eat- and/or exercise-induced rhabdomyolysis is a problem that plagues military recruits in basic training, physically fit and well-conditioned career military service members and the physicians called upon to treat them. It is clear that under extreme physical and environmental conditions, anyone may develop rhabdomyolysis. Less clear, though, is who is predisposed, who will develop sequelae, who will have recurrence and who should be retained or discharged from the military. It is not surprising when rhabdomyolysis occurs in poorly conditioned, un-acclimated military recruits asked to perform extreme physical activity in extreme heat. More vexing are the sudden and unexplained cases of rhabdomyolysis in the physically fit, well-conditioned and acclimated service members who have been exercising all their lives without previous problems. At the Uniformed Services University of the Health Sciences (USUHS), neurologists, sports medicine specialists, geneticists and anesthesiologists have collaborated to address this problem in a variety of clinical and laboratory protocols.

A U.S. soldier operates a bulldozer on a construction project near Balad, Iraq. His unit, which works seven days a week, switched its operations from day to night to avoid the brutal desert heat. Photo courtesy of U.S. Army 2nd Lt. Mike Bennon.

The associations between unexplained exercise-induced rhabdomyolysis, asymptomatic hyperCKemia and malignant hyperthermia (MH) are strongly suggested by the literature.^1-3 Wappler et al. performed the in vitro contracture test (IVCT), the only validated European diagnostic test for MH susceptibility, on muscle biopsies from 12 unrelated patients with exercise-induced rhabdomyolysis and no prior personal or family histories of MH. Ten of these 12 had positive contracture tests, and three of those 10 were found to have mutations in the ryanodine type 1 receptor gene (RyR1),² the gene most likely associated with MH susceptibility.⁴

For many years, the protocol for evaluation of rhabdomyolysis at the Walter Reed Army Medical Center has included consultations with neurologists or rheumatologists with muscle biopsy for standard histology and histochemistry. The results of these biopsies, however, were frequently normal or showed nonspecific changes. These results were a stimulus for a new protocol to investigate the link between MH and rhabdomyolysis in a more systematic manner. In 2006, six healthy, physically fit career service members without family or personal histories of MH symptoms developed repeated unexplained episodes of exercise-induced rhabdomyolysis and were referred to USUHS for the caffeine-halothane contracture test (CHCT), the North American equivalent to the IVCT.

Four were CHCT-positive by North American MH standards. Molecular genetic screening of the entire RyR1 gene for mutations causative for MH and screening of genes for the metabolic myopathies commonly associated with rhabdomyolysis — namely carnitine palmitoyltransferase deficiency, adenosine monophosphate deaminase deficiency and muscle glycogen phosphorylase deficiency — will be completed in the coming months.

The CHCT was developed and validated as a diagnostic test for MH following a clinical event suspicious for MH. In that development process, the sensitivity was 97 percent, but the specificity was only 78 percent,⁵ indicating a 22-percent false positive rate. Since clinical correlation of MH was used to validate the CHCT, it is difficult to know if patients with rhabdomyolysis and positive CHCT are truly MH-susceptible or false positives. While there may be a commonality of a ryanodine receptor mechanism for both disease processes since some people with prior clinical episodes of MH are at increased risk of developing heat- and exercise-related problems in their futures,6 it also is important to make the distinction that the vast majority of heat stroke and exertional rhabdomyolysis cases are not related to MH susceptibility.

The colored flags raised around this stateside Marine base signify to units engaging in physical training what kind of training is authorized under the present heat conditions. When a black flag is raised, signifying the average temperature on base is 90 degrees Fahrenheit or higher, commanders are encouraged to avoid any unnecessary training to prevent heat injuries. Photo courtesy of Lance Cpl. Kaitlyn M. Scarboro.

While mutations in the RyR1 gene are the most likely causative mutations associated with MH susceptibility, there are a multitude of other candidate genes that are being explored with regard to rhabdomyolysis. In previous studies, RyR1 mutations were found in only 22 percent to 25 percent of people who were CHCT positive^7,8 when screening for the North American panel of the most common mutations.9 The current strategy, based on results from Japan and several European centers, recommends screening the entire RyR1 gene, the approach now employed at USUHS. Experts have agreed that complete RyR1 gene sequencing is required for all CHCT-positive patients, a complex task given the gene’s size at more than 159,000 nucleotides.

Although the incidence of MH is rare, estimated at one in 50,000 adults undergoing general anesthesia,¹⁰ two recent epidemiologic studies estimate the incidence of RyR1 mutations at 1 in 2,000 in the general population.^11,12 The fact that MH-susceptible people do not develop detectable signs and symptoms each and every time they are exposed to anesthetic triggering agents may be due to MH being a subclinical myopathy that is not manifest more often because of “variable expression.” This raises the possibility that unknown MH-susceptible people are developing other signs and symptoms, namely those manifested as rhabdomyolysis. Since the defect in MH occurs at the level of skeletal muscle calcium regulation,¹³ compensatory homeostatic mechanisms occurring at the cellular level likely prevent detection by insensitive clinical monitors measuring global physiologic responses. Detection by standard anesthesia monitors likely occurs only after cellular decompensation takes place. Because of the possible association, however, it may be prudent to administer non-MH-triggering agents to patients with histories of rhabdomyolysis.

Other environmental factors have been implicated as precipitators of rhabdomyolysis, including the ingestion of dietary supplements such as creatine monophosphate, ephedrine-based products and anabolic steroids.^14-16 Still, people develop rhabdomyolysis when denying use of these products. Military physicians are faced with the problem of what to do with service members who develop recurrent rhabdomyolysis, positive CHCT or clinical MH events. Service members are required to be worldwide deployable and combat ready. This means being stressed with extreme physical labor in desert climates such as Iraq.

Department of Defense regulation 6130.4 states that MH is a disqualifying condition for appointment or enlistment into the armed services. Retention of service members identified as MH-susceptible, however, is often left to the discretion of the individual service branches. There are multiple justifications for military discharge, including nonavailability of dantrolene in forward-deployed units, insufficient resources to treat an MH crisis during a mass casualty and the unpredictability of environmental exposures triggering an MH crisis. Service members also may be discharged at the discretion of the individual branches for rhabdomyolysis, myoglobinuria or heat stroke regardless of any connection to MH or CHCT results. These decisions are based on the severity of the illness and the impact on the performance of duties.

Are people with histories of rhabdomyolysis and positive CHCT truly MH susceptible? These classifications have huge personal and professional ramifications. Presently the discharged service member with a diagnosis of MH susceptibility receives no medical disability compensation because the military considers it an inherited pre-existing medical condition prior to enlistment and not a military service-related injury. The Department of Veterans’ Affairs, however, has been known to award disability benefits, but the service members had to apply for them. Furthermore the respective service branches do not apply the rules equally; some service members are retained while others are discharged. These policies and their sometimes arbitrary applications are just as disconcerting as the diagnosis to the service members and their physicians. This apparent discrepancy among the service branches could be a fruitful topic of discussion for the ASA Committee on Uniformed Services & Veterans’ Affairs.

Acknowledgement: I would like to thank Sheila M. Muldoon, M.D., for her assistance in preparing this article.

References:
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John F. Capacchione, M.D., is Assistant Professor, Uniformed Services University of the Health Sciences, Walter Reed Army Medical Center, Bethesda, Maryland, and Washington, D.C.