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Address correspondence to Baisheng Wang, Oral and Maxillofacial Surgery Department, Xiangya Stomatology Hospital, Central South University, Changsha, 410008, Hunan, China.
Address correspondence to Zhangui Tang, Oral and Maxillofacial Surgery Department, Xiangya Stomatology Hospital, Central South University, Changsha, 410008, Hunan, China.
Malignant hypothermia (MH) is a potentially fatal hypermetabolic reaction of skeletal muscle. It is an autosomal dominant disorder that generally occurs in people with RYR1, CACNA1S, or STAC3 mutations. And these genetic abnormalities often cause the imperfection of calcium release channels of skeletal muscle. The incidence of MH among different racial groups across the world ranges from approximately 1:5,000-1:250,000, but there is no national statistic MH incidence in China. It is not clear whether there are racial or regional differences in the incidence, but patients under 18 years old may be more affected. MH can be triggered by anesthetics, or other stimuli, such as strenuous exercise, heat-stroke, and emotional stress. While viral infection, statins, hyperglycemia, and muscle metabolic dysfunctions might accelerate the onset of MH. The onset of MH is insidious and rapid, with the preclinical stage characterized by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature. Medical history, family history, clinical presentation, in vitro caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing are commonly diagnostic methods of MH. As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities. For symptomatic treatment, “5C principles” were summarized as an algorithm to guide clinicians.
Objectives (1) Define malignant hyperthermia (MH). (2) Discuss the pathogenesis of MH. (3) Review the predisposing factors and clinical manifestations of MH. (4) Discuss the management of an MH crisis.
Malignant hyperthermia (MH) and MH susceptibility (MHS) were first identified and described by Denborough and Lovell in Australia in 1960.
After that, knowledge of MH pathogenesis and treatment has substantially improved. MH mortality has consequently decreased from 70% to 80% in the 1970s to approximately 1.4% to 10% in recent years.
Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States.
However, in some countries and regions, which lack the only known antidote to MH and in which clinicians pay insufficient attention to or lack sufficient understanding of MH, the mortality rate due to MH remains high.
Additionally, younger people and children are significantly more vulnerable to MH than other age groups and they often experience a more severe MH crisis, making this group the biggest victim of MH.
Stomatologists and plastic surgeons often use inhaled anesthetics, but because of insufficient knowledge about MH, they may not routinely assess MH risk before procedures. As a result, once the MH occurs, they might face a lack of support from physicians and anesthesiologists. These additional risk factors may lead to increased MH risk.
The main cause of MH is the dysfunction of calcium channels in skeletal muscle cells caused by various genetic mutations. Therefore, MH is likely to be triggered by any factor that can increase the burden of cellular calcium channels as long as there are related gene mutations. In addition to the anesthetic exposure, other risk factors should be noted, such as thermal radiation, excessive exercise, metabolic diseases and so on. These risk factors are so common in some populations that they require special attention. When a suspected MH occurs, a quick and decisive decision is required. But many clinical workers are not familiar with MH.
This purpose of this review was to summarize the knowledge of different aspects for MH to benefit researchers, clinicians, nurses, and related service providers who may encounter this disease but without sufficient understanding of MH. The “5C principles” is a recommended algorithm to guide clinicians when MH occurs.
Epidemiology
MH is a rare but deadly disease to which all races worldwide are equally susceptible. Studies performed in different countries have reported the prevalence of MH as follows: between 1:5,000 and 1:50,000-100,000 anesthetic procedures in the US
Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States.
These investigations relied on anesthesia crisis reports and excluded drug-free MH; therefore, the actual incidence may be higher than these figures suggest. In Europe and the US, the mortality rate due to MH is 1.4% to 10% with proper treatment and use of dantrolene.
No large-scale epidemiological investigation has explored MH in China, and sporadic case reports from Chinese clinicians are therefore the only data available to roughly estimate the status of MH in China. According to those reports, the mortality rate of MH in China is higher than 48%; and the number of MH cases that occurs in China is increasing, in a manner consistent with reports of cases in other countries.
This worldwide increasing trend of MH may be attributed to the improvement and popularization of diagnostic technologies and the increase in total number of surgeries annually.
MH patients are mostly male, with a male-to-female ratio of approximately 2:1 to 4:1. Among the published cases, patients under the age of 18 years constitute the largest population, accounting for approximately 30% to 60% of all cases, and elderly patients (older than 60 years) are relatively rare. Geographically, in the US, studies have shown that the MH incidence varies regionally.
Whether MH incidence correlates with regional environmental differences is unclear, some scholars reported that the incidence of MH might be related to regional temperature differences,
Identification of malignant hyperthermia-susceptible ryanodine receptor type 1 gene (RYR1) mutations in a child who died in a car after exposure to a high environmental temperature.
Researchers worldwide have explored the genetic basis of MH susceptibility over the past 3 decades. The origin of these studies was based on the hypothesis that Ca2+ is the chief regulator of muscle contraction, and that defective Ca2+ regulation may be the primary cause of MH. The first gene associated with MH was RYR1, which encodes the Ca2+ releasing channel located on sarcoplasmic reticulum (SR) membranes, ryanodine receptor 1(RyR1). MacLennan and McCarthy et al. successfully located and identified the relevant RYR1 gene mutation.
Studies then followed up on their results and found that more than 300 mutations in RYR1 are associated with MH susceptibility and/or central core disease and that these mutants are widely present in MH and MHS populations. Screenings of the RYR1 region were performed to identify sequence variants in MH/MHS populations and found that RYR1 mutations accounted for up to 56.9% of MH/MHS cases in Japan,
Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population.
The controlling core of excitation-contraction (EC) coupling is the calcium channel protein complex, which is mainly composed of 2 key molecules. In addition to RyR1, a transmembrane protein complex dihydropyridine receptor (DHPR), also known as L-type Voltage gated calcium (CaV1.1) channel, is located on the T tubular membrane. Based on the same hypothesis, Stewart et al. conducted a gene mutation screening of DHPR in many northern American populations, and they found that a mutation in the gene that encodes the α1 subunit of DHPR, CACNA1S, was related to MH.
Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia.
Besides, they revealed that the MH-associated genetic alterations in CACNA1S were present in approximately 1% of the northern American. Researches from other countries found that CACNA1S mutations exist in around 1.7% of UK MHS population,
Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families.
Finally, at the level of T tubule-SR membrane triad, there are many accessory proteins of calcium channel complex, such as calsequestrin, FKBP12, triadin, junctophilin, junctate, junctin and STAC3, which are all involved in the adjustment or structure formation of EC coupling mechanism.
Except the variation of STAC3, there is no evidence that other accessory proteins are related to MH/MHS. However, theoretically, the variation of these accessory proteins also might cause MH/MHS, which is a problem worth further exploration.
To date, more than 300 RYR1 mutations have been reported; however, few have been confirmed to cause MH in experimental studies addressing their functional impact on intracellular Ca2+ homeostasis. The European MH Group published several diagnostic mutations on its website (www.emhg.org). To improve genetic testing and prevent surgical testing, this chart needs to be expanded by constantly searching for new mutations.
Etiology
The discovery of an increasing number of MH-related gene variants suggests that the underlying genetic etiology of MH is complex. Motoneurons trigger a series of action potentials in muscle cells, these action potentials diffuse along the T tubular membrane and cause depolarization of T tubular membrane. Depolarization of the T tubular membrane causes the configuration change of DHPR, which opens the calcium channel anchored on the SR membrane, namely RyR1, through protein interaction, to release Ca2+ from the SR.
When the action potential of T tubular membrane returns to its resting value, RyR1 shuts down, allowing intracellular Ca2+ to be pumped back into the SR via Ca2+ ATPase, and muscle cells recover relaxation after contraction.
In healthy muscles, EC coupling is a very powerful process that can only be triggered by motoneuron excitation. It starts the release of Ca2+ and subsequent contraction of the muscle, which can be reversibly altered by fatigue.
However, in MH/MHS, patients often have abnormalities in calcium channel regulation mechanisms. Although these abnormalities of Ca2+ channel in skeletal muscle does not affect the EC coupling process in the daily state, they can induce the imbalance of the Ca2+ channel regulation after receiving some specific stimuli, thus leading to the occurrence of MH. The etiology of MH is shown in Figure 1.
Figure 1Etiology of MH. RYR1 encodes the Ca2+ release channel (RyR1) in SR membranes, while the α1 subunit of the DHPR is encoded by CACNA1S. DHPR is in the T tubular membrane, and is the voltage controller gate of RyR1. The STAC3 protein interacts with DHPR to control the RyR1 in EC coupling. In MH/MHS, when RYR1 mutated, the RyR1 unable to close normally; when CACNA1S mutated, the DHPR unable to prevents Ca2+ leakage from the RyR1 during rest voltage. Induced factors like improper use of anesthetic drugs, heat stroke, exertional exercise and viral infection can lead to MH episode. This figure is available in color online at www.jopan.org.
In MHS population, the most common mutation is the abnormal coding of the Ca2+ releasing channel protein RyR1. As previously mentioned, RyR1 is the "gate" for releasing Ca2+ from the SR into the cytoplasm. While the "gate" in MHS patients tends to be unable to close normally, their intracellular Ca2+ concentration is high.
Opposite to MH, another disease caused by RYR1 mutation is central core disease (CCD). The mutation of RYR1 in CCD makes DHPR unable to completely open the "gate", thus insufficient Ca2+ concentration in the cytoplasm causes EC decoupling, and finally leads to clinical muscle weakness.
Reduced threshold for store overload-induced Ca(2+) release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease.
DHPR is an effector that converts physiological electrical impulses to ion concentration gradient and thus activates EC coupling. Therefore, based on its key role in EC coupling, the mutations of DHPR often lead to serious neuromuscular disease. Mutations in the CACNA1S that encodes the α1 subunit of DHPR cause 2 major neuromuscular diseases: type 1 hypokalemic periodic paralysis (HypoPP1) and MH.
These 2 diseases are completely opposite in clinical manifestations, mainly because the mutation of the CACNA1S occurs in different site, resulting in different types of calcium channel regulation imbalance. The mutation that causes HypoPP1 results in abnormal depolarization of muscle fibers under resting voltage, which fails to achieve the voltage gate effect of DHPR, and finally leads to temporary skeletal muscle weakness or paralysis in patients.
In MH, the mutation impairs the function of DHPR that prevents Ca2+ leakage from the SR during rest voltage. Due to the increased Ca2+ release at rest, MHS population become more prone to muscle hypermetabolic states after contacting certain stimuli, such as exposure to volatile anesthetics or excessive labor.
STAC3 is expressed specifically in skeletal muscle and is localized to the skeletal muscular membrane system and interacts with the RyR1 and DHPR complex. It mainly assists the voltage gating function of DHPR, and is the key to controlling the conformation of RyR1 and the EC coupling of skeletal muscle after membrane pressure changes.
In addition, STAC3 may be involved in regulating the transport of DHPR's α1 subunit to the T tubule, so the DHPR structure is often incomplete when STAC3 mutation exists.
Thus, the primary cause of MHS/MH is the potential imperfection of calcium release channels of skeletal muscle. Such functional incompleteness would not generally reflect in daily life, but once patients are exposed to specific stimuli, a series of pathophysiological phenomena will occur under the accumulated effect of imbalanced Ca2+ regulation.
Anesthetic-Induced MH
The most well-known risk factor for MH is the use of anesthetic drugs. Volatile anesthetic gases, such as halothane, isoflurane, sevoflurane, desflurane, and/or the depolarizing skeletal muscle relaxant, succinylcholine, have been reported to be high-risk medications that can lead to MH.
Halothane-induced MH seems to contribute to the most MH crises; however, according to a report from Japan, of all volatile anesthetics, the prevalence of MH was relatively high when using sevoflurane.
Reports showed that succinylcholine alone, when administered without concomitant volatile anesthetics, triggered adverse events in approximately 15.5% of MHS patients who presented the high inductivity of succinylcholine alone.
However, the combination of potent inhaled anesthetic agents and succinylcholine can significantly increase the risk of MH.
Although volatile inhalation anesthetics and succinylcholine are the agents that most commonly induce MH, other anesthetics can trigger MH. Amide local anesthetics, such as lidocaine and bupivacaine, are frequently used in epidural analgesia and arrhythmia, and reports suggest that these anesthetics can also induce MH.
Some studies suggest that amide anesthetics can be alternatives when MH crisis occurs; however, the possibility of amide-induced MH should be considered, especially by outpatient surgeons and dentists who frequently use amide anesthetics.
Non-Anesthetic Induced MH
MH may occur upon exposure to other factors in the absence of classic anesthetic triggering agents. Previous reports indicate that in some rare cases, nonclassical factors, such as viral infections, environmental heat stroke (HS), exertional rhabdomyolysis (ER), and extreme emotions can lead to MH occurrence.
Increasing evidence indicates that the HS and ER caused by vigorous exercise and environmental heat can induce a life-threatening hyperthermic crisis in susceptible individuals.
In 2001, Tobin et al. reported the first case of a non-anesthetic, stress-induced hyperpyrexia death. A 12-year-old male experienced MH crisis during a humerus fracture operation and recovered without sequelae. However, just 8 months later, he experienced a series of MH responses followed by sudden death after an exertional football game.
In other reports, patients with HS have been found to have histories or family histories of MH or an association among MH-related genetic flaws such as RYR1 variants.
Exercise-induced rhabdomyolysis and stress-induced malignant hyperthermia events, association with malignant hyperthermia susceptibility, and RYR1 gene sequence variations.
The correlation between MH and non-anesthetic stress is also supported by studies performed on animals. Pigs carrying a mutant RYR1 gene can be induced to experience an MH episode by both halothane and stressful conditions, such as elevated environmental temperatures and/or emotional or physical stress.
One group showed that MHS mice did not develop ER if their core body temperature was maintained at 36°C, suggesting the importance of combined mechanical and thermal stress for triggering MH-related ER.
Michelucci et al. subjected RYR1Y522S/WT and CASQ1-null mice (type 1 calsequestrin-encoding gene-null mice) to an exertional-stress protocol, and the results showed that the mortality rates were as high as 80% and 78.6% in RYR1Y522S/WT and CASQ1-null mice, respectively, compared with 0% in wild-type mice. After pretreatment with azumolene, an analog drug of dantrolene, the mortality rates were reduced to 0% and 12.5% in the RYR1Y522S/WT and CASQ1-null mice, respectively.
These results suggest that although the triggering conditions may differ, common molecular mechanisms underlie anesthetic-induced MH and stress-induced MH.
In addition to HS- and ER-related MH, some case reports have shown that emotional stress may also cause or contribute to stress-induced MH.
Gronert et al. reported a 42-year-old white male evaluated aching joints, malaise, fevers of 40°C caused by extreme physical or emotional stress or fatigue for the past 20-25 years and 1.1mg/kg oral dantrolene can relieve the symptoms within 2–3 h, after diagnosed MHS, he experienced a surgery without the common triggering anesthetics but still happened MH symptoms and got recovered with intravenous dantrolene.
In addition to factors that may directly cause MH, other factors can accelerate MH onset, including viral infection, statins, hyperglycemia, and muscle metabolic dysfunctions.
It has been confirmed that chronic viral infection can cause myopathy like chronic inflammatory myopathy (CIM),
Epidemic myalgia and myositis associated with human parechovirus type 3 infections occur not only in adults but also in children: findings in Yamagata, Japan, 2014.
reported a 6-year-old African American female who with RYR1 gene mutation developed severe rhabdomyolysis and MH crisis induced by parainfluenza and HSV1 infection. These cases suggest that viral infection and chronic viral infection caused myopathy could be risk factors of MH.
Statins are one of the most important cholesterol-lowering agents, but studies have revealed that statin-associated muscle disease can contribute to MH crisis episodes, and the underlying etiology may be impaired Ca2+ homeostasis.
Statin-induced muscle toxicity and susceptibility to malignant hyperthermia and other muscle diseases: a population-based case-control study including 1st and 2nd degree relatives.
Human and animal studies have shown that the mechanism for statin-related myopathy is increased cytosolic Ca2+ efflux, which impairs EC coupling of skeletal muscle fibers. Statins can affect skeletal muscle and produce statin associated muscle symptoms (SAMS) by increase RYR1 activity, which is why statins intake is associated with MH/MHS.
Moreover, statins are suggested to cause glycogen accumulation in muscles secondary to impaired glucose oxidation, which may lead to eventual development of insulin resistance,
Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents.
One retrospective study analyzed fasting or random concentrations of blood glucose and glycosylated hemoglobin (HbA1c) in 356 MHS patients in Canada. Of these patients, 148 (42%) had a random increase in blood glucose levels or hyperglycemia. To explore the glucose impairment observed in the MHS group, these researchers performed an animal experiment using MHS (RyR1 R163C+/−) mice and MH-normal (MHN) mice (WT littermates). Their findings showed that MHS mice had impaired glucose tolerance tests (GTTs) and that dantrolene pretreatment normalized GTT to near MHN concentrations. Moreover, these researchers found that blood glucose levels were positively correlated with contracture responses to caffeine and halothane in MHS patients.
Because skeletal muscle is one of the most important tissues in regulating blood glucose and is an MH etiology tissue, these studies strongly suggest a close correlation between MHS and hyperglycemia.
Besides hyperglycemia, other muscle metabolism dysfunctional may also contribute to MHS. Thompson et al. assessed skeletal muscle metabolism of 29 MHS patients and 20 healthy controls, the results showed that MHS patients had significantly lower ATP produced by oxidative pathway and impaired anaerobic capacity following 30 and 60 seconds high-intensity exercise bouts.
This research shall explain the exercise intolerance exhibited in MHS patients.
Pathogenesis and Corresponding Clinical Manifestations
When the relevant trigger factors mentioned previously are present, abnormally increased Ca2+ concentrations in the skeletal muscle cytoplasm can cause a series of functional disorders. The key pathophysiological factors of MH are shown in Figure 2.
Figure 2The key pathophysiological factors of MH. When MH occurred, Ca2+ concentrated in the cytoplasm of myocytes, caused the continuous contraction of myofilaments, consumption of oxygen and glycose which led to the massive accumulation of CO2, lactate, and heat. As a result, rigidity, acidosis, and heat appeared. This figure is available in color online at www.jopan.org.
First, muscle contractile activity increases via the EC coupling mechanism as the Ca2+ concentration increases in the SR. The resulting involuntary contraction of skeletal muscle may only manifest as masseteric spasms in the early stage.
Therefore, this phenomenon should be treated with caution when observed in clinical practice. MH outbreak or further progression of the disease can manifest as whole-body muscle rigidity and even opisthotonos. Myocardial cells may also be affected and can show signs of tachycardia or supraventricular or ventricular arrhythmia. Notably, in the early clinical manifestations of MH, nonspecific sinus tachycardia may be wrongly identified as insufficient anesthesia, which often delays the MH diagnosis.
To support continuous pathological contractions, the skeletal muscles enter a high metabolic state, oxygen, and glucose consumption increase. Carbon dioxide production is increased as a direct response to this phenomenon. Consequently, one of the early sensitive and specific manifestations of MH is an increased concentration of end-tidal carbon dioxide (ETCO2) or hyperventilation during spontaneous respiration.
Hypercapnia and hypoxemia appear as carbon dioxide accumulates. Oxygen and glucose supplies run low, phosphorylase is simultaneously activated, intensifying glycolysis, and resulting in production of large amounts of lactic acid, leading to lactemia. These imbalances ultimately result in fulminant uncompensated mixed respiratory and metabolic acidosis.
The large amount of biological energy consumed during these processes sharply increases the heat generated and eventually leads to a rapid rise in body temperature over a short period. Because it takes time for the body's temperature to reach ≥38.8°C, a rapid increase of 1-2°C over 5-15 minutes is diagnostically more relevant than is the peak temperature.
Notably, a sharp increase in body temperature may not occur in cases that are treated early.
Researchers collected information related to MH cases that occurred after anesthesia in the US and Canada from 2007 to 2012 and found that all fatal cases occurred in patients whose peak temperature was 38.9°C or higher (mean temperature of 41.6 ± 1.7°C). They also found that the first sign observed in fatal MH events occurred >30 minutes after inducing anesthesia.
Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.
Consequently, these studies suggested that the body's core temperature should be monitored intraoperatively for at least 30 minutes after inducing anesthesia.
In the second stage of disease progression, muscle cells begin to undergo necrosis and disintegration due to local hypoxia, acid-base imbalance, excessively high temperatures and an inability to release from contraction for the above reasons. Rhabdomyolysis occurs when many skeletal muscle fibers break down, leading to lethal hyperkalemia, increased creatine phosphate kinase (CK), and increased myoglobin levels, which may lead to acute renal failure. Additionally, extensive necrosis of the extremity muscles, when combined with high edema, can lead to compartment syndrome.
Theoretically, during the last stage, the patient would experience systemic metabolic disorders, continuous myocyte breakdown, core hyperthermia, severe arrhythmia, and congestive heart failure. All these eventually develop into disseminated intravascular coagulation (DIC) and multiple organ failure, leading to death. The pathogenesis and corresponding clinical manifestations were summarized in Figure 3.
Figure 3Diagram of pathogenesis and corresponding clinical manifestations. This figure is available in color online at www.jopan.org.
MH is diagnosed based on four components: medical history or/and family history of MH/MHS, clinical presentation, in vitro caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing.
Identifying a patient's medical history and family history is the best way to prevent MH, so careful communication with the patient should be made before making clinical decisions. The establishment of a database for MH patients should be advocated. After the MH patients are diagnosed, relevant information should be provided to their families.
The presence of one or more of the following items simultaneously may suggest MH onset:
•
Muscular spasm or rigidity of a certain part of the body, such as masseteric spasm or whole-body rigidity.
Body temperature that rises rapidly in a short time (1–2°C over 5–15 minutes) and quickly reaches 38.8°C or even ultrahigh temperatures of 41–42°C.
•
Respiratory and circulatory system failure in a short time: cyanosis, arrhythmia, and oliguria.
Blood biochemical tests, IVCT/CHCT and genetic tests related to further diagnoses should be then conducted based on existing conditions. Currently, the internationally recognized gold standard for diagnosing MH is IVCT/CHCT, which is mainly targeted at patients who are strongly suspected of having MH and their immediate family members. IVCT and CHCT are two widely used forms of in vitro contracture tests. One is recommended by the European Malignant Hyperthermia group (www.emhg.org), and the other was developed by the North American Malignant Hyperthermia group (www.mhaus.org). Both tests measure changes in muscle tone at different concentrations of halothane and/or caffeine, and the main differences between the two tests includes the concentrations of and methods used with the test reagent. However, the results of both tests can be affected by underlying myopathic processes, which can cause sarcoplasmic Ca2+ concentrations to increase, causing a false-positive diagnosis.
At present, the IVCT/CHCT is expensive and limited to professional testing centers. In addition, use of this method requires surgery to obtain muscle tissue from the patient, making it an invasive test, thus making it difficult for some people to accept.
MH-related gene abnormalities are the basis of the molecular biology of MH pathogenesis. At present, some specific mutations in MH-related genes are listed on the European Malignant Hyperthermia group website (www.emhg.org). Theoretically, a clear diagnosis can be made by detecting the presence of known genetic mutations; however, MH is associated with complex genetic changes and genetic heterogeneity, while gene mutation analyses are prone to false-negative results. Thus, a genetic diagnosis alone is insufficient to confirm MH and can only be used as an auxiliary means to obtain a diagnosis. In addition, timely genetic testing is difficult to perform in affected patients, and most existing case reports worldwide present delayed genetic testing.
In the absence of immediate IVCT/CHCT and genetic testing, a more convincing diagnosis can be reached using the clinical grading scale that Larach et al. developed in 1994, combined with clinical manifestations and blood biochemical test results.
this method is the most recommended to make auxiliary diagnoses until a better solution is found.
Treatment and Symptomatic Management
MH crisis progresses rapidly and is life-threatening. The diagnosis and treatment algorithm for MH is shown in Figure 4. Once MH suspected, a series of measures should be taken immediately.
Figure 4Diagnosis and treatment algorithm for MH. MH, malignant hyperthermia; IVCT/CHCT, in vitro caffeine-halothane contracture testing.
First, any drugs that may have induced MH onset, such as succinylcholine or halothane, should be stopped or replaced. It is important to note that anesthetic drugs may remain in the anesthetic pipeline, so new circuits or activated charcoal filters should be used. Besides, the ongoing surgery should be terminated as soon as possible, or convert to a trigger free anesthetic, such as total intravenous anesthesia (TIVA), if surgery cannot be terminated.
Meanwhile, professional help and dantrolene should be obtained immediately.
After MH is diagnosed or during diagnostic treatment, when conditions permit, dantrolene, the only specific drug for treating MH, should be used. Dantrolene depresses the intrinsic mechanisms underlying EC coupling in skeletal muscles, thereby depressing the MH episode. Notably, research on dantrolene in recent years has indicated that dantrolene requires Mg2+ to arrest MH
; thus, an appropriate concentration of Mg2+ must be maintained in the blood for dantrolene to work.
Although dantrolene is the only antidote for MH, this drug is currently unavailable in some countries and regions. In these situations, MH patients can only gain this drug through foreign donations. In the absence of dantrolene, careful treatment and monitoring is very important for MH patients.
We summarized a set of effective symptomatic treatment methods based on the following “5C principles”:
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Convulsion relief: sedation and adequate oxygen supply
•
Cooling
•
Correcting water and electrolyte imbalance, stabling the cell membrane
•
Calcium supplements and narcotic drugs should be used with caution
•
Closely monitoring vital signs, temperature, blood gas indicators, acid-base balance indicators, and serum ions for at least 24 hours
The 5C principles outline the clinical decisions that practitioners need to make after MH occurs. Because they all start with C, it could be easier to remember. Figure 4 briefly describes the treatment regimen.
For sedation and convulsion relief, chlorpromazine, meperidine, hydergine and promethazine could be considered.
Physical cooling typically is more direct and effective in MH. The following methods can be used:
•
Ice cooling by placing an ice bag wrapped in gauze or a sterile towel around the body.
•
Intravenously infusing an iced fluid for internal cooling via submerging the lower end of the infusion tube in ice water or using a special cooling infusion device.
Another way to quickly lower the core body temperature is to use an ice bath or immersion cooling, in which patients are partly submerged to the upper torso or neck in a bath of cold water or ice water slurry. Reports have shown that the cooling rates can reach 0.35°C/min and that immersion in water at even higher temperatures of 14-20°C can also produce experimental cooling rates of 0.15-0.19°C/min.
Patients may exhibit different degrees of dehydration during fever; fluid should therefore be supplemented according to the condition, and a daily physiological number of fluids (2000-2500ml for adults) should be included. Treating acidosis and hyperkalemia is often effective in correcting arrhythmias. Moreover, booster drugs or diuretic drugs should be used to stabilize the hemodynamics to prevent circulatory and kidney failure during this period. Depending on the situation, corticosteroid use can be considered.
Part of the Ca2+ in the muscle is released into the plasma; therefore, when MH occurs, serum Ca2+ levels will increase to varying degrees, potentially causing hypercalcemia.
During MH treatment, patients may not survive due to aggravation of the disease if calcium supplements are mistakenly taken. In patients with suspected MH, calcium supplements should be used with caution.
The patient's condition and progress should be closely monitored for at least 24 hours, with timely and effective symptomatic treatment, to prevent the disease from becoming unmanageable. Hemodialysis ultrafiltration and advanced life support should be available in case of an emergency. Admission of the patient to the intensive care unit for on-going management is recommended.
Discussion
The onset of MH can be very insidious and not easily detected. Some risk factors may be ignored by practitioners. MH can be triggered not only by anesthetics, but also can be triggered by other stimuli such as strenuous exercise, heat stroke or even stress. Some scholars have noted that MH and other stress-induced diseases, such as HS and ER, share associations with the same clinical manifestations and pathophysiological mechanisms, including hyperthermia, muscle rigidity, tachycardia, elevated serum creatine kinase levels, abnormal muscle metabolism and sympathetic system involvement. Based on these commonalities, previous authors proposed the “human stress syndrome” hypothesis to explain these collective illnesses.
Hypothesis: exertional heat stroke-induced myopathy and genetically inherited malignant hyperthermia represent the same disorder, the human stress syndrome.
This brings a new idea to the study of MH: is there any other mechanism besides calcium channel gene variation in the pathogenesis of MH? Do psychosocial or endocrine factors, for example, play a role in the development of disease? This is a question worth exploring.
Moreover, as an autosomal dominant disorder, compound heterozygous RYR1 mutations may produce phenotypic variability. Researchers reported that the mutant c.14918C>T (p.Pro4973Leu) in RYR1 can lead to MHS, arthrogryposis multiplex congenita and prenatal central nervous system (CNS) bleeding in preterm infants.
This phenomenon suggests that the genetic variations associated with MHS may coexist with other phenotypes. For example, certain genetic defects in the orofacial cleft population may be related to MHS mutations. Studies identified a novel orofacial cleft-related region, 19q13.11, in a multiethnic genome-wide association study and found that it was very near the RYR1 region (19q12-q13.2).
A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.
Some scholars have reported that native American myopathy (NAM), which presents as cleft palate and skeletal anomalies, makes an individual highly susceptible to MH.
These studies suggest that the genetic diseases overlapped with the possible gene variation regions of MH should be alert to the occurrence of MH.
Conclusion
MH can be triggered by anesthetics, or other stimuli, such as strenuous exercise, heat-stroke, and emotional stress. While viral infection, statins, hyperglycemia, and muscle metabolic dysfunctions might accelerate the onset of MH. The onset of MH is insidious and rapid, with the preclinical stage characterized by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature. Medical history, family history, clinical presentation, in vitro caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing are commonly diagnostic methods of MH. As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities. For symptomatic treatment, “5C principles” were summarized as an algorithm to guide clinicians. MH is a disease caused by genetic defects that cause reduced homeostasis maintenance function of cellular calcium channels. Therefore, once the MHSs are exposed to certain stimuli, their muscles will develop uncontrollable spasm and eventually lead to the onset of MH. In conclusion, the prevention and treatment of MH focus on the history and family history of patients, closely observe the symptoms, timely diagnosis and correct treatment.
Acknowledgments
We would like to thank America Journal Expert (www.aje.com) for English language editing.
Test ID W101921 – Expiration Date October 31, 2023
Malignant Hyperthermia: A Killer If Ignored
2.0 Contact Hours
Purpose of the Journal of PeriAnesthesia Nursing: To facilitate communication about and deliver education specific to the body of knowledge unique to the practice of perianesthesia nursing.
Outcome of this CNE Activity: To enable the nurse to increase knowledge on malignant hyperthermia.
Target Audience: All perianesthesia nurses
Article Objectives
1.
Define malignant hyperthermia (MH).
2.
Discuss the pathogenesis of MH.
3.
Review the predisposing factors and clinical manifestations of MH.
4.
Discuss the management of an MH crisis.
Accreditation
American Society of Perianesthesia Nurses is accredited with distinction as a provider of nursing continuing professional development by the American Nurses Credentialing Center's Commission on Accreditation.
Provider approved by the California Board of Registered Nursing, Provider Number CEP5197, for 2.0 contact hours.
Additional provider numbers: Alabama #ABNP0074
Contact hours: Registered nurse participants can receive 2.0 contact hours for this activity.
Disclosure
All planners and authors of continuing nursing education activities are required to disclose any significant financial relationships with the manufacturer(s) of any commercial products, goods or services. Any conflicts of interest must be resolved prior to the development of the educational activity. Such disclosures are included below.
Planners and Author Disclosures
The members of the planning committee for this continuing nursing education activity do not have any financial arrangements, interests or affiliations related to the subject matter of this continuing education activity to disclose.
The authors for this continuing nursing education activity do not have any financial arrangements, interests or affiliations related to the subject matter of this continuing nursing education activity to disclose.
Requirements for Successful Completion: To receive contact hours for this continuing nursing education activity you must complete the registration form and payment, read the article, complete the online posttest and achieve a minimum grade of 100%, and complete the online evaluation.
Directions
A multiple-choice examination, designed to test your understanding of Malignant Hyperthermia: A Killer If Ignored according to the objectives listed, is available on the ASPAN website: https://learn.aspan.org/
To earn contact hours from the American Society of Perianesthesia Nurses (ASPAN) Continuing Nursing Education Accredited Provider Unit go to the ASPAN website: (1) select the article, complete the registration form and payment; (2) read the article; (3) complete the posttest on the ASPAN Website and achieve a minimum score of 100%; and (4) complete the online evaluation.
This all must be completed prior to the expiration date of October 31, 2023.
Your certificate will be available for you to print upon successful completion of the activity and completion of the online evaluation.
Online payment is required: ASPAN member: FREE per test; nonmember: $15.00 per test.
Cardiac arrests and deaths associated with malignant hyperthermia in north america from 1987 to 2006: a report from the north american malignant hyperthermia registry of the malignant hyperthermia association of the United States.
Identification of malignant hyperthermia-susceptible ryanodine receptor type 1 gene (RYR1) mutations in a child who died in a car after exposure to a high environmental temperature.
Screening of the entire ryanodine receptor type 1 coding region for sequence variants associated with malignant hyperthermia susceptibility in the north american population.
Identification of the Arg1086His mutation in the alpha subunit of the voltage-dependent calcium channel (CACNA1S) in a North American family with malignant hyperthermia.
Analysis of the entire ryanodine receptor type 1 and alpha 1 subunit of the dihydropyridine receptor (CACNA1S) coding regions for variants associated with malignant hyperthermia in Australian families.
Reduced threshold for store overload-induced Ca(2+) release is a common defect of RyR1 mutations associated with malignant hyperthermia and central core disease.
Exercise-induced rhabdomyolysis and stress-induced malignant hyperthermia events, association with malignant hyperthermia susceptibility, and RYR1 gene sequence variations.
Epidemic myalgia and myositis associated with human parechovirus type 3 infections occur not only in adults but also in children: findings in Yamagata, Japan, 2014.
Statin-induced muscle toxicity and susceptibility to malignant hyperthermia and other muscle diseases: a population-based case-control study including 1st and 2nd degree relatives.
Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents.
Malignant hyperthermia deaths related to inadequate temperature monitoring, 2007-2012: a report from the North American malignant hyperthermia registry of the malignant hyperthermia association of the United States.
Hypothesis: exertional heat stroke-induced myopathy and genetically inherited malignant hyperthermia represent the same disorder, the human stress syndrome.
A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13.
Funding: This study was supported by the National Natural Science Foundation of China [No. 81671003]; and the China Hunan Provincial Science and Technology Department [No. 2017SK2430]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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