Malignant Hyperthermia: From the OR to the Sidelines

Malignant hyperthermia (MH) is an autosomal dominantly inherited pharmacogenetic disease characterized by a life-threatening syndrome of abnormal rapid heat production in skeletal muscle of animals and humans. The syndrome occurs after exposure to certain anesthetic drugs and is initially expressed by increases in oxygen consumption and concomitant carbon dioxide production. This can be followed by tachycardia, metabolic acidosis, rapid increases in core temperature, and skeletal muscle rigidity. If not diagnosed and treated early, MH can progress to stages of skeletal muscle cell necrosis, hyperkalemia, arrhythmias, and death. If the syndrome does not have a lethal outcome, there can be morbity from rhabdomyolysis, such as risks from renal failure or from disseminated intravascular coagulopathy. After the discovery of MH, it was soon determined that mortality was 70%, and no effective treatment was available. It became the anesthesiologist's worst nightmare as otherwise healthy individuals presenting for routine, minor surgical procedures were dying from MH. During the 20-year period after its discovery, published MH episodes exhibited clinical mayhem as treatment was completely symptomatic and often unsuccessful. The research of MH has resolved the etiology to a molecular level, provided essential diagnostic testing, and discovery of a unique efficacious drug for treatment. These historical events represent an excellent model for translational medicine as basic scientists and clinicians interacted to solve the mysteries of a disease and provide effective means of diagnosis and treatment. MH is Discovered The significance of the original 1960 MH report by Denborough and Lovell (1) went unnoticed for almost 6 years and not until a Canadian anesthetist, Dr. Beverly Britt, began searching the literature for evidence of why a patient she assisted with died an unusual death. Britt, working with Dr. Werner Kalow, the father of pharmacogenetics, discovered that survivors of MH and some of their relatives had abnormal in vitro skeletal muscle contracture responses to caffeine (2). Dr. Britt also learned of a group of families in Wisconsin that were experiencing the MH episode and working with Dr. Locher, pedigrees confirmed the report by Denborough that MH was genetically predisposed. The publication of these findings triggered the publishing of several MH case reports, and it was finally introduced as a true clinical entity. MH Diagnostic Test The finding by Britt and Kalow that MH skeletal muscle biopsy produced abnormal contracture response to caffeine provided a means of testing for susceptibility. Subsequent research showed that MH muscle biopsy also produced abnormal contracture responses when exposed to halothane. These abnormal, in vitro pharmacologic responses of MH muscle not only provided a diagnostic test but also revealed the site of defect. Although limited genetic screening for MH is possible, the in vitro skeletal muscle contracture test remains the gold standard for MH diagnosis. This in vitro test is invasive (anesthesia and surgery for biopsy), expensive, and is performed only at a few specialized centers. MH Etiology Malignant hyperthermia is caused by defective calcium regulation in skeletal muscle (3). Increased myoplasmic calcium concentrations activate contraction and metabolism, and in normal muscle, the changes in calcium concentration during excitation–contraction coupling are finely controlled. The majority of human MH is caused by mutations in the RYR1 calcium channel, and these can, under certain environmental conditions, produce sustained increases in calcium concentrations and hypermetabolic consequences. Research has shown that trigger anesthetics cause MH by increasing the open state of the mutant RYR1 calcium channel which produces the sustained myoplasmic concentrations of calcium. Treatment for MH is Discovered The only treatment of MH when it occurred in the operating room (OR) was to immediately stop the trigger anesthetic and treat symptomatically. The earlier the diagnosis was made, the less likely mortality and morbidity would occur. A late diagnosis followed by symptomatic treatment increases the incidence of mortality. An effective treatment drug was desperately needed. A pharmacologist at Norwich Eaton Pharmaceuticals discovered a drug that had unique skeletal muscle relaxant properties. The muscle relaxants used in anesthesia act at the neuromuscular junction outside the muscle cell, and the nondepolarizing drugs, like curare, were ineffective in treating MH. The depolarizing relaxants, like succinylcholine, actually exacerbate the MH syndrome. Dantrolene acts inside the muscle cell and decreases contractility by blocking calcium release. Dr. Gaisford Harrison obtained dantrolene and tests in MH pigs determined that it was efficacious for treating and preventing MH. However, only oral formulation of dantrolene was available, and desperate attempts were made to dissolve the drug for emergent intravenous administration. Norwich Eaton produced an intravenous formulation that was quickly approved by the U.S. Food and Drug Administration. A study in pigs determined that 95% of the maximum dantrolene effect was efficacious for treatment of MH. A similar study in normal, human volunteers determined that 2.5 mg/kg would produce the same effect and was used as the recommended dose. As a consequence of these research efforts, dantrolene became available in ORs around the world, and mortality was changed from 70% to less than 2% today. Porcine Stress Syndrome Our research with pigs at the College of Veterinary Medicine at Oklahoma State University led to discovery that some pigs were dying of anesthetic-induced MH and others by stress alone. By selectively breeding pigs to improve skeletal muscle mass and quality, the swine industry inadvertently selected the RYR1 mutation that predisposed pigs to lethal stress and anesthetic syndromes. For the swine industry, this was disastrous, but for human MH research, it provided a spontaneous animal model which could be used to determine which drugs are safe and which are not, a supply of affected muscle for etiologic investigation and for many other types of experiments. The MH pig results also raised the possibility that MH humans might develop the syndrome from various stressors, such as exertion and heat. MH Episodes Outside The OR During a 25-year period of MH diagnostic testing, we had no basis for counseling susceptible families about avoiding stressors, such as heat or exercise. We simply advised them to use good judgments. However, recent publications indicate that RYR1 mutations may be predisposing to events, such as exertional heat illness (4–8). It is difficult to address the semantics of this issue and define what is and is not MH. Our past arena of thinking was influenced by the full-blown clinical episode of MH where rapid increases in oxygen consumption, metabolic acidosis, hyperthermia, and skeletal muscle rigidity were the criteria for an unequivocal diagnosis. A clinical grading scale was produced by which the likelihood of an event being MH or not was assessed (9). Our semantics of MH may require change as there may be a spectrum of clinical consequences caused by RYR1 mutations that include MH. It also is possible that some RYR1 mutations may respond to stressors but not to anesthetic drugs. These issues can only be resolved by appropriately designed studies from which conclusions can be made. Genetic studies have shown that RYR1 mutations are not as rare as the occurrence of MH as 1 in 500 healthy individuals are heterozygous for loss of function variants in RYR1. This is much higher than the incidence of MH in the OR so what is the explanation? There are too many variables to conjecture or attempt to answer the question but we can list a few. First is that we do not know which of these RYR1 mutations have consequence and which do not. What is becoming known is that exertion-induced episodes of hyperthermia and/or rhabdomyolysis are occurring in individuals with RYR1 mutations but how many of these are MH susceptible is not known. We can state that not all MH susceptible individuals are prone to exertional heat illness because some of these are professional or amateur athletes who have not had exercise-related issues. Studies in pigs demonstrate the importance of body temperature for the development of the MH syndrome. Our studies showed that lowering the pig’s core temperature from 39°C to 36°C ablated the hypermetabolic response to halothane and that cooling the body provided protection. As shown in MH pigs and RYR1 knock-in mice, MH can be triggered in the absence of trigger drugs by simply raising the core temperature above normal. How these findings relate to heat-induced syndromes in athletes remains unknown, but our report of the death of a young football player who had previously survived an episode of MH draws attention to the possibility that some MH individuals may be more susceptible to a heat-induced syndrome (10). In the future, improved technology will help establish the genotype/phenotype relationships for these environmentally induced syndromes and avoid the mortality and morbidity they cause. In the meantime, vigilance in the OR and on the sidelines will detect the syndrome onset and demand appropriate treatment. The Malignant Hyperthermia Association of the United States is available to everyone as a source of information and maintains an MH hotline for emergency or clinical consultation.

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