INTRODUCTION
The aim of this report is to examine the current understanding of malignant hyperthermia (MH) and heat-related illness. We will briefly discuss MH and EHI separately, then explore areas of similarity from molecular, pathophysiological, and clinical viewpoints. We will focus on the following questions: 1) Is exertional heat illness (EHI) or exertional heat stroke pathogenetically related to MH, and should patients with EHI be considered at risk for MH? 2) What appropriate tools differentiate EHI and MH, if they are mechanistically related? 3) What is the current understanding in terms of signaling molecules involved in EHI and MH? Examining the similarities and differences will provide more insight into the diagnosis and treatment of these potentially fatal conditions.
MALIGNANT HYPERTHERMIA
Human MH, a potentially fatal, heterogeneous, pharmacogenetic disorder, is caused (induced or triggered) in predisposed individuals by volatile anesthetics (e.g., halothane or isoflurane) and/or the depolarizing skeletal muscle relaxant, succinylcholine. A fulminant MH episode or crisis apparently results from a rapid and sustained rise in myoplasmic Ca2+. This constitutes a hypermetabolic state manifest as hypercapnia, tachycardia, and metabolic acidosis. Muscle rigidity in association with structural muscle membrane damage leads to release of intracellular muscle constituents, such as creatine kinase, lactate dehydrogenase, myoglobin, and potassium. Hyperthermia, for which the syndrome is named, is a late sign and is likely a consequence of the hypermetabolic state. If not treated promptly by administering dantrolene (an inhibitor of the release of Ca2+ from intracellular stores in the sarcoplasmic reticulum in skeletal muscle), withdrawing the anesthetic, and cooling the patient, the mortality is >70%.
A striking characteristic of the clinical syndrome is its variability. For instance, MH-susceptible individuals do not develop acute episodes with each exposure to anesthetic drugs. Also, the rate of onset and severity of an acute MH episode can vary widely. Some individuals require more than one exposure to the anesthetic before an acute episode is induced, and some have anecdotally reported spontaneous MH episodes without any exposure to anesthetic drugs. These observations suggest that MH susceptibility stems from an interaction between genes and environmental factors. Most MH-susceptible persons are clinically normal unless challenged by the anesthetics. However, a subset of known MH-susceptible cases (∼5–8%) develops symptoms with exercise, emotional stress (14), and/or environmental heat exposure. This can be interpreted as a consequence of minor Ca2+ leakage from the sarcoplasmic reticulum with higher energy utilization, which leads to a relative energy shortage. Alternatively, this may be evidence that environmental factors are important in the etiology of both MH and EHI. This overlap in the clinical presentations suggests that MH and EHI might have a common etiology.
Physiological and biochemical studies of skeletal muscle from a porcine model of MH, as well as human tissues, have revealed that the inhalational anesthetics cause a massive unregulated release of Ca2+ from the sarcoplasmic reticulum through the type I ryanodine receptor (RYR1), which overwhelms the normal mechanisms of the cell to control cellular Ca2+ levels (e.g., ATP-dependent Ca2+ pump, calcium sinks, and binding sites (mitochondria)). In addition, muscles from MH-susceptible pigs and humans are hypersensitive to agonists such as caffeine, halothane, and 4-chloro-m cresol that stimulate the release of Ca2+ from RYR1.
Diagnosis of susceptibility currently relies on the measured in vitro contracture responses of skeletal muscle to these agonists. Two standardized tests, the North American test called the caffeine halothane contracture test (CHCT), and the European test called the in vitro contracture test (IVCT), are widely used to diagnose patients as MH-susceptible or MH-negative. Both tests are highly sensitive (93–97%), but not highly specific (78–93%), and are invasive, requiring a surgical biopsy of leg muscle (Vastus lateralis). The search is ongoing for methods to improve the diagnosis with a less invasive and more specific test. Magnetic resonance spectroscopy has been used to diagnose MH noninvasively, and changes in the content of adenosine triphosphate, phosphocreatine, and other phosphomonoesters, along with intracellular pH, have been measured in MH patients. However, because most of the observed changes are similar to those seen in other muscle disorders, the technique lacks the required specificity to diagnose MH (9). Sei et al. reported that RYR1 is expressed in human lymphocytes (B cells), where it regulates an intracellular pool of Ca2+ (12). Thus measurements of B cell Ca2+ have the potential to diagnose MH, but require further validation.
MH susceptibility exhibits an autosomal dominant mode of inheritance. The condition demonstrates both locus and alleleic heterogeneity with six loci implicated so far. However, one locus, the RYR1 on chromosome 19, accounts for at least 50% of MH-susceptible cases. At least 40 point mutations have been identified within three main regions, or “hot spots,” in the gene (7) (Fig. 1). A panel of the 17 most frequent causative mutations in the RYR1 has been identified, and will be offered to supplement CHCT diagnostic testing for MH in North America in 2004. A similar program has been used safely in Europe since 2001. Another causative gene identified encodes the alpha subunit of the dihydropyridine receptor, (L type Ca2+ channel) on the muscle plasma membrane, but very few patients have been identified with mutations in this gene.
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Figure 1.: RYR1 gene structure and mutational hot spots. Terminal domains are indicated as NH2 and COOH, respectively. Myoplasmic and transmembrane domains are shown at the bottom, and downward arrows indicate DHPR and calmodulin binding sites. Boxes indicate mutational hot spots, with amino acid numbers below. The ovals represent mutations associated with malignant hyperthermia (light gray), central core disease (black), or both (dark gray). DHPR, dihydropyridine receptor; RYR1, ryanodine receptor type I. (Reprinted from Miller, R., et al. Miller’s Anesthesia. Elsevier 1999. Copyright © 1999 Elsevier Science. Used with permission.)
Susceptibility to MH is not confined to humans; it also occurs in dogs, horses and, most importantly for research into the etiology of MH, a specially inbred strain of pigs. In this porcine model of MH, a single mutation in the RYR1 gene (Arg615Cys) causes the disease. All pigs homozygous for the disorder develop acute, i.e., fulminant, malignant hyperthermia episodes in response to inhaled anesthetics, but also in response to heat and/or other behavioral stressors. Interestingly, in the homozygous pig, a period of mild exercise 1 h before anesthesia accelerates progression of clinical signs and shortens time to death. Similarly, in susceptible humans, the acute syndrome may occur more readily after the stress of physical exercise. This is supported by reports from the Danish Malignant Hyperthermia registry of acute fulminant episodes in injured athletes under anesthesia (8). Perhaps the combination of a mutated RYR1 gene, coupled with either a triggering anesthetic or exercise-induced muscle perturbations that release inflammatory mediators, is needed to unmask differences.
EXERTIONAL HEAT ILLNESS AND HEAT STROKE
Heat stroke, the most severe form of EHI, is a life-threatening acute illness characterized by hyperthermia (above 40.6°C) and neurological abnormalities that occur after exposure to high ambient temperature and humidity. Heat stroke from high environmental temperature is called classic, or nonexertional, heat stroke, whereas heat stroke from strenuous exercise is called exertional heat stroke (EHS). Classic heat stroke occurs most commonly in elderly and infirm persons during heat waves, and is characterized by three prominent findings: high temperature, anhidrosis (skin usually dry and flushed), and profound dysfunction of the central nervous system. There is no known association between classic heat stroke and MH.
Exertional heat stroke, as the name implies, is a hyperthermic state in which heat is produced by muscular work at a rate that exceeds the body’s capacity to dissipate it. Subjects are usually normal and healthy working in the heat. Since transient hyperthermia can occur with massive exercise without apparent illness, the diagnosis of EHI cannot be made on the basis of hyperthermia alone. In contrast to classic heat stroke patients, exertional heat stroke victims retain the ability to sweat; therefore, fluid and electrolyte losses may amount to 2 L·h−1 or more. Neurological impairment may first appear through inappropriate behavior or impaired judgment, which can rapidly progress to delirium, seizure activity, and coma. All EHI patients have tachycardia and may present with high cardiac output, moderately decreased blood pressure, low peripheral resistance, and moderately elevated central venous pressure. These hemodynamic alterations are correctable by adequate fluid and electrolyte replacement and cooling. Other patients can present with a hypodynamic cardiovascular system (low cardiac output, low blood pressure, and high central venous pressure). These patients require aggressive hemodynamic support. Metabolic acidosis and electrolyte disturbances are common at time of admission. Liver function abnormalities are invariably present.
In addition to the typical signs of heat stroke, patients with exertional heat stroke present with muscle membrane destruction (rhabdomyolysis, elevated serum creatine kinase, myoglobinuria, and hyperkalemia). The most serious complications are those falling in the category of multi-organ dysfunctional syndrome. These include encephalopathy, rhabdomyolysis, acute renal failure, acute respiratory failure, myocardial injury, hepatocellular injury, intestinal ischemia, and infarction and hemorrhagic complications, especially disseminated intravascular coagulation. It should be noted that any or all of these complications has been described alone or in combination in patients dying from untreated or inadequately treated MH, underscoring the overlap in clinical appearance of these two disorders.
Current concepts in the progression of EHI to EHS have presented evidence that a systemic inflammatory response is important in the pathogenesis (2). In the acute phase response, interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα) have been most extensively studied. Because core body temperature is normally held constant by the hypothalamic set point of 37°C, a net gain in body heat must be dissipated with a redistribution of cardiac output from internal organs to the cutaneous circulation. This results in splanchnic vasoconstriction, which can cause gastrointestinal ischemia, with subsequent damage to the intestinal mucosal membrane. Damage to intestinal mucosa may lead to hyperpermeability and leakage of endotoxin, which in turn activates macrophages and stimulates the immune system to produce inflammatory cytokines, including TNFα, interleukin-1β, IL-6, and others. IL-6 levels correlate with the severity of heat stroke and decrease toward normal with cooling. Inflammatory cytokines, IL-6, IL-1β, and IL-10 appear to be produced locally in skeletal muscle in response to exercise, which may contribute to the development of heat stroke. However, the role of skeletal muscle as a cofactor or signaling pathway in the initiation of EHI has not been determined.
In summary, EHI appears to be a continuum, with different clinical presentations sharing certain common mechanisms. Besides dehydration and hyperthermia, a systemic inflammatory response may be important in the pathogenesis, and muscle injury may contribute to or aggravate the pathogenesis. A better understanding of the inflammatory processes in EHI may lead to other means of prevention and/or treatments.
RELATIONSHIP BETWEEN MALIGNANT HYPERTHERMIA AND EHI
Figure 2 illustrates the known pathways for development of the potentially lethal hyperthermia from MH and EHI. In the case of MH, hyperthermia is the consequence of uncontrolled massive release of Ca2+ and the hypermetabolic changes resulting from cellular efforts to retain Ca2+ control. Chief among the cellular alterations are severe depletion of energy stores and muscle contracture. Pyrogenic cytokines released from damaged muscle can raise the set point of the hypothalamic thermoregulatory center. It is conceivable that the release of cytokines from muscle could contribute to the hyperthermia in MH. This hypothesis requires future testing in vivo, but there is in vitro evidence in its support. Girard et al. (5) demonstrated that immortalized B cells from MH-susceptible individuals expressing the RYR1 mutation (V2168M), stimulated to release Ca2+ with caffeine and 4-chloro-m cresol produced five times more interleukin (IL)-1β compared to cells from healthy controls. Furthermore, dantrolene abolished IL-1β release from these cells, thus providing additional pharmacological evidence for involvement of cytokines in the pathophysiology of MH. Ducreux et al. (4) reported that in human myotubes the abnormal release of calcium via mutated RYR1 (V2168M) enhance the production of the inflammatory cytokine IL-6.
Figure 2.:
Pathways for the development of malignant hyperthermia (MH) and exertional heat illness (EHI). In MH the mechanisms of heat generation during anesthesia are a consequence of the uncontrolled release of Ca2+ from the sarcoplasmic reticulum through the RYR1 in skeletal muscle (solid arrow). Elevations in Ca2+ concentrations cause muscle contracture and disruption of muscle membrane. This trauma to the muscle fibers may lead to the production of pyrogenic cytokines either directly from the muscle (dotted arrow), or indirectly through activation of formed elements of the immune system, such as macrophages and neutrophiles (stippled arrow). Pyrogenic cytokines elevate the thermoregulatory set point in the hypothalamus. The mechanism of exercise-induced MH could follow the same pathway as anesthetic-induced MH (bold arrow). Exercise-induced heat illness stimulates the thermoregulatory center in the hypothalamus to redistribute the cardiac output to skin and muscle for heat dissipation and energy demand, respectively. This in turn causes a relative ischemia in the splanchnic organs, likely associated with formation of reactive oxygen/nitrogen species that can damage the mucosal membrane of the intestines. As a consequence, endotoxin can enter the systemic circulation and stimulate the immune system with the formation of pyrogenic cytokines. RYR1, ryanodine receptor type I; CNS, central nervous system; GI, gastrointestinal.
In EHI the sequence of events is fundamentally different from that in MH. As discussed, with prolonged exercise or work in the heat, a progressive increase in skin and muscle blood flow displaces blood flow from the mesenteric circulation, leading to ischemia of the gut, intestinal wall hyper-permeability, and leakage of intestinal contents into the systemic circulation, resulting in endotoxemia. Studies have reported increased levels of endotoxins and cytokines in humans subjected to strenuous exercise. When athletes exercise at 80% or more of their maximal oxygen consumption, concentrations of endotoxin, inflammatory cytokines, and acute phase proteins increase in the blood (2).
How does this information help differentiate between MH and EHI in a patient who collapses while exercising in the heat, or one with a history of MH who collapses? Can MH be triggered by strenuous exercise? Exercise testing under standardized conditions has been performed in several institutions, and it has consistently been reported that known MH-susceptible patients fail to show differences from non–MH-susceptible patients in terms of temperature, metabolic and electrolyte parameters (6). However, it seems that the MH-susceptible subjects in these studies did not include the subset of MH patients who have had symptoms with exercise, stress and heat (14).
Other important questions that have been raised are: Is the individual who has suffered an MH crisis under anesthesia at increased risk of exertional heat stroke? Is the person who has one or two episodes of exertional heat stroke at increased risk of MH when given an inhalational anesthetic? One way to address these questions is to perform the diagnostic contracture tests (CHCT/IVCT) for malignant hyperthermia on individuals who have collapsed from EHI. A number of clinical investigators have performed such studies, and about 1/3 of the reported cases have been diagnosed as MH-susceptible. The strongest evidence linking MH and exercise-induced muscle symptoms has been reported by Wappler et al. (15). These investigators performed IVCT on 12 patients presenting with symptoms of muscle membrane breakdown (rhabdomyolysis) and muscle cramps with exercise. Ten patients were MH-susceptible, one was normal, and one had an equivocal result. Of the 10 MH-susceptible patients, three had mutations causative for MH in the RYR1. The number of patients in other studies is too small to permit a general conclusion about the specific relationship between MH and EHI with confidence.
Table 1 presents further data addressing the relationship of EHI, positive IVCT/CHCT, and RYR1 mutation analysis. When mutations are found in the RYR1, they confirm the diagnosis of MH. In cases where an RYR1 genetic mutation was not identified, there are at least two explanations. The first is that although these persons are MH-susceptible, the RYR1 defect could not be detected because current RYR1 screening examines only selected “hot spots,” and not the entire gene. The second explanation is that the genetic defect may not be on the RYR1 gene. MH is clinically and genetically heterogeneous. Mutations could reside in one of the other loci known to be associated with MH or in the mitochondrial genome. The only large series of EHS patients who have undergone IVCT testing was reported by Bendahan et al. (1). These investigators reported on 26 exertional heat stroke cases diagnosed as MH-susceptible. However, genetic analysis, which would have been informative, was not given.
TABLE 1: Published articles addressing the relationship across EHI, positive IVCT/CHCT, and RYR1 mutation analysis
CLINICAL RELEVANCE
The following two cases illustrate the value of RYR1 genetic analysis in EHI or MH susceptibility. The first case is of a 12-yr-old boy who underwent general anesthesia with an inhalational anesthetic for reduction of a humerus fracture. Fifteen min after induction of anesthesia, he showed signs of hypermetabolism, with an increase in end tidal CO2, an increase in heart rate to 150 bpm, and an increase in temperature. Diaphoresis (severe sweating), but not muscle rigidity, was observed. Later he was found to have a maximum serum creatine kinase of 9,000 U·L−1. A diagnosis of MH was made. He was treated with dantrolene and supportive measures, and recovered without sequelae. Eight months later a catastrophic development occurred when the boy participated in a football game at ambient temperatures near 80°F. After the game he complained of muscle stiffness and ascending weakness as he showered. Emergency medical personnel found him hot, sweating profusely, with a rapid respiratory rate, and complaining of tingling in his extremities. Seizure activity and respiratory arrest ensued. Endotracheal intubation was unsuccessful because of jaw rigidity, and ventricular fibrillation developed. On arrival at the hospital his temperature was 108°F, he was severely acidotic, and serum potassium was elevated to 8.8mEq·L−1. He was given dantrolene in addition to other resuscitation medications. Postmortem analysis of DNA revealed an altered RYR1 gene sequence with a substitution of Arg163Cys, identified as causative for MH (12). The same mutation was later found in his father. If the mutation information had been available before the heat stroke incident, MH experts might have counseled this athlete and his family against competitive sports in hot and humid weather, and dantrolene could have been more readily available for treatment.
The second case is of a 16-yr-old male who presented to an emergency room at a local hospital unresponsive, hyperthermic (rectal temperature 42.2°C), respiratory rate 58 breaths·min−1, heart rate 168 bpm, sweating profusely and cyanotic, immediately after football practice in 80°F weather. The patient previously had been well, except for one episode of rhabdomyolysis 7 d before, when he had complained of generalized muscle cramps. All of his clinical tests were normal, except for his serum creatine kinase, which was elevated to 1400 Units. Following a few days of rest, he resumed football practice. In the emergency room he was diagnosed with EHS and placed on controlled ventilation. He had a metabolic acidosis with a base deficit of −8.5mEq·L−1; his serum potassium was moderately elevated to 5.9mEq·L−1. Active cooling, sodium bicarbonate, dantrolene, diuretics, and fluid and electrolyte administration lowered his temperature to 39°C. However, the next day he developed multi-organ dysfunction with liver failure, cardiac dysfunction, severe rhabdomyolysis, and disseminated intravascular coagulation, prompting institution of plasma exchange. He recovered over the next 14 d. Several months later he underwent a CHCT and RYR1 genetic screen to determine if he was MH-susceptible. The CHCT and the RYR1 genetic screen were negative, and the patient was diagnosed MH-negative. Although the MH diagnostic work was negative, this athlete appears predisposed to EHI, the genetic basis of which remains to be identified. Alternatively, the athlete is not practicing common sense measures (acclimatization and adequate hydration) to avoid the adverse effects of strenuous exercise in the heat.
Effects of Dantrolene in Exertional Heat Illness and Malignant Hyperthermia
Dantrolene is a direct acting skeletal muscle relaxant that alters muscle contractility. Its relaxant effect appears to be mediated by inhibiting release of Ca2+ from intracellular storage sites in the sarcoplasmic reticulum. Dantrolene is the drug of choice for treating acute episodes of MH. It has been studied for possible use in heat stroke during pilgrimages to Mecca, but no statistically significant differences have been noted between the dantrolene-treated and control groups. Heat stroke in these pilgrims may be classic or exertional, but dantrolene may only be effective in the latter. Of interest is the finding that dantrolene is effective in the treatment of muscle membrane breakdown associated with both MH and exertional rhabdomyolysis. Other recent data indicate that dantrolene, when used in an animal model of septic shock, decreases plasma and tissue concentrations of inflammatory cytokines and improves survival. This observation could be a stimulus for new research on therapies for EHI/MH. Additional investigations, both functional and genetic, would be useful to clarify the clinical efficacy of dantrolene in the treatment of acute EHI.
CONCLUSION
EHI and MH are two potentially deadly diseases. Although the trigger mechanism for EHI is different from that of MH, both conditions can lead to cellular energy depletion with intracellular acidosis, calcium accumulation, and excessive heat production. These processes may overwhelm the heat-dissipating capacity of the organism and result in fatal multiple organ failure. In both MH and EHI, multiple organ failure could be mediated in part by cytokines, as endotoxin-induced cytokine release by the gut may occur in any patient whose temperature exceeds 40°C. The majority of MH-susceptible cases, and some heat stroke cases, have an abnormality in the RYR1 gene. Screening heat stroke victims for mutations in this gene is a new and valuable tool for insight into the relationship between EHI and MH.
Emergency treatment for patients with signs of EHI should include intravenous fluids and aggressive cooling. Re-breathing bags and masks should not be used to slow the respiratory rate, because fast respiratory rates compensate for metabolic acidosis. A complete history including risk factors for heat-related illness and MH should be obtained in all EHI cases. In the presence of either a personal or a family history of MH, dantrolene should be given in a therapeutic dose as soon as possible.
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