Definition
Malignant hyperthermia (MH) is a pharmacogenetic disorder that manifests as a hypermetabolic response to potent inhalation agents (such as halothane, isoflurane, sevoflurane, desflurane), the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to stressors such as vigorous exercise and heat. The two genes that have been definitively associated with MH causative mutations are RYR1 and CACNA1S, which will be discussed later.
As almost all patients who are MH susceptible have no phenotypic changes without anesthesia, it is impossible to diagnose susceptibility without either exposure to the “trigger” anesthetics or by specific diagnostic testing. The key clinical features include an unexplained elevation of expired carbon dioxide, despite increased minute ventilation, muscle rigidity and rhabdomyolysis, hyperthermia, tachcardia, acidosis and hyperkalemia. The majority of patients with Central Core Disease (CCD), an inherited myopathy characterized by muscle weakness, are susceptible to MH. Multi-minicore Disease (MmD), central nuclear myopathy and King-Denborough syndrome also predispose to episodes of MH.
Epidemiology
The incidence of MH episodes during anesthesia is between 1:10,000 and 1:250,000 anesthetics [
1,
2]. Even though an MH crisis may develop at first exposure to anesthesia with those agents known to trigger an MH episode, on average, patients require three anesthetics before triggering. Reactions develop more frequently in males than females (2:1) [
3,
4]. All ethnic groups are affected, in all parts of the world. The highest incidence is in young people, with a mean age of all patients experiencing reactions of 18.3 years. It has been found that children under 15 years age comprised 52.1 % of all reactions [
5]. Although described in the newborn, the earliest reaction confirmed by testing is six months of age [
6]. The oldest is 78 years.
The estimated prevalence of genetic abnormalities associated with MH susceptibility may be as great as one in 3000 individuals (range 1:3000 to 1:8500), with a more recent estimate being 1 in 400 [
7].
Mauritz et al. [
8] found an incidence of 1:37,500 in patients who had been diagnostically tested, which was similar to the incidence estimated by Robinson et al. (1:30,000) [
9] although wide variability has been reported. A recent report suggested that the MH susceptible (MHS) trait may be present in 1:2000–3000 of the French population [
10]. A similar incidence was reported for the Japanese population [
11]. Bachand and colleagues traced the pedigrees of MH patients in Quebec, Canada to the original immigrants from France and found an incidence of MH susceptibility of 0.2 % in this province. However, that represented only five extended families. Similarly 1/200 patients presenting for anesthesia in the Manawatu region of New Zealand are either susceptible or related to MHS individuals (unpublished data – N Pollock, T Bulger).
A study of 12 million hospital discharges in the state of New York demonstrated the prevalence of MH to be one in 100,000 surgical procedures although the type of anesthetic was not indicated. This likely represents an underestimate of MH in association with general anesthesia [
4].
MH crises develop not only in humans but also in other species, particularly pigs, which have been a valuable source for research. Reactions have also been described in horses, dogs and other animals [
12].
Clinical description
MH may occur at any time during anesthesia as well as in the early postoperative period, but not after an hour of discontinuation of volatile agents [
13]. The earliest signs are tachycardia, rise in end-expired carbon dioxide concentration despite increased minute ventilation, accompanied by muscle rigidity, especially following succinylcholine administration. Body temperature elevation can be a dramatic sign of MH. Larach et al. found that increased temperature was the first to third earliest sign in 63.5 % of MH reactions [
14]. This confirms Sessler’s comment that core temperature should be monitored in most patients undergoing general anesthesia for periods lasting more than 30 min and in all patients with anesthesia lasting 60 mins [
15].
Although end-tidal carbon dioxide (ETCO
2) is a sensitive early sign of MH [
16], in recent years, with a decline in the use of succinylcholine, rather than an abrupt rise in CO
2, a more gradual rise is often noted. Indeed, by increasing minute ventilation it is possible to mask this rise [
17].
Hyperthermia can be marked, with an increase in core temperature at a rate of 1–2 °C every five minutes. Severe hyperthermia (core temperature greater than 44 °C) may occur, and lead to a marked increase in oxygen consumption, CO
2 production, widespread vital organ dysfunction, and disseminated intravascular coagulation (DIC) [
18].
Uncontrolled hypermetabolism leads to respiratory and in most cases metabolic acidosis due to rapid consumption of energy stores and ATP. If untreated, continuing myocyte death and rhabdomyolysis result in life-threatening hyperkalemia; myoglobinuria may lead to acute renal failure. Additional life-threatening complications include DIC, congestive heart failure, bowel ischemia, and compartment syndrome of the limbs secondary to profound muscle swelling. Indeed, when body temperature exceeds approximately 41 °C, DIC is the usual cause of death.
Disorders associated with malignant hyperthermia
Succinylcholine induced masseter muscle rigidity (MMR) occurs in 1 in 100 children with anesthesia induced by halothane and given succinylcholine [
31]. The incidence is probably the same following induction with sevoflurane, but much less following induction with thiopental [
32]. The clinical incidence of MH as defined by arterial blood gas changes is about 15 % after MMR. However, muscle biopsy reveals that 50 % of patients experiencing MMR are MH susceptible [
33]. Patients with generalized rigidity along with MMR are at much greater risk for MH. Kaplan (personal communication,) has hypothesized that children with “jaws of steel” as opposed to mild rigidity after administration are at greater risk for MH. He has hypothesized that the children with the more dramatic masseter rigidity are more often referred for biopsy and hence the high incidence of positive biopsies.
Central Core Disease (CCD) is a rare non-progressive myopathy with mainly autosomal dominant inheritance, presenting in infancy and characterized by hypotonia and proximal muscle weakness. A few families demonstrate autosomal recessive inheritance. Histological examination of affected muscles shows a predominance of type I fibres containing clearly defined areas (cores) lacking oxidative enzyme activity [
34‐
36].
CCD patients are often susceptible to MH as confirmed by accepted muscle biopsy caffeine-halothane contracture testing (either IVCT or the CHCT-caffeine halothane contracture test – see laboratory diagnostic methods section), but MH and CCD phenotypes do not always co-segregate within families. Patients with MH may present with cores despite being clinically asymptomatic and with some
RYR1 variants (specifically some of those in the C-terminal transmembrane domain of the protein) specific to CCD. DNA Sequencing showed that
RYR1 variants occurred in over 93 % (25 out of 27) of Japanese patients with CCD [
37]. While this is of importance, it may not reflect the incidence of
RYR1 mutations in other populations. Another study indicated that the distribution and frequency of
RYR1 variants differed markedly in the Japanese MH susceptible population as compared to the North American and European MH susceptible population [
11]. Although
RYR1 variants are the most common identified cause of CCD, it does show genetic heterogeneity, with several rare susceptibility loci known (the
ACTA1 gene, in association with nemaline myopathy, and the
MYH7 gene, in association with hypertrophic cardiomyopathy), with further loci yet to be identified [
38].
Other myopathies that have been suggested to be associated with MH susceptibility include MmD and centronuclear myopathy. MmD is an early onset congenital myopathy that may affect bulbar, respiratory and extraocular muscles and has autosomal recessive inheritance [
39]. Recessive variants in
RYR1 have been associated with MmD, some of which result in altered Ca
2+ release from intracellular stores and others that do not [
40]. Taken together, these observations suggest that there may be a subset of
RYR1 variants that result in both MH and MmD and a subset that are associated only with MmD, similar to the situation with MH and CCD. Consequently, it will be important to distinguish between
RYR1 variants that result in MmD, and those that do not.
King (or King-Denborough) syndrome [
41] is a rare myopathy characterized by dysmorphic facies, ptosis, down-slanting palpebral fissures, hypertelorism, epicanthic folds, low-set ears, malar hypoplasia, micrognathia, high-arched palate, clinodactyly, palmar simian line, pectus excavatum, winging of the scapulae, lumbar lordosis and mild thoracic scoliosis. The patients with King-Denborough syndrome also present congenital hypotonia, slightly delayed motor development, diffuse joint hyperextensibility and mild proximal weakness. Such patients are MH susceptible. Gillies et al. identified a causative mutation in one family affected with King-Denborough syndrome [
42]. Dowling however, did not find a causative mutation to be a consistent feature in this syndrome [
43].
Etiology
MH is considered to be a pharmacogenetic disorder which results in a hypermetabolic state [
44]. Experimental evidence clearly indicates that the signs and symptoms of MH are related to an uncontrolled release of intracellular Ca
2+ from skeletal muscle sarcoplasmic reticulum (SR) [
45]. In MH susceptible swine and in “knock-in” mice, a variety of environmental conditions can trigger accelerated Ca
2+ release from the SR such as environmental heat, exercise and stress. In humans, however, clinical MH results most often from exposure to potent inhalation anesthetics +/− succinylcholine. The enhanced intracellular Ca
2+ results in abnormal skeletal muscle metabolism manifesting as activation of muscle contraction, increased oxygen consumption and CO
2 production, ATP hydrolysis and heat production. The normal sequestration of released Ca
2+ by the SR/ER Ca
2+ -ATPase (SERCA) is inadequate and energy is expended in a futile manner, in an attempt to lower intracellular Ca
2+. Presumably, the declining levels of ATP lead to failure of membrane integrity and release of potassium and CK, although the exact steps in the process have not been definitively demonstrated.
A defective or disordered Ca
2+ channel located in the SR membrane underlies MH susceptibility. This channel is termed the ryanodine receptor (RyR1). As many as 70 % of families susceptible to MH harbor one of 34 causal mutations for MH, with many other variants yet to be characterized [
46]. The channel is closely associated with many other proteins, such as the dihydropyridine receptor (DHPR) Ca
2+ channel, situated in the T-tubule region of the sarcolemma that mediates transfer of voltage change to the RyR1 receptor. Other proteins with potential or known roles in RyR1 function include integral SR membrane proteins (eg. SRP-27 [
47], junctate [
48], the transient receptor potential cation channel (TRPC) family [
48‐
50] and triadin [
51]), plasma membrane-associated proteins (eg. CIC-1 chloride channels [
52] and Na
+/Ca
2+ exchangers [
53]), as well as proteins that appear to have a role in stabilizing the junction between the plasma membrane and sarcoplasmic reticulum (eg. junctophilin and caveolin-3) by interacting with both DHPR and RyR1 [
54]. Proteins that modulate the function of RyR1 include the FK508 binding protein FKBP12 [
55], the Ca
2+ binding protein calmodulin [
56], the histidine-rich Ca
2+ protein, HRC [
57] and the luminal Ca
2+ buffer calsequestrin. HRC is also a luminal protein known to interact with both triadin and SERCA and has been suggested to have a role in mediating cross talk between SR Ca
2+ uptake and release [
57].
At least six genetic loci, other than
RYR1 have been implicated in MH, although only one other gene,
CACNA1S, encoding the main subunit of the DHPR, has been shown to be altered by an MH-linked variant [
58‐
60]. Calsequestrin has been suggested as another candidate for MH from studies using a
CASQ1 knock-out mouse [
61‐
63]. These mice exhibited susceptibility to heat- and anesthetic-induced mortality, analogous to MH. While some
CASQ1 variants have been identified in humans [
64], there is thus far no definitive evidence that variants in this gene can cause MH [
65]. Recently, a variant in the
STAC3 gene has been linked to MH susceptibility in a native American tribe in the USA [
66]. Ablation of
stac3 in Zebrafish results in a severe locomotor defect and a decrease in excitation-contraction coupling [
67].
STAC3 knock-out mice exhibit paralysis and perinatal lethality as well as a range of musculoskeletal defects [
68]. In support of a role in excitation-contraction coupling, the STAC3 protein was shown to traffic together with the DHPR and has been suggested to be an essential chaperone of DHPR in skeletal muscle [
69].
JP-45, encoded by
JSPR1, is another integral SR protein that has been shown to colocalize with the RyR1 and also interacts with the DHPR and calsequestrin. Overexpression of JP-45 in a mouse myotube cell line has been shown to decrease charge movement through the DHPR. Depletion of JP-45 in the same system decreased both the content of DHPR and charge movement through this channel [
70]. Two
JSPR1 variants have been recently identified in patients with and without MH. Expression of either one of these JP-45 variants in mouse muscle fibres exhibited a decrease in the sensitivity of DHPR to activation. These results suggest that the overall phenotype of an individual with both a
JSPR1 mutation and a causative
RYR1 mutation would be less severe than if the
RYR1 mutation was expressed alone [
71]. These observations highlight the possibility of polymorphic variants modulating
RYR1 function and may help to explain the variable phenotype observed for MH susceptibility [
9,
72].
Genotype-phenotype correlations are weak for both the clinical expression of MH and the response of isolated muscle to caffeine or halothane. It therefore seems clear that a variety of modulators influence the manifestations of the syndrome. Fatty acids represent one set of modulators that has been studied in this respect [
73,
74]. Certain unsaturated fatty acids have been demonstrated to increase the sensitivity of halothane-induced Ca
2+ release
in vitro. Such an increase in fatty acids may result from breakdown of triglycerides as a result of enzymatic abnormalities. More recently, a decrease in S-palmitoylation at cysteine residues in the N-terminal region of RyR1 has been shown to decrease stimulus-coupled Ca
2+ release via RyR1 [
75]. Ryanodine receptor function can also be altered by other post-translational modifications. Phosphorylation, glutathionylation, oxidation and nitrosylation of
RyR1 have each been shown to modulate Ca
2+ release from the SR, but the causes and functional consequences of these modifications are not well defined [
76‐
80]. Eight of the eighteen cysteine residues subject to S-palmitoylation are also targets for N-nitrosylation or S-oxidation, suggesting that post-translational cross-talk may have a role in regulating RyR1 [
75]. SERCA and the DHPR are also subject to S-palmitoylation suggesting that fatty acids may have more extensive roles in excitation-contraction coupling and hence MH.
In addition, cultured muscle cells from MH susceptible patients show a shift of subtypes of sodium channels leading to a longer membrane depolarization and an increased Ca
2+ release from the terminal cisternae [
81,
82]. Changes in sodium channel function, either through sodium channel mutations or through effects of fatty acids may influence the phenotypic expression of MH, especially muscle rigidity.
Ca
2+ depletion of the SR via skeletal muscle RyR1 activity has also been shown to induce Ca
2+ influx across the plasma membrane. Both store-operated Ca
2+ entry (SOCE) and excitation-coupled Ca
2+ entry (ECCE) are involved [
83‐
85]. While the exact mechanisms that control these phenomena are unclear, membrane proteins such as STIM1, Orai1 and the TRPCs have been implicated, as have their potential interactions with RyR1 [
86]. The DHPR is thought to be a major contributor to ECCE [
87]. STIM1 and Orai1 have been shown to colocalize to the skeletal muscle triad junction [
88]. In another study, STIM1 was shown to interact with the DHPR in a Ca
2+-independent manner and overexpression of STIM1 attenuated Ca
2+ -release in a DHPR receptor-dependent manner suggesting that STIM1 negatively regulates Ca
2+-release from the SR [
89] and thus may be involved in both SOCE and excitation-contraction coupling. Muscle cells from the
RYR1 R163C mutant mouse exhibited elevated myoplasmic free Ca
2+ due to a passive leak from the SR. Inhibition of non-specific plasma membrane cation channels in these cells was more effective at reducing Ca
2+ entry and myoplasmic free Ca
2+ than overexpression of a dominant negative Orai1. These results suggested that SOCE was not due to a STIM1/Orai1 pathway but to a non-specific plasma membrane channel, which in turn has been implicated in the MH phenotype [
90]. Thus functional dysregulation associated with any one of these proteins could also affect the function of RyR1 and have implications for susceptibility to MH.
Transfecting cultured muscle cells or myotubes with one of the known causal mutations results in enhanced intracellular Ca
2+ release when the cells are exposed to agents such as halothane, caffeine or 4-chloro-m-cresol [
91‐
96]. Several mouse models of MH have been developed by introducing the rabbit
RYR1 cDNA into the dyspedic mouse [
97], providing insights into the functional significance of introduced
RYR1 variants [
98‐
103]. It is clear from these studies that different
RYR1 variants have different functional effects and that not every
RYR1 variant when expressed in a mouse model will exhibit a classic MH-sensitive phenotype. For example
RYR1 R163C [
104] or Y522S [
98] heterozygous knock-in mice exhibit symptoms like MH and are associated with increased flux of Ca
2+ into the cytosol, while the I4898T (I4895T in mice) CCD variant causes muscle weakness, likely due to a reduction in Ca
2+ release [
105]. In addition, the Y522S homozygous mice are non-viable, while R163C and T4826I homozygous mice are viable.
Laboratory diagnostic methods
The “gold standard” for diagnosis of MH is currently an
in vitro contracture test, which is based on contracture of muscle fibers in the presence of halothane or caffeine. Two widely used forms of this test have been developed; one (IVCT) by the European Malignant Hyperthermia group (EMHG) and the other (CHCT) by the North American Malignant Hyperthermia Group (NAMHG) [
108,
109]. Using the EMHG protocol, an individual is considered susceptible to MH (MHS) when both caffeine and halothane test results are positive. An individual is considered not susceptible to MH (MHN) when both tests are negative. An individual is also diagnosed as MHS when either a positive halothane or caffeine test alone is obtained and these individuals are designated MHS(h) or MHS(c). This nomenclature was determined at the 32
nd EMHG meeting in Basel, Switzerland, 2013. This test is similar to the NAMHG protocol but there are differences in the concentrations used and mode of testing agents. Sensitivity of 99 % and a specificity of 94 % are obtained with the EMHG protocol [
110] while figures of 97 % sensitivity and 78 % specificity are reported for the NAMHG protocol [
111], which provide some confidence to the results obtained. The specificity of either protocol may be affected by neuromuscular disorders unrelated to MH, which have an associated increase in myoplasmic Ca
2+ concentration [
109,
112]. Studies based on results from monozygotic twins however, indicate that the IVCT has acceptable reproducibility [
113]. A third variation of the IVCT, the caffeine skinned fiber test, does not appear to be used diagnostically outside of Japan, and has lower specificity and sensitivity than either the EMHG or NAMHG protocols [
114].
IVCT is expensive, confined to specialized testing centers, requires a surgical procedure and can yield false positive or negative results. Modifications of the EMHG protocol include the use of ryanodine [
115] or 4-chloro-m-cresol [
116] (but to date these agents have not been included in the standard protocol). A possible alternative testing agent is the fluorinated ether sevoflurane, however trials with this agent have not found responses consistent with halothane [
117].
Other biochemical, hematological and physical tests lack significant sensitivity and specificity to be used diagnostically. A further caveat with these tests is that the results may be difficult to interpret in a patient suffering from a myopathy other than MH such as Duchenne Muscular Dystrophy where intracellular Ca2+ is elevated at baseline.
A variety of minimally invasive diagnostic tests have been investigated. These include nuclear magnetic resonance spectroscopy to evaluate ATP depletion [
118], metabolite assays and microdialysis of caffeine to elicit an enhanced release of carbon dioxide from the muscle tissue [
119]. The ethics of injecting a triggering agent, even a small volume into a potentially susceptible individual have to be questioned and determination of cutoff points would be difficult.
DNA analysis, however, offers an alternative to the IVCT, requiring only a blood specimen, which can be sent to an accredited diagnostic laboratory. To date 50 to 70 % of MH susceptibility has been linked to
RYR1 with over 400 variants associated with MH being identified within this gene [
120]. While the majority of variants lead to a single amino acid change in the receptor, deletions or truncations have also been reported. A number of recessive variants result in MH, CCD or related disorders [
121‐
124].
At least 44 variants have been reported in the
RYR1 gene in association with CCD. In general terms, a single point
RYR1 variant can cause (a) CCD only, (b) MH only, (c) MH with variable CCD penetrance. In this latter case, the likelihood of an
RYR1 mutation resulting in both MH and CCD depends on a number of factors including sensitivity of mutant protein to agonists, size of the intracellular Ca
2+ pool and the level of abnormality in channel-gating [
125]. All individuals with the variant should be considered as MH susceptible, while they may or may not have CCD. If a variant specific to CCD is identified in a family, MH is not automatically excluded as a second variant may be present and MH susceptibility needs to be assessed by IVCT or CHCT or family members treated as if they are MH susceptible [
126]. An MH negative parent eliminates susceptibility in the children although CCD may still be present.
While traditional DNA sequencing from either genomic DNA or complementary DNA prepared from muscle biopsy tissue are time consuming and laborious, the advent of massively parallel sequencing (or next generation sequencing, NGS) provides potentially cost effective, rapid and high throughput platforms for both variant discovery and diagnosis at the whole genome level [
127]). A number of
RYR1 or
CACNA1S variants have been identified using next generation sequencing (NGS) [
128‐
131]. Some caution in this approach should however, be exercised as none of the currently available platforms for sequencing, or chemistry for sample preparation, or analysis software are able to yield 100 % coverage of all exons in the human genome [
132]. Pathogenicity prediction is problematic (see below) and an additional consideration is the ethical dilemma associated with the reporting of incidental findings [
133].
The EMHG has established criteria including functional studies of DNA variants to establish that the variant is clinically significant [
134]. Thirty-four mutations within
RYR1 have been shown to cause an alteration in Ca
2+ release from intracellular stores. A number of functional tests have been used successfully to assess the role of
RYR1 variants in Ca
2+ release. These include the use of lymphoblastoid cell lines generated from MHS individuals [
40,
135‐
138], COS-7 or HEK293 cells transfected with the cDNA for rabbit or human [
93,
95]
RYR1 carrying point mutations introduced by site-directed mutagenesis, myotubes generated from muscle biopsy tissue and 1B5 dyspedic myotubes transduced with wild type or mutated
RYR1 cDNA [
97,
139,
140]. Ca
2+ release can be monitored and quantified directly using Ca
2+-specific indicators or indirectly using [
3H] ryanodine binding assays [
94] or by proton release [
138,
141]. Systems using 1B5 dyspedic myotubes are more physiological as they constitutively express all the components of the skeletal muscle with the exception of
RYR1 [
97]. To date, all mutations functionally characterized have been shown to cause alterations in Ca
2+ flux through the ryanodine receptor Ca
2+ release channel.
Pathogenicity prediction of new variants
Whole exome or targeted exon NGS is becoming the preferred option for variant detection and is being used diagnostically. The vast numbers of identified variants of unknown significance (VUS), which may or may not be associated with a certain disease have to be filtered. This is a significant bottleneck in DNA-based diagnosis for MH because of the large size of the RYR1 gene, the large number of known uncharacterized variants and the technical difficulty involved with functional analysis. To be able to predict accurately the pathogenicity for a specific variant would considerably aid diagnosis and prevention of MH episodes.
There are many bioinformatic tools freely available (for example PolyPhen2 [
142], Pmut [
143], SIFT [
144], MutPred [
145] and SNPs&GO [
146] that allow pathogenicity prediction of VUS. The accuracy of the predictions however, varies from program to program. Some of them have been trained on mutations in the on-line mendelian inheritance in man (OMIM) and human genome mutation database (HGMD) repositories, whereas others predict pathogenicity according to sequence homology of ortholog proteins.
PolyPhen2 scores are displayed in the Exome Variant Server (EVS) while both PolyPhen and SIFT scores are provided in the 1000 genomes browser. According to all the available information about a variant from the literature, genome databases as well as bioinformatic analysis and segregation analysis, the variants are classed into “definitively benign, probably benign, uncertain pathogenicity, probably pathogenic and definitely pathogenic” [
7]. There is always a degree of uncertainty with any
in silico analysis. While such predictions are useful in selecting variants for functional analysis it would be premature to begin using them for clinical diagnosis of MH susceptibility.
In summary, because of the heterogeneity of the disorder, as well as discordance within families, a negative DNA result cannot be used to rule out MH susceptibility. In addition, only those variants that have been biochemically characterized to affect SR Ca2+ release can be used to test for MH susceptibility.
Differential diagnosis
A variety of unusual conditions may resemble MH during anesthesia including sepsis, thyroid storm, pheochromocytoma, and iatrogenic overheating. Hence, a high index of suspicion for these disorders as well as the ability to measure ETCO2 and obtain arterial and venous blood gas analysis is essential in order to differentiate them from MH. Particularly problematic is the unexplained hyperthermia following anesthesia. Since anesthetic gases generally inhibit the febrile response, the first sign of sepsis may be marked hyperthermia on emergence from anesthesia. Response to antipyretics as well as the clinical setting is often helpful in differentiating this response from MH. As stated earlier hyperthermia occurring after one hour post anesthesia is not related to MH. The differential diagnosis of unexplained increased ETCO2 includes hyperthermia secondary to sepsis, or iatrogenic warming, machine valve malfunction, rebreathing, as well as faulty equipment.
Outside the operating room, an MH-like syndrome may occur following injection of ionic contrast agents into the cerebrospinal fluid, cocaine overdose, and in neuroleptic malignant syndrome (NMS), serotonin syndrome and 3,4-methylenedioxy-methamphetamine (MDMA) overdose. NMS is a potentially fatal hyperthermic syndrome that occurs as a result of ingestion of drugs used in the treatment of mental and nervous conditions such as schizophrenia. The incidence is approximately 0.01–0.02 % of those being treated with these drugs such as older as well as newer antipsychotics and haloperidol, a sedative agent often used in the ICU to treat agitation. Other dopamine antagonists also have been reported to cause NMS.
The signs of NMS include muscle rigidity, acidosis, high fever and rhabdomyolysis. The pathophysiology is thought to result from dopamine receptor blockade. Treatment includes benzodiazepines, bromocriptine and even dantrolene. There does not appear to be any cross over susceptibility to MH or
vice versa. There is no laboratory diagnostic test for the syndrome either [
147,
148]. The serotonin syndrome can be associated with hyperthermia, changes in muscle tone and rhabdomyolysis in conjunction with the use of drugs that inhibit serotonin uptake or increase receptor sensitivity to serotonin. Heat-related illnesses are discussed in a later section.
If a high ionic, water-soluble radiologic contrast agent is injected intrathecally, usually as a result of drug mixup, a characteristic progression of signs occurs. After the injection, the patient appears to recover normally, but within thirty minutes involuntary jerking movements begin in the lower extremities and ascend to the upper body, finally resulting in seizures and hyperthermia. This is the result of the contrast agent entering the cerebral ventricles and requires a rapid symptomatic treatment of muscle activity, hyperthermia, and acidosis (cooling, nondepolarizing neuromuscular blockers, ventilation, and sedation [
149]). The response of signs of hyperthermia, tachycardia and tachypnea to dantrolene in such syndromes is non-specific. In other words, the response to dantrolene does not
per se prove MH susceptibility.
A syndrome often confused with MH is sudden hyperkalemic cardiac arrest during or shortly after anesthesia in young males. Following sporadic reports of such arrests, Larach and colleagues identified that patients with an occult myopathy, especially a dystrophinopathy such as Duchenne’s muscular dystrophy [
150], are at risk to dramatic life-threatening hyperkalemia upon administration of succinylcholine. More recently, it has been shown that administration of potent volatile agents to such patients may produce a similar syndrome [
151].
Since the most common muscular dystrophy (Duchenne’s) is found with a frequency of 1 in 3500 live male births, and the onset of symptoms of muscle weakness may be as late as 6–8 years of age, some apparently healthy children may really be at risk of succinylcholine induced hyperkalemia. Hence, when a young child or young adult experiences a sudden and apparently unexpected cardiac arrest, think of hyperkalemia, document and treat it in the standard fashion (Ca2+, bicarbonate, glucose and insulin, and hyperventilation). Muscle tissue should be obtained and preserved for testing for a myopathy, specifically a dystrophinopathy. In general, the patient with a dystrophinopathy that develops these anesthetic-related complications does not also exhibit classic signs of MH, such as hyperthermia or marked muscle rigidity. They do, however, develop rhabdomyolysis. Therefore, this reaction is not malignant hyperthermia per se, since the dystrophinopathies are caused by mutations on the X chromosome and dantrolene will not be effective.
In response to the presentation of over 30 such cases to the Food and Drug Administration Agency (FDA) of the USA in 1992, a warning was issued to avoid the use of succinylcholine in children and young adolescents for elective cases. Succinylcholine should be reserved for those cases of full stomach and possibly airway related emergencies.
Disorders not associated with MH include muscular dystrophies, myotonias, neuroleptic malignant syndrome, osteogenesis imperfecta and arthrogryposis.
Dantrolene
There are two preparations of Dantrolene available. The conventional version, Dantrium®, is available in 20 mg vials which are poorly soluble and each require 60 mL of sterile water to prepare. An average adult may therefore require 8–10 ampoules for initial treatment. Ryanodex® is a new alternative preparation approved by the FDA, available in 250 mg ampoules which only require 5 mL of sterile water diluent to reconstitute, and solubility has been improved. Therefore initial treatment can now be achieved with administration of only one ampoule. Titrate dantrolene to tachycardia and hypercarbia; there is no upper limit to the dose of dantrolene [
16]. If however, more than 10 mg/kg of dantrolene is administered, the diagnosis of MH should be reconsidered. Other possible causes of MH-like symptoms include sepsis, NMS, intracranial hemorrhage, pneumonia, baclofen withdrawal [
162].
Patients experiencing MH should receive dantrolene and be monitored closely for 48–72 h, since (even despite dantrolene treatment) 25 % of patients will experience a recrudescence of the syndrome [
163]. Tests for disseminated intravascular coagulation (DIC) should be included as well as observation of urine for myoglobinuric renal failure. DIC is most frequent when body temperature exceeds about 41 ° C.
Since masseter muscle rigidity (MMR) may presage MH, it is most advisable to discontinue the trigger anesthetic after MMR. In an emergency, the anesthesia may continue with “non-trigger” drugs. Following MMR, patients should be admitted to an intensive care unit and monitored for signs of MH. Rhabdomyolysis occurs in virtually all patients experiencing MMR and the creatine kinase (CK) values should be checked regularly. Dantrolene should be administered if the other signs of MH occur along with MMR. Muscle biopsy for definitive diagnosis should be carefully considered.
It is remarkable that dantrolene may be efficacious in treating hyperthermia from many causes unrelated to MH with anesthesia. Based on the similarity between a variety of drug induced hyperthermic syndromes and MH, dantrolene has been used effectively to treat several other syndromes such as the neuroleptic malignant syndrome, MDMA toxicity and hyperthermia related to new onset of juvenile diabetes in adolescents [
164,
165].
In many countries, a “hotline” has been established to provide emergency assistance in the management of MH. Many are listed on the web site of the Malignant Hyperthermia Association of the USA [
160].
Experience from the Malignant Hyperthermia Hotline in the US as well as a recent retrospective review has shown that dantrolene may dramatically reverse life-threatening hyperthermia in a nonspecific manner. Considering that the toxicity of dantrolene is minimal when used for short periods clinicians have found the drug to be extremely useful. Adverse effects of dantrolene in short term administration are minor and may include phlebitis in 9 % of cases, transient muscle weakness in 21 %, gastrointestinal upset in 4 % and respiratory compromise in patients with preexisting muscle disorders [
166]. A caveat is that success in controlling hyperthermia does not imply that the patient is at risk for Malignant Hyperthermia Syndrome.
Preventive measures
Preventative measures include preoperative assessment and identification of an inherited association with a known family, managing a patient with a suspected history as MH susceptible until testing is undertaken, an operating theatre list of susceptible names in the community and an indication of MH susceptibility on the anesthetic record audit form, labeling hospital records together with a national alert warning on records, and family education is helpful.
Patients with any form of muscle disorder should not receive succinylcholine and caution should be exercised with administration of inhalational agent to patients with other muscle disorders particularly muscular dystrophies especially hypokalemic periodic paralysis, CCD, Duchenne or Becker.
All patients receiving more than a brief general anesthetic should have their core temperature monitored.
Young patients (below age 12 approximately) should not receive succinylcholine for elective procedures, in order to avoid the possibility of hyperkalemic response in a patient with undiagnosed muscular dystrophy.