Susceptibility to malignant hyperthermia: Evaluation and management

INTRODUCTION — Malignant hyperthermia (MH) is a complex genetic disorder of skeletal muscle typically manifesting clinically as a hypermetabolic crisis when a susceptible individual receives a halogenated inhalational anesthetic agent or succinylcholine [1-3]. Patients who are susceptible to MH have skeletal muscle receptor abnormalities that allow excessive myoplasmic calcium to accumulate in the presence of the aforementioned anesthetic triggering agents. Very little is known about the specific mechanisms by which anesthetics interact with these abnormal receptors to trigger an MH crisis [4-6].

Susceptibility to MH (MHS) may arise de novo or be inherited in an autosomal dominant fashion. MHS is suspected in individuals with a history of a clinical event indicative of an acute MH crisis or with a family history of susceptibility. The mainstay of prevention is the identification of these genetically susceptible individuals. Avoidance of anesthetic triggers in MHS patients and prompt administration of dantrolene when an acute event occurs have reduced the mortality associated with MH from historic rates of 70 percent to <10 percent [7-9].

This topic will review the genetic basis and testing for MHS and the safe administration of anesthesia to MHS patients. The pathophysiology, clinical manifestations, diagnosis, and management of an acute MH crisis are discussed separately. (See "Malignant hyperthermia: Diagnosis and management of acute crisis".)

PREVALENCE — The prevalence of MHS is difficult to determine. Published rates of MH susceptibility vary widely depending upon the population studied and the method and criteria for diagnosing MHS. A population based study using family cohorts of patients known to be MHS in France estimated MHS at approximately 1:2000 to 1:3000 [10]. Similarly, the prevalence of mutations known to be associated with MH in the ExAC Browser gene database is 1:2750 [11]. However, less than 75 percent of cases of MHS are associated with these known variants [12]. Lack of exposure to MH triggering agents, incomplete penetrance, and variable expressivity lead to a lower incidence of MH episodes than suggested by gene prevalence rates. For example, in an analysis of 370 individuals in 125 European and Canadian family pedigrees with RYR1 MH-causative mutations, the likelihood of an individual with an RYR1 mutation developing MH during a triggering anesthetic was approximately 40 percent [13].

MUTATIONS CAUSING SUSCEPTIBILITY TO MALIGNANT HYPERTHERMIA — MHS is conferred by mutations of genes associated with proteins controlling levels of cytosolic calcium and, therefore, skeletal muscle contraction [14,15]. The inheritance of MH follows an autosomal dominant pattern in almost all human cases. A few cases, especially those associated with various myopathies, may follow an autosomal recessive inheritance pattern. Genomic sequencing will help clarify the inheritance pattern in families [16]. Genes responsible for coding proteins of the calcium channel in the sarcoplasmic reticulum are most commonly affected: the ryanodine receptor (RYR1) and the closely-associated dihydropyridine (DHP) and SH3 and cysteine-rich domains 3 (STAC3) receptors [17-20]. Mutations in the gene ASPH (Aspartate Beta-Hydroxylase) expressing junction, a sarcoplasmic reticulum protein that interacts with RYR1 and calsequestrin, have been associated with MHS or exertional heat illness (EHI) [21].

The likelihood that a susceptible patient will develop MH depends upon the specific type of receptor mutation [22]. Because of incomplete genetic penetrance and variable expressivity, there is great variability in the clinical expression of the syndrome among individuals and between anesthetic episodes in the same individual [13,23]. (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Clinical Features'.)

More than 50 percent of known cases of MH are caused by RYR1 mutations; MH causative mutations are not limited to the amino-terminal of the RYR1 receptor on chromosome 19 in regions that encode the hydrophilic, amino-terminal portion of the RYR1 receptor [6,24,25]. Although nearly 700 distinct RYR1 variants have been described [26-35], only 48 have been formally shown to be causative [25]; the remainder await confirmatory studies.

A small number of known MH-related mutations (approximately 1 percent) are caused by a mutation of the gene CACNA1S that encodes for a subunit of the DHP receptor located on chromosome 1 or on the gene encoding for the STAC3 protein on chromosome 12 [26,31-35]. (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Pathophysiology'.)

MUSCLE DISEASES NEEDING NON-TRIGGERING ANESTHETICS — The diagnosis of a muscle disease raises concern that the patient may also have MHS; association with MHS or with rhabdomyolysis depends on the specific diagnosis (table 1). Patients with myopathies caused by RYR1 mutations, notably central core myopathy, are assumed to be MHS. Patients with a history of unexpected or recurrent exertional rhabdomyolysis or exertional heat illness (EHI) may also have a higher than normal risk of MHS and should be treated as MHS unless caffeine-halothane contracture testing is negative or testing reveals a non-MH associated mutation that confers susceptibility to exertional rhabdomyolysis/EHI. In addition, patients with severe statin-induced myopathy may be at increased risk for having an RYR1 mutation, and should receive non-triggering anesthetics [36].

Patients with several other muscle diseases, notably Duchenne and Becker muscular dystrophy, develop rhabdomyolysis and severe hyperkalemia when exposed to succinylcholine and volatile anesthetics; although this is not MH, one should avoid succinylcholine and volatile anesthetics. For patients with other muscle diseases with sporadic case reports of rhabdomyolysis related to these agents, non-triggering anesthetics have been administered as a precaution, although there is no evidence of MHS. (See 'Management of anesthesia in malignant hyperthermia-susceptible patients' below and "Anesthesia for children with myopathy and for children who undergo muscle biopsy", section on 'Anesthesia-induced rhabdomyolysis and myopathy'.)

Myopathies with ryanodine receptor abnormalities — Individuals with myopathy who have MH-linked mutations or variants of unknown significance (VUS) in RYR1, CACNA1S, STAC3, or ASPH, should be anesthetized using non-triggering agents. Caffeine-halothane contracture testing to confirm MHS is not necessary. These conditions include:

●Central core myopathy [31,37-40]

●Multiminicore disease [41]

●King-Denborough syndrome [1,42]

●STAC3 myopathy, in individuals homozygous for STAC3 mutations

MH episodes have not been described in heterozygotes [17]. STAC3 myopathy was first described as Native American Myopathy, though it is not limited to Native Americans.

●Any other myopathy associated with or caused by an RYR1, STAC3, or ASPH mutation

●Patients with CACNA1S MH-causal mutations or VUS associated with a personal or family history of MH, rhabdomyolysis, or hyperCK-emia

Exertional rhabdomyolysis — Patients with a history of unexpected rhabdomyolysis triggered by either heat or exercise may have a higher incidence of MHS than the general population, based on case reports and small series of MH episodes or MHS (by testing) [43-48]. The possibility of a common etiology is illustrated by a series of six patients with a history of exertional rhabdomyolysis and positive contracture tests, in which five had RYR1 mutations [49]. These findings were confirmed in a Canadian cohort of patients with a history of exertional rhabdomyolysis and a subsequent positive MH contracture biopsy and known MH-causative mutations [50]. Because of these findings, some experts, including the authors, advocate treating patients with a history of unexpected heat- or exercise-induced rhabdomyolysis as MHS unless such episodes are proven to be caused by a heritable disorder of muscle metabolism, inflammatory or endocrine disorder. We suggest genetic testing for an MH-causative mutation, and counsel MHS patients they might be at higher than normal risk of exertional heat illness [51-56]. (See 'Risk of non-anesthesia-related MH-like episodes' below.)

Severe statin-induced myopathy — Severe myopathy is a rare adverse effect of therapy with statin medications. (See "Statin muscle-related adverse events".)

Patients with severe statin-induced myopathy (ie, incapacitating muscle pain and/or weakness related to statin therapy, often accompanied by rhabdomyolysis and plasma creatine kinase elevation) may be at increased risk for having the RYR1 mutation [57-59]. We treat these patients as MHS and suggest genetic testing for the RYR1 mutation.

Muscle disorders with intraoperative rhabdomyolysis — A number of muscle disorders do not appear to confer higher risk of MHS, but are associated with development of hyperkalemia or rhabdomyolysis following administration of succinylcholine or, less often, when volatile anesthetics are used (table 1).

Dystrophinopathies — Duchenne and Becker muscular dystrophy are both X-linked, recessive disorders that lead to abnormal formation of dystrophin, a muscle-stabilizing protein. They are associated with severe hyperkalemia, leading to cardiac arrest following administration of succinylcholine, and rhabdomyolysis may result from administration of volatile anesthetics [60,61]. While this clinical syndrome may resemble acute MH and is related to abnormal calcium release in the muscle, the etiology is different. Although many patients with dystrophinopathies have received halogenated volatile agents safely, most experts now recommend administration of non-triggering anesthetics to these patients.

Enzymopathies of skeletal muscle — There are case reports of patients with these diseases who have had positive caffeine-halothane contracture tests (CHCTs), but the interpretation of this test in the setting of a coexisting myopathy is unclear [61]. Due to case reports of rhabdomyolysis, we consider it prudent to avoid succinylcholine. The limited evidence does not support superior safety of total intravenous anesthesia (TIVA) or omitting potent inhalation anesthetics in patients with these conditions:

●Myoadenylate deaminase deficiency [62]

●Myophosphorylase deficiency (McArdle disease) [63-65]

●Carnitine palmitoyltransferase type 2 deficiency [66,67]

Brody disease — Brody disease is a very rare (1 in 10 million) autosomal recessive myopathy that results in exercise-induced muscle stiffness and cold-induced myalgia and muscle cramps. It is associated with mutations in the ATP2A1 gene, which encodes for the sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase type 1 (SERCA1) protein. A report of the clinical characteristics of 40 patients described two that manifested hyperthermia and rhabdomyolysis following general anesthesia with MH triggering agents [68]. Although this was unlikely to represent true MH, it would be prudent to avoid inhalation gases and succinylcholine in these patients.

MUSCLE DISEASES COMPATIBLE WITH MALIGNANT HYPERTHERMIA-TRIGGERING AGENTS — A number of other genetic syndromes have historically been associated with MHS, but patients with these syndromes are now thought to be at no greater risk for MH than the general population.

●MH-triggering agents (ie, volatile anesthetics and succinylcholine) are not contraindicated for patients with the following conditions:

•Osteogenesis imperfecta [69-72]

•Noonan Syndrome [73]

●Volatile anesthetics may be used, but succinylcholine should be avoided in patients with the following conditions, which result in myopathy or muscle atrophy, because of potential for life threatening hyperkalemia. The response to nondepolarizing neuromuscular blocking agents may also be unpredictable.

•Arthrogryposis multiplex congenita [74-76] (most often due to neurologic disorder rather than primary muscle disease).

•Myotonias [77,78].

•Hypokalemic periodic paralysis (HypoPP) is a rare autosomal dominant disorder that is often due to mutations in CACNA1S; approximately 1 percent of MH patients have mutations in CACNA1S not associated with HypoPP. A theoretical association between MH and HypoPP in this small subset of patients has been made, but never confirmed [79].

•Mitochondrial myopathies [62] (see "Anesthesia for children with myopathy and for children who undergo muscle biopsy", section on 'Neuromuscular blocking agents' and "Clinical use of neuromuscular blocking agents in anesthesia", section on 'Adverse effects of succinylcholine').

•Neuroleptic malignant syndrome (NMS) [80-83], an idiosyncratic response to neuroleptic medications. Succinylcholine should be avoided in patients with NMS with significant rhabdomyolysis.  

IDENTIFICATION OF MALIGNANT HYPERTHERMIA-SUSCEPTIBLE PATIENTS — The mainstay of MH prevention is the identification of genetically susceptible individuals. This is primarily done by obtaining a personal and family history of prior adverse reactions to anesthetics and examining these events in detail; there are no practical MHS screening tests. Patients with a suspicious personal or family history are presumed to be MHS for the purpose of planning anesthesia until further evaluated by history, review of medical and anesthetic records, or testing.

Anesthetic history — The majority of patients with a suspected MH event will deny a history of prior problems related to anesthesia. However, a negative prior history does not exclude MHS. Approximately one-half of patients who develop acute MH have one or two uneventful exposures to triggering agents [84,85], and many patients who develop MH have had multiple previous uneventful anesthetics that included administration of triggering agents [86].

When a patient reports a personal history or relative with a history of an adverse reaction to anesthesia, the affected patient's anesthesia and hospital records (if available) should be reviewed and assessed for the likelihood of MH (see "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Clinical signs'). If details of a suspicious episode are unavailable, it is prudent to treat the patient as MHS until further evaluated by testing.

A clinical grading scale has been developed to help determine the likelihood that a prior event represents true MH [87]. The scale assigns points to family history and clinical diagnostic criteria in the categories that define MH events, including rigidity, rhabdomyolysis, fever, tachycardia, respiratory acidosis, and other laboratory abnormalities (calculator 1). The MH clinical grading scale was developed by a consensus of experts, and has not been validated by confirmatory genetic or contracture testing. Nonetheless, many experts believe that the scale can be used to counsel patients and make recommendations for testing.

In the MH grading scale, important clinical indicators that a reported event was likely MH include the following:

●Respiratory acidosis – The presence of end-tidal carbon dioxide (ETCO₂) >55 mmHg or partial pressure of carbon dioxide (PaCO₂) >60 mmHg with controlled ventilation; ETCO₂ >60 mmHg or PaCO₂ >65 mmHg with spontaneous ventilation.

●Metabolic acidosis – Base deficit >8 mEq, pH <7.25.

●Muscle rigidity – Severe masseter muscle rigidity (MMR) or generalized rigidity that does not abate with non-depolarizing neuromuscular blocking agents.

●Muscle breakdown – Serum creatine kinase (CK) >20,000 international units/L following succinylcholine use; >10,000 international units/L without succinylcholine; cola-colored urine in the postoperative period.

●Temperature – Rapidly increasing temperature, or core temperature >38.8°C (101.8°F)

Non-anesthesia-related MH-like episodes — MH susceptibility (and RYR1 myopathy) should be in the differential diagnosis for patients who exhibit unexplained stress-induced fever, muscle cramping or rigidity, or other characteristics of MH, unrelated to exposure to anesthesia. (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Clinical Features'.) Isolated fever (ie, without rhabdomyolysis or exaggerated carbon dioxide production) is not consistent with MH.

There are a number of case reports of patients who have developed unexplained fevers and/or muscle cramping in response to either hot environments and/or strenuous exercise, or infection, and who were either known to be MHS or were subsequently found to be MHS related to an RYR1 MH-causative variant [51-54,88,89]. These events have been referred to as "awake MH" [51], to distinguish them from MH triggered by anesthetics. In most cases, symptoms have abated either spontaneously or after self-administration of oral dantrolene, but several cases have rapidly proceeded to accelerated hyperthermia, hyperkalemia, and death [51,54,90].

We suggest prescribing as-needed oral dantrolene for MHS patients who have a history of stress-induced MH-like signs and symptoms, as discussed below. Clinicians may consider prophylactic intravenous dantrolene prior to non-triggering anesthesia in this small subset of MHS individuals, as the reported anesthetic experience with these patients is limited and includes case reports of MH despite avoidance of volatile anesthetic agents. (See 'Risk of non-anesthesia-related MH-like episodes' below.)

Malignant hyperthermia susceptibility testing — Candidates for testing for MHS are those with a past episode likely to have been MH (eg, a clinical grading score of 20 or higher) and family members of MHS patients. The MH testing sequence we follow for patients and family members is shown in an algorithm (algorithm 1). (See 'Anesthetic history' above and 'Testing for family members' below.)

Testing options — The most sensitive test for MHS is the contracture test; it is considered the definitive test to rule out MH. Contracture testing is an in vitro muscle bioassay available only at specialized testing centers, and may not be paid for by insurance [91]. The test is highly sensitive, so negative results generally rule out a diagnosis of MHS [92,93]. However, there is up to a 20 percent false-positive rate. (See 'Contracture test' below.)

Patients with a positive contracture test should undergo genetic testing to look for a causative MH mutation. If one is found, other family members may be tested to look for similar mutations to confirm their MHS status as well. Not all mutations that cause MH have been identified, so absence of an MH-causative mutation does not rule out MH susceptibility. An estimated 14 to 23 percent of MHS families in the United Kingdom do not have an MH causative mutation in RYR1, CACNA1S, or Stac3. Positive genetic tests in patients with negative contracture tests have occurred [23,94]. (See 'Genetic tests' below.)

Despite the possibility of a false-negative result with genetic testing, most patients choose to undergo molecular genetic testing first, as this test requires only a blood sample, thereby avoiding the surgery and cost of contracture testing.

Other patients prefer to simply consider themselves and their family members MHS without testing. This strategy is practical, but it does not provide guidance or specific answers to the patient or their family members. Furthermore, the patient is then labeled as MHS, with implications for future anesthetics, ineligibility for military service, and possible limitations in occupational and insurance choices.

It has been suggested that a baseline elevation of CK can be used as a screening tool for MHS, but this has not proven to be sufficiently sensitive nor specific for MHS.

Contracture test

Indications for contracture testing

●Patients with a history suspicious for MH (wait three to six months post event, depending upon the degree of rhabdomyolysis). (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Clinical signs'.)

●Patients with MMR during anesthesia with a triggering agent with evidence of rhabdomyolysis (eg, CK over 10,000). (See "Malignant hyperthermia: Diagnosis and management of acute crisis", section on 'Masseter muscle rigidity'.)

●Patients with a known MHS relative (as determined by positive muscle contracture test or suspicious episode), but without a known MH-causing mutation. (See 'Testing for family members' below.)

Other clinical scenarios in which contracture testing may be helpful include:

●Unexplained rhabdomyolysis following anesthesia

●Severe or recurrent inexplicable exercise- or heat-induced rhabdomyolysis

●Patients with a suspicious history who are contemplating military service

Contracture test protocols — Contracture tests evaluate the in vitro response of the patient's skeletal muscle (a 3- to 4-inch biopsy from the thigh) to RYR1 agonists (caffeine and halothane). The testing is a bioassay using fresh tissue, so the biopsy must be performed at an MH Muscle Biopsy Center. A list of centers that perform contracture testing and muscle biopsies for MHS can be found on the Malignant Hyperthermia Association of the United States (MHAUS) website. Abnormally high levels of contractile force with agonist exposure indicate MHS. Testing should occur at least three to six months after a suspected MH event, depending upon the degree of rhabdomyolysis.

Two different protocols were developed independently:

●The caffeine-halothane contracture test (CHCT) by the North American Malignant Hyperthermia Group, with sensitivity 97 percent, specificity 78 percent [95].

●The in vitro contracture test (IVCT) by the European Malignant Hyperthermia Group, with sensitivity 99 percent, specificity 94 percent [96].

Although these protocols use slightly different methodologies, there are no appreciable differences in test accuracy. The reported differences in sensitivity and specificity are due to the unique methods used, for a test that has no true gold standard for definitive diagnosis. The true rates of false-positives and false-negatives are therefore unknown.

Contracture test results — A contracture test is considered positive if the patient's muscle demonstrates an exaggerated response to exposure to either halothane or caffeine. Results of the CHCT used in North America are discussed here.

●Negative – There is a low false-negative rate (sensitivity >97 percent), so this generally rules out a diagnosis of MHS [92]. These patients may receive triggering anesthetics. There have been case reports, however, of individuals with known MH mutations and negative contracture test results [31].

●Positive – These patients are considered MHS and should not receive triggering anesthetics. Perhaps one in five patients with a positive contracture test has a false-positive result [92]. Despite a relatively high false-positive rate, most MH experts believe that patients with a positive test should be considered MHS because of the potential life-threatening consequences of an MH episode. A positive CHCT result should be followed up with genetic testing to guide further testing for family members. However, some mutations have not been identified, and absence of known pathogenic variants does not change the diagnosis of MHS for the index patient (algorithm 1).

Genetic tests — Molecular genetic testing requires only a blood sample that is sent to a testing center. A list of laboratories that perform testing for MHS can be found at the Malignant Hyperthermia Association of the United States (MHAUS) list of Genetic Testing Centers. Genetic testing laboratories have slightly different approaches to testing for MHS; NextGen sequencing is the standard methodology.

Typically, a genetic panel evaluates the most common RYR1 mutations on chromosome 19 [23,28,97-100] and mutations associated with CACNA1S and STAC3 genes. Once a specific MH-causing mutation is discovered, other family members can be tested for only that causative mutation at a reduced price. However, more than one pathogenic variant may exist within a family, and some experts advise that family members who test negative to a proband's known mutation should still undergo contracture testing to definitively rule out MHS [10,101,102]. (See 'Genetic test results' below.)

Indications for genetic testing — Genetic testing is indicated for:

●Patients with a positive contracture test, to determine the presence of an MH-causative mutation

●Individuals with a family member who has a positive contracture or genetic test

●Patients with a clinical history suspicious for MH prior to contracture testing

Genetic test results — Results of genetic testing will indicate:

●No DNA variation found – This does not rule out MHS; these patients should be treated as MHS unless they have negative contracture testing. Since the genetic basis for MHS is incompletely understood, the overall sensitivity of full RYR1 panel testing is only about 70 percent [23,35,103]. Whole exome sequencing using next-generation DNA sequencing will detect all known pathogenic variants and is being implemented by genetic testing laboratories. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

●Mutation associated with MH – These patients are MHS. With a known mutation causing MHS, biologic relatives may have genetic tests rather than contracture tests to determine MHS status. However, if a family member does not have the same mutation as the affected patient, it does not necessarily mean he/she is definitely MH negative [103,104]; such family members should be considered MHS and offered next generation sequencing of RYR1, CACNA1S, and ASPH or contracture testing. Individuals with STAC3 myopathy are homozygous for a STAC3 mutation that results in MH-susceptibility. Heterozygotes for STAC3 mutations are not myopathic and have not been reported to experience MH episodes.

●DNA variation of uncertain significance (VUS) found in RYR1, CACNA1S or ASPH – This does not rule out MHS. These patients should be treated as MHS unless they have negative contracture testing.

COUNSELING — When patients have a diagnosis of presumed MHS, we recommend avoidance of triggering anesthetic agents. Anesthesiologists caring for them must be informed that they are MHS. This should continue lifelong, unless definitive testing (contracture testing) is negative. Methods to ensure appropriate treatment of the MHS patient include:

●A letter from the anesthesiologist who supervised the initial incident

●Notation in the patient's personal records and electronic medical record

●Identification bracelets specific for MH (available through the Malignant Hyperthermia Association of the United States [MHAUS] and MedicAlert)

We counsel MHS patients and their families to learn as much as possible about the nature of the disorder and direct them to appropriate educational resources. (See 'Malignant hyperthermia resources' below.)

Risk of non-anesthesia-related MH-like episodes — MHS patients should be questioned about physical stress-induced fever or muscle cramps, and should be cautioned about the possibility of developing heat stroke or MH-like symptoms in hot environments or with exercise. (See 'Non-anesthesia-related MH-like episodes' above.)

In light of continuing reports of MHS individuals who have developed fatal MH-like reactions that were not associated with administration of triggering agents [51-55], we advise MHS individuals to aggressively treat muscle cramping or increases in body temperature as a result of exposure to hot environments, vigorous exercise, or associated with an infectious illness. Unless symptoms are promptly alleviated the patient should seek medical care urgently.

●We suggest early institution of surface cooling or immersion in cold water if available.

●We suggest antipyretics (eg, acetaminophen and/or nonsteroidal antiinflammatory drugs) for fever when there is an infectious or inflammatory component.

●For MHS individuals who have a history of non-anesthetic-related fevers, muscle cramping, or rhabdomyolysis, we suggest prescribing oral dantrolene for self-administration if cramping or unexplained fever occur. We recommend 1 to 2 mg/kg oral dantrolene, though the optimal dose of dantrolene in this setting is unknown; in one case report, doses between 1 and 2 mg/kg orally successfully alleviated symptoms of awake MH [88]. It is unknown whether self-administered oral dantrolene can prevent the evolution of these symptoms into a fatal MH-like illness [51,105].

MHS individuals are advised to obtain yearly influenza vaccines, since influenza has been associated with rhabdomyolysis [106] and thus, could be particularly hazardous in MHS individuals.

Testing for family members — Because MHS has an autosomal-dominant inheritance, first-degree relatives (parents, siblings, and children) have up to a 50 percent chance of MHS and should consider testing (algorithm 1). Other biologic relatives (eg, cousins) may consider testing as well. If the proband has survived the MH episode, we recommend that he/she undergo molecular genetic testing. We would then recommend evaluating the patient's parents to identify the side of the family (maternal or paternal) carrying the mutation; absent consanguinity, this eliminates the need to test the unaffected side of the family if only one mutation has been identified. If the proband does not have an MH-causative mutation, caffeine-halothane contracture testing may be offered to both parents. If both parents are negative for MHS by contracture testing, suggesting a spontaneous mutation, the risk to family members other than the patient's children is low.

MANAGEMENT OF ANESTHESIA IN MALIGNANT HYPERTHERMIA-SUSCEPTIBLE PATIENTS — MHS patients can be safely anesthetized using non-triggering agents. End-tidal carbon dioxide (ETCO₂) levels, minute ventilation, and core body temperature are monitored closely in MHS patients.

Equipment preparation — The anesthesia machine should be "cleaned" of traces of volatile anesthetics. The Malignant Hyperthermia Association of the United States (MHAUS) recommends using activated charcoal filters if available (picture 1). Flush with high fresh gas flows (≥10 L/min) for 90 seconds prior to placing the activated charcoal filters on both the inspiratory and expiratory ports. These filters are effective in keeping gas concentration below 5 ppm for up to 12 hours with fresh gas flows of at least 3 L/min [107,108].

If activated charcoal filters are not available, MHAUS recommends flushing with high-flow (at least 10 L per minute) oxygen, with an unused breathing bag attached to the Y-piece of the circle system and the ventilator set to inflate the bag periodically. Due to variability in anesthesia machines, the manufacturer's guidelines regarding duration should be followed [109]. Some anesthesia machines require flushing for more than two hours to achieve residual volatile anesthetic concentrations lower than 5 ppm. If activated charcoal filters are not used, high-flows should be continued throughout the case, as plastic and rubber components of the anesthesia machine may emit previously absorbed volatile agents [110-112].  

Anesthetic vaporizers should be removed or taped over with dial in “OFF” position to avoid accidental administration of volatile anesthetic. New or disposable breathing circuits should be used. Some experts, including MHAUS, recommend changing the carbon dioxide (CO₂) absorbent [109].

The MH treatment cart should be readily available with supplies and medications needed to treat an acute MH episode (table 2).

Safe anesthetic agents — General anesthesia, regional anesthesia (neuraxial anesthesia or nerve blocks), or monitored anesthesia care are all options for these patients if triggering agents are avoided. Other patient- and situation-specific factors should be considered in choosing the type of anesthesia. In a large population-based study of approximately 958,000 patients who underwent general anesthesia in Canada, 2900 patients who were known or strongly suspected to be MH susceptible and received a non-triggering anesthetic had no higher risk of adverse postoperative outcomes (ie, death, readmission to hospital, or major postoperative complication, within 30 days of surgery) than patients who were not MH susceptible [113].

MH-triggering agents are the volatile anesthetics (eg, sevoflurane, desflurane, isoflurane, halothane) and succinylcholine; all other medications are safe [15].

"Non-triggering" agents that can be safely administered to MHS patients include:

●All intravenous anesthetic and sedative agents, including propofol, ketamine, etomidate, dexmedetomidine, and barbiturates

●All local anesthetics (eg, lidocaine, bupivacaine, ropivacaine)

●Nondepolarizing neuromuscular blocking agents (eg, vecuronium, rocuronium, cisatracurium)

●Pain relievers and anxiolytics, including opioids and benzodiazepines

●Antiemetics

●Inhalational agents limited to nitrous oxide and xenon

Administration of perioperative dantrolene for prophylaxis is not necessary [114].

Ambulatory surgery — Routine day surgery discharge criteria are applicable to MHS patients who have not received anesthetic triggering agents and otherwise do well during and following their surgery [115]. A prospective study of 125 MHS patients who received non-triggering anesthetics reported no evidence of MH-related problems when standard post-anesthesia care unit discharge criteria were followed [116]. In the previously mentioned retrospective Canadian database study, MH susceptibility in patients who had ambulatory surgery was not associated with an increase in major adverse postoperative events, but was associated with an increase in postoperative emergency department visits within 90 days [113].

Upon discharge, the patient should be instructed to call their clinician or go to the emergency department if elevated temperature or brown urine develops.

Susceptibility to malignant hyperthermia in pregnancy — A pregnant MHS patient may safely receive neuraxial anesthesia or analgesia; if general anesthesia is required, non-triggering anesthetic agents should be administered.

If the partner of a parturient is MHS, the fetus may be MHS. Although there are no cases reported of a fetus developing an MH crisis from in utero exposure to triggering agents, MHAUS recommends using a non-triggering technique if a pregnant woman carrying a potentially susceptible fetus requires general anesthesia [117].

MALIGNANT HYPERTHERMIA RESOURCES

●Malignant Hyperthermia Association of the United States (MHAUS) – MHAUS was formed in 1981 to educate the medical community and the public about MH and serve as a resource for affected families. A wide variety of educational information for health professionals and the public is available at their internet site.

MHAUS maintains a free, 24-hour "hotline" for acute cases (1-800-MH HYPER) that is continuously staffed by anesthesiologists who are experts in managing cases of MH, answering questions about prospective management of MHS patients, and directing callers to appropriate resources.

●The North American MH Registry was established to collect and analyze information about clinical episodes of MH and the results of laboratory tests.

●European Malignant Hyperthermia Group provides information on European protocols.

●Malignant Hyperthermia Unit at St. James Hospital, UK, British Malignant Hyperthermia Association.

●Malignant Hyperthermia Australia and New Zealand.

●Japanese Malignant Hyperthermia Association – 4^th Nishi Tenma Park Bldg, 3-13-9 Nishi Tenma, Kita-ku, Osaka-shi, 530-0047, Japan. C/O COML (Consumer Organization for Medicine & Law). Japanese Malignant Hyperthermia Association membership and inquiry counter (telephone/fax: 06-6361-3446; email: [email protected]).

●The RYR1 Foundation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Malignant hyperthermia".)

SUMMARY AND RECOMMENDATIONS

●Genetics of malignant hyperthermia (MH)

•Susceptibility to malignant hyperthermia (MHS) is a genetic disorder of skeletal muscle calcium regulation that can manifest clinically as a hypermetabolic crisis (malignant hyperthermia [MH] crisis) in genetically-susceptible individuals exposed to volatile anesthetics or succinylcholine. (See 'Introduction' above.)

•MHS individuals have skeletal muscle receptor abnormalities, allowing excessive intracellular calcium to accumulate in response to volatile anesthetics or succinylcholine; this triggers intracellular events, leading to skeletal muscle hypermetabolism. MHS is caused by mutations in genes that are responsible for coding calcium channel proteins and receptors (RYR1, DHP, ASPH and STAC3). (See 'Mutations causing susceptibility to malignant hyperthermia' above.)

•MHS is usually inherited in an autosomal-dominant fashion. Its prevalence is unknown but is estimated at 1:1500. Due to variable penetrance, not all exposures of MHS patients to triggering agents result in MH crisis. (See 'Prevalence' above.)

•Patients with some muscle diseases have genetic abnormalities in RYR1, CACNA1S, ASPH or STAC3 genes that confer MHS; these include central core myopathy (and all other ryanodinopathies), Native American myopathy, and King-Denborough syndrome (table 1). (See 'Myopathies with ryanodine receptor abnormalities' above.)

●Identifying MH susceptibility – The mainstay of prevention of MH is the identification of MHS individuals.

•MHS is suspected in patients with a prior likely MH event and is confirmed by susceptibility testing. A clinical grading scale for possible MH events assists in determining whether past events were actually MH. (See 'Identification of malignant hyperthermia-susceptible patients' above.)

•Patients with a history of exercise- or heat-induced rhabdomyolysis or with severe statin-induced myopathy may have a higher incidence of MHS than the general population. For patients with heat or exercise induced rhabdomyolysis we suggest testing for MHS (Grade 2C). We also suggest testing for MHS for patients with severe statin induced myopathy (Grade 2C). We assume that these patients are MHS unless they have tested negative. (See 'Exertional rhabdomyolysis' above and 'Severe statin-induced myopathy' above.)

●Myopathies associated with rhabdomyolysis – Some myopathic conditions are associated with increased risk for life-threatening rhabdomyolysis or hyperkalemia after receiving a volatile anesthetic or succinylcholine. This clinical syndrome may resemble, but is not, acute MH. Associated conditions include the dystrophinopathies, myoadenylate deaminase deficiency, McArdle disease, and carnitine palmitoyltransferase type 2 deficiency (table 1). Patients with dystrophinopathies are not MHS, but the MH-triggering agents should probably be avoided. (See 'Muscle disorders with intraoperative rhabdomyolysis' above.)

Succinylcholine should be avoided in patients with disorders of muscle metabolism or myopathy.

●MH testing – There are no practical MHS screening tests for the general population. Testing for MHS is indicated only in a patient with an event suspicious for MH or in family members of a patient with positive tests (algorithm 1). (See 'Identification of malignant hyperthermia-susceptible patients' above.)

•Contracture testing is the definitive test for individuals with an event suspicious for MH. It requires a surgical muscle biopsy and is offered at only a limited number of centers. Contracture testing has few false negatives; a negative test effectively rules out MHS. The caffeine-halothane contracture test (used in North America) has about a 20 percent false-positive rate; positive results should be followed up with genetic testing. (See 'Contracture test' above.)

•Genetic testing is indicated in individuals with a positive contracture test, positive family history for a gene mutation, and those who are unable or unwilling to undergo contracture testing. Genetic testing identifies 60 to 75 percent of MHS individuals. (See 'Genetic tests' above.)

●Anesthetic management for patients who are MHS – These patients may safely have general anesthesia, administered without triggering agents (volatile anesthetic gases and succinylcholine). Anesthesia machines should be cleaned of trace potent anesthetic gases, and an MH cart with supplies and medications to manage acute MH (including dantrolene) should be available prior to anesthesia. (See 'Management of anesthesia in malignant hyperthermia-susceptible patients' above.)

●Non-anesthesia-related MH like episodes – Some MHS individuals have developed non-anesthetic-related MH-like episodes, triggered by exposure to hot environments and/or strenuous exercise or infection, some of which were associated with fatal hyperkalemia and hyperthermia. For MHS patients with such episodes:

•We suggest surface cooling or immersion in cool or cold water for hyperthermia (Grade 2C).

•We suggest early administration of antipyretics (eg, acetaminophen or nonsteroidal antiinflammatory drugs) for fever due to inflammation or infection (Grade 2C).

•For MHS patients who have a history of non-anesthetic-related fevers, muscle cramping, or rhabdomyolysis, we suggest prescribing oral dantrolene for self-administration if unexplained fever or muscle cramps occur (Grade 2C). If symptoms do not resolve, urgent medical care should be sought.

●MH resources – Information and resources are available from the Malignant Hyperthermia Association of the United States (MHAUS) and the European Malignant Hyperthermia Group. MHAUS maintains a free, 24-hour "hotline," for assistance in MH emergencies (1-800-MH HYPER). (See 'Malignant hyperthermia resources' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ronald S Litman, DO, ML (deceased), who contributed as an author to earlier versions of this topic review.