, new genetic techniques such as exome sequencing have identified unsuspecting families as MHS.[20][33][65]​​

Detection of muscle enzyme deficiencies

MH is commonly associated with an increase in creatine kinase, and some patients with susceptibility to MH will have chronic elevations. If a patient has a recurrent elevation in creatine kinase more than 5 times the upper limit of normal, muscle enzyme deficiencies associated with rhabdomyolysis should be investigated.[37][51] The exercise intolerance panel includes specific tests for these deficiencies, including carnitine palmitoyltransferase 2 (CPT2) deficiency, myophosphorylase deficiency, and myoadenylate deaminase deficiency.

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