MALIGNANT hyperthermia (MH) is an inherited disorder of skeletal muscle that manifests clinically as a hypermetabolic crisis when a susceptible individual receives a halogenated inhalational anesthetic agent or succinylcholine.1–3 The clinical signs that ensue from this exposure in susceptible individuals include hypercapnia, masseter muscle and/or generalized muscle rigidity, acidosis, peaked T waves that indicate hyperkalemia, and hyperthermia and are caused by the dysregulated entry of myoplasmic calcium, which results in a hypermetabolic cascade involving sustained muscular contractures, depletion of adenosine triphosphate, and muscle cell death.4 The inheritance of pathogenic variants (i.e., mutations) in three genes are primarily associated with MH susceptibility and account for the genetic basis of approximately 70% of patients investigated (fig. 1). The majority of MH–associated variants are found within the RYR1 gene that encodes the skeletal muscle ryanodine receptor type I protein.2,5–7 This protein regulates the movement of calcium from the sarcoplasmic reticulum into the intracellular space of the muscle cell. In MH–susceptible individuals, abnormalities of the ryanodine receptor result in the accumulation of excessive myoplasmic calcium in the presence of one of the anesthetic triggering agents. Nearly 700 variants have been identified in RYR1; however, only 35 have been functionally validated as MH–causative pathogenic variants (an up-to-date list as well as the criteria for causality may be found at the European Malignant Hyperthermia Group website).8 The remainder await validation studies.
The most common RYR1 variants that confer susceptibility to MH result from gain-of-function mutations in specific amino acids and regions of the RYR1 protein. These mutations may arise de novo or may be inherited, and the MH phenotype manifests variable expressivity and incomplete penetrance. Inheritance of MH causative pathogenic variants is suspected in individuals with a history of a likely MH clinical event or in those patients with a family history of MH susceptibility or a likely MH event. The mainstay of prevention of MH is the identification of these genetically susceptible individuals so that clinicians can then avoid triggering anesthetic agents.
There is a wide range of both dominant and recessive disorders associated with RYR1 pathogenic variants, and many of these inherited myopathies and related conditions have been linked with MH susceptibility.9–11 Therefore, in clinical anesthesia practice, MH susceptibility has often been assumed in patients with nonspecific muscle weakness but without a definitive diagnosis. This shotgun approach is less than ideal because most causes of muscle weakness are not associated with MH susceptibility, and this process then only results in the inaccurate labeling of patients (and their families) who would otherwise be able to safely receive volatile anesthetic agents and succinylcholine.
In this article, we build upon and summarize a body of data that have linked specific genotypic or phenotypic findings with susceptibility to MH and offer suggestions to anesthesiologists about the types of patients that should or should not receive a trigger-free general anesthetic. We discuss anesthetic management of certain congenital myopathies that may predispose to MH–like symptoms during general anesthesia, and we offer an approach to the anesthetic management of the undiagnosed patient with muscle weakness.
Diseases Associated with MH Susceptibility
The most common diseases associated with MH susceptibility are those associated with known RYR1-associated phenotypes, the “ryanodinopathies” (table 1). Not all patients with one of these clinical phenotypes or a proven RYR1 myopathy will assuredly be susceptible to MH, but because MH susceptibility and myopathy co-occur in a relatively large percentage of individuals with an RYR1 pathogenic variant (estimated to be at least 30% of individuals with RYR1 myopathies),12 they should be considered MH–susceptible unless proven negative by a specialized MH contracture biopsy.*17,18 In addition, it must be stressed that the clinical spectrum of the ryanodinopathies is broad, often changes with the age of the patient, and is potentially variable even within the same family where the causative pathogenic variants are the same.10
Patients with an RYR1 pathogenic variant, whether or not they exhibit MH susceptibility, may appear clinically normal and may not demonstrate typical phenotypic findings of a neuromuscular disease. In fact, most patients who have demonstrated clinical MH and who have an RYR1 variant have no overt clinical phenotype.19–21 Some may even demonstrate enhanced muscle mass and above average athletic skills.22 A subset of these phenotypically normal patients may develop rhabdomyolysis in response to certain conditions such as heat, exercise, administration of statin medications, or viral illness.23–32 It is estimated that MH–related RYR1 pathogenic variants may account for between 20 and 30% of cases of heat- or exercise-induced rhabdomyolysis.4 Some of these patients may demonstrate an elevated baseline serum creatine kinase level,6 and some may exhibit bleeding tendencies.33 Patients without a phenotypic or genotypic diagnosis that have demonstrated exaggerated or frequent muscle breakdown under normal or atypical conditions should be assumed to have an underlying RYR1 pathogenic variant that confers MH susceptibility, should not receive anesthetic triggering agents, and should undergo diagnostic neuromuscular and genetic evaluation.34–38
Some patients with an RYR1 variant demonstrate a clinically evident myopathy of varying degrees in the absence of administration of anesthetic triggering agents.39,40 In fact, RYR1 variants are the most common cause of nondystrophic muscle disease in children.4 Histopathologic phenotypes that have been associated with RYR1 variants include central core disease,40,41 multiminicore myopathy,40,42–45 congenital myopathy with cores and rods,46,47 centronuclear myopathy,48 and congenital fiber type disproportion.49 Importantly, however, patients with RYR1 variants may have histopathologic findings that change with age and also may only have nonspecific myopathic or dystrophic changes. Patients with an RYR1 variant may manifest King–Denborough syndrome, an extremely rare but classically described condition that is characterized by dysmorphic features, abnormal gait, and MH susceptibility.50–53
For the various histopathologic subtypes of congenital myopathy, only those individuals with an RYR1 variant (as well as CACNA1S and STAC3, see below) are linked to MH susceptibility. However, many of these patients have been phenotyped (i.e., histologic findings on muscle biopsy plus clinical characteristics) without confirmatory genetic analysis and thus are also considered MH–susceptible before genetic testing studies. Conversely, patients with these phenotypes and a confirmed causative variant other than RYR1 are not considered MH–susceptible. As an example, a patient with nemaline myopathy associated with a confirmed RYR1 variant is considered MH–susceptible,54 whereas a patient with the same disease caused by a variant of NEB or ACTA1 (among others) would not be considered MH–susceptible and does not need MH precautions.
It is well known that patients with acute or progressive muscle atrophy (i.e., congenital myopathy patients and many individuals with other forms of muscle disease) may demonstrate exaggerated release of myoplasmic potassium after administration of succinylcholine.55,56 Although these patients should not receive succinylcholine, it is not for the purpose of avoiding MH. This is discussed more fully below.
Less common loci of causality of MH susceptibility (approximately 2% of cases) are variants in the α-1 subunit of the dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor (CACNA1S), also part of the excitation–contraction complex in skeletal muscle. MH causative variants in CACNA1S have been associated with a normal clinical phenotype,57–59 as well as with congenital myopathies that resemble some subtypes of RYR1 myopathy60,61 and dynamic phenotypes like potassium-related periodic paralysis.62,63 Patients with periodic paralysis without genetic confirmation and those with a documented MH–causative RYR1 or CACNA1S variant should be considered MH–susceptible. It is not yet clear whether patients with recessive CACNA1S-related myopathies will be at risk of MH and for now should be considered MH–susceptible until further data are available.61 Periodic paralysis is also associated with variants in SCN4A, which is not associated with MH susceptibility.64,65
Last, MH susceptibility is associated with pathologic variants in the STAC3 gene. These variants are manifested most commonly as Native American myopathy,66–68 a rare disorder found in the Lumbee Native Americans of North Carolina. More recently, individuals with MH outside of the Lumbee population have also been reported to have STAC3 variants, but the exact association between STAC3, MH susceptibility, and the other features of Native American Myopathy are not yet clear.
In the modern era of increasingly accessible genetic analysis, we can now more precisely associate certain diseases with MH susceptibility based on the presence of similar variants that alter the contractile apparatus and its response to exposure to anesthetic triggering agents. However, there is no definitive method by which to characterize with certainty the link between an inherited condition and MH susceptibility. Therefore, patients with a personal or family history of an MH–like event related to the administration of general anesthesia and who have demonstrated the presence of an RYR1, CACNA1S, or STAC3 gene variant should be considered MH–susceptible unless proven negative by contracture biopsy. Patients with associated phenotypes that have not been characterized by genotype should also be considered MH–susceptible until found to have an unrelated variant that is not associated with MH susceptibility.
Diseases Associated with Non-MH Anesthetic-induced Rhabdomyolysis
Some myopathic conditions have been associated with the development of fatal or life-threatening rhabdomyolysis upon exposure to volatile anesthetic agents or succinylcholine (table 2). The most common of these conditions are Duchenne and Becker muscular dystrophy. Although rhabdomyolysis with hyperkalemia can be a feature of MH, the MH syndrome usually manifests signs of hypermetabolism, such as respiratory acidosis, metabolic acidosis, and excessive heat production. The development of life-threatening rhabdomyolysis with hyperkalemia after administration of succinylcholine to patients with Duchenne or Becker muscular dystrophy is well documented;69 therefore, succinylcholine is contraindicated in patients with these disorders and other conditions with acute or progressive muscle atrophy (e.g., acute burns, stroke, and others).55 The use of volatile anesthetics without succinylcholine have been reported to cause non–MH–related rhabdomyolysis and hyperkalemia in patients with these dystrophies,70–75 and even though published case series have documented the safe administration of volatile agents to patients with Duchenne and Becker dystrophy,76,77 some authors and patient organizations have advocated the strict avoidance of volatile anesthetics in this patient population.78–81 Conversely, the use of intravenous anesthesia alone has been implicated in the development of heart failure related to preexisting disease in patients with Duchenne dystrophy.82,83 Thus, existing and potential comorbidities (i.e., cardiac and respiratory dysfunction) in this patient population may also be important factors that determine overall perioperative outcomes.84 Other myopathies reported to be associated with rhabdomyolysis around the time of administration of general anesthesia include carnitine palmitoyltransferase type 2 deficiency85,86 and merosin-deficient congenital muscular dystrophy.87,88 There is currently insufficient evidence to make firm suggestions for avoidance of MH–triggering anesthetics in patients with these phenotypic entities.
There exist a number of case reports that describe distinct phenotypic entities that have, on occasion, demonstrated MH or an MH–like syndrome (i.e., hyperthermia, rhabdomyolysis, and others) in response to volatile anesthetic agents. Invariably, these reports do not contain enough information to confirm a clinical diagnosis of MH, and there is not an established genetic link between the phenotype and an MH–associated genotype. For these reasons, we do not consider them to have a known or suggested association with MH susceptibility. They include Schwartz–Jampel syndrome, Noonan syndrome, arthrogryposis multiplex congenita, all mitochondrial myopathies, osteogenesis imperfecta, and Freeman–Sheldon syndrome.89–94
Approach to Undiagnosed Hypotonic Patients
One of the most vexing clinical situations faced by anesthesiologists is how to determine the MH–susceptibility status of a hypotonic and/or weak patient that has not yet received a phenotypic or genotypic diagnosis. Although the clinical spectrum of the ryanodinopathies is extensive,95 it would be unreasonably cautious to consider all hypotonic patients (and their extended families) to be MH–susceptible because most hypotonia in children is central in origin.96 Because RYR1 variants presently constitute the most common nondystrophic type of congenital muscle disease, we suggest that genetic testing be performed before muscle biopsy because current recommendations for the evaluation of congenital myopathies and congenital muscular dystrophies are now favoring genetic testing before biopsy in the diagnostic process.97 However, in the absence of a diagnosis, patients should be considered MH–susceptible when they possess any of the following clinical characteristics: (1) statement from the patient’s primary physician or other healthcare worker that they or a closely related family member are suspected to have an RYR1-, CACNA1S-, or STAC3-related myopathy based on their medical history or physical findings; (2) personal or closely related family history of suspected MH during general anesthesia with triggering agents in the absence of a negative contracture biopsy (i.e., caffeine–halothane contracture test or in vitro contracture test); or (3) personal or closely related family history of frequent exaggerated episodes of creatine kinase increase, rigidity, or evidence of rhabdomyolysis in response to exercise, heat exposure, or statin administration.
Ideally, infants with hypotonia should have a neurologic consultation before the administration of general anesthesia to provide the anesthesia team with the best possible information about their diagnosis and risk of MH susceptibility. In neonates with hypotonia, nearly all underlying diagnoses are not associated with an increased risk of MH. Most cases of neonatal hypotonia are caused by central nervous system dysfunction such as hypoxic ischemic encephalopathy or chromosomal syndromes such as trisomy 21, and these conditions are distinguishable from myopathies by history and examination. In the setting of weakness in an older child where a muscle disease may be suspected, nontriggering agents may be considered until the appropriate diagnosis has been established or when RYR1, CACNA1S, and STAC3 mutations have been excluded. However, the extensive clinical experience of the authors has shown that these conservative measures are unnecessary because of the paucity of cases of intraoperative MH in these undiagnosed children when triggering anesthetics are used.
Anesthesiologists should be well versed about the anesthetic implications of the diagnoses and should consult with an MH expert from the Malignant Hyperthermia Association of the United States to determine the risk of MH with triggering agents. The decision about the most appropriate anesthetic technique should be discussed beforehand with the surgical team as well as with the patient, and/or their parents when applicable, especially when the diagnosis is unknown.
Who Needs a Nontriggering Technique?
In this review, we attempted to develop a categorization scheme that uses phenotypic and genotypic classifications to determine the types of diseases that are linked with MH susceptibility (table 3). Nearly all of the diseases associated with MH susceptibility can reasonably be assumed to be due to pathogenic variants in RYR1, with a few additional patients having variants of CACNA1S and STAC3 that are also associated with MH susceptibility. Although the preponderance of patients with MH susceptibility may appear phenotypically normal, MH is associated with certain defined clinical phenotypes related to RYR1 variants including but not limited to central core disease, multiminicore myopathy, congenital myopathy with cores and rods, congenital fiber type disproportion, centronuclear myopathy, and, rarely, King–Denborough syndrome. An increased incidence of MH susceptibility has also been noted in patients that have experienced exaggerated and repeated (and sometimes fatal38 ) rhabdomyolysis as a result of heat, exercise, or statin administration. A unique situation that may occasionally be encountered is a patient with a proven RYR1 variant that has not been strictly characterized as causative according to the European Malignant Hyperthermia Group criteria. The MH susceptibility status of these patients should be made on a case-by-case basis, taking into account other pertinent factors in the history and physical examination, such as evidence of previous MH in the patient or their family and input from experts in the genetic testing for MH.14
Until further knowledge in this area has accumulated, there will be areas of uncertainty where anesthesiologists will have to use their contextual clinical judgment regarding whether to proceed with a nontriggering technique without definitive cause, thus labeling the patient and their family as MH–susceptible for an indefinite period. For example, in Brody myopathy with fast-twitch skeletal muscle sarcoplasmic reticulum Ca2+ adenosine triphosphatase mutations,98 there is only slight evidence of a possible link between the disease and MH susceptibility,99 but the pathophysiologic aspects of the disease would suggest that anesthetic triggering agents may cause an abnormal increase in myoplasmic calcium, triggering an MH–like event. In cases like this, avoidance of triggering agents is probably the safest approach, even though a definitive link is unproven. A more common example where anesthesiologists must use their contextual judgment is when a healthy patient presents with a vague history of a relative who developed hyperthermia in the perioperative period, often in the distant past, and no medical records about that relative’s episode are available. This situation should prompt a thorough, yet time-sensitive review of the medical history of the family in an attempt to search for comorbidities, other complications or MH–like episodes during anesthesia, and occurrences of previous anesthetics with and without triggering agents. Administration of both triggering and nontriggering agents may be reasonably justifiable, depending on the individual circumstances.
Other degenerative primary muscle disorders, such as Duchenne or Becker muscular dystrophy, are associated with development of life-threatening rhabdomyolysis during or immediately after exposure to triggering agents, but this response does not represent classic MH because of the lack of concomitant hypermetabolic symptoms. These patients should not receive succinylcholine or inhaled anesthetic agents unless indicated for unavoidable clinical reasons.
The authors gratefully acknowledge the assistance of the anonymous reviewers, who greatly enhanced the quality of this paper, and Henry Rosenberg, M.D., director of medical education and clinical research, Saint Barnabas Medical Center, Livingston, New Jersey, for his lifelong dedication to helping patients with MH, and for his unselfish collegiality that made possible the academic careers of many MH researchers and educators, and resulted in the publication of this paper.
Support was provided solely from institutional and/or departmental sources.
The authors declare no competing interests.
MH contracture testing is considered the “gold standard” for diagnosis of an individual’s MH susceptibility and is the only way to rule out MH susceptibility. In North America, it is referred to as the caffeine–halothane contracture test (CHCT), and in Europe, it is referred to as the in vitro contracture test (IVCT). Although there are minor differences in methodology, both contracture tests are based on the contractile response of the individual’s fresh muscle tissue when it is bathed in caffeine and halothane. The sensitivity (true negative) of the CHCT is 97% (95% CI, 84 to 100%),13 and the sensitivity of the IVCT conducted according to the European Malignant Hyperthermia Group protocol has been reevaluated as 100%.14 Therefore, patients who have tested negative by CHCT or IVCT are ruled out for MH susceptibility and may safely receive triggering agents.15,16