Exertional Heat Stroke and Susceptibility to Malignant Hyperthermia in an Athlete: Evidence for a Link?

Abstract

Objective: To describe the possible association (pathophysiologic and clinical features) between exertional heat stroke (EHS) and malignant hyperthermia (MH).Background: Both EHS and MH are acute and lifethreatening disorders. It has repeatedly been shown that EHS can occur in well-trained patients with known MH-associated mutation in the RYR1 gene in the absence of any extreme environmental conditions or extreme physical activity, thereby supporting a possible link between EHS and MH. In this case, a highly trained 30-year-old male athlete suddenly collapsed while running. He had initial hyperthermia (40.28C) and progressive multiple organ failure requiring medical management in an intensive care unit. After he recovered completely, a maximal exercise test was performed and showed an obvious abnormality of oxidative metabolism in muscle; genetic analysis of the RYR1 gene identified a heterozygous missense variation p.K1393R. Consequently, the athlete was given appropriate information and allowed to progressively return to sport competition.Differential Diagnosis: Doping, use of drugs and toxic agents, exercise-associated hyponatremia, exertional heat illness.Treatment: Initial management started with the basic resuscitative guidelines of airway, breathing, and circulation (intubation). Cooling, administration of fresh frozen plasma, and intensive rehydration resulted in improvement.Uniqueness: To our knowledge, ours is the first description of this MH mutation (p.K1393R) in the RYR1 gene that was associated with exertional rhabdomyolysis involving a dramatic impairment of oxidative metabolism in muscle.Conclusions: Common features are shared by EHS and MH. Careful attention must therefore be paid to athletes who experience EHS, especially in temperate climates or when there are no other predisposing factors.

Heat-hypersensitive mutants of ryanodine receptor type 1 revealed by microscopic heating

“…In summary, by taking advantage of local heating technology, we demonstrated that abnormal RyR1 heat sensing caused HICR in RyR1 mutant–expressing HEK293 cells and in skeletal muscles from MH mice. These findings suggest that an additional positive feedback loop between thermogenesis and heat-sensing via heat-hypersensitive RyR1 mutants irrepressibly elevates body temperature during MH and, presumably, during exertional heat stroke under extreme environmental conditions ( 63 – 65 ).…”

Individual risk factors associated with exertional heat illness: A systematic review

“…Health conditions: Hypohidrosis (Lim et al., 2016); malignant hyperthermia (Poussel et al., 2015); altered cytokine production (Chang, 1993); type II fibre predominance (Hsu, Lee, Chang, Shieh, & Tsao, 1997); burns (Seth & Juliana, 2011); sympathectomy (Sihoe, Liu, Lee, Lam, & Cheng, 2007); sickle cell trait (Singer et al., 2018)…”

“…Individual volition Armstrong et al (1990) Being overweight or obese Bedno et al (2010Bedno et al ( , 2014; Chung and Pin (1996); Donoghue and Bates (2000); Epstein et al (1999); Gardner et al (1996); Moore et al (2015); Rav-Acha et al ( 2004 (Epstein et al, 1999;Armed Forces Health Surveillance Center, 2009Nelson et al, 2018b); sex (Armed Forces Health Surveillance Center" 2009Nelson et al, 2018a); ethnicity (Carter et al, 2005) Health conditions: Hypohidrosis (Lim et al, 2016); malignant hyperthermia (Poussel et al, 2015); altered cytokine production (Chang, 1993); type II fibre predominance (Hsu, Lee, Chang, Shieh, & Tsao, 1997); burns (Seth & Juliana, 2011); sympathectomy (Sihoe, Liu, Lee, Lam, & Cheng, 2007); sickle cell trait (Singer et al, 2018) Environmental factors Accumulation of thermal load (previous day of exposure); (Garzon-Villalba et al, 2006;Wallace et al, 2006); high wet-bulb globe temperature (Day & Grimshaw, 2005;Garzon-Villalba et al, 2006; Organizational factors Branch of Armed forces and personnel rank (Bedno et al, 2014;Armed Forces Health Surveillance Center, 2009Nelson et al, 2018a); early stage of recruit training and aptitude on entry (possible link to inexperienced personnel; Nelson et al, 2018b); intense physical work (Armstrong et al, 1990;Day & Grimshaw, 2005;O'Donnell, 1975); time into exercise (suggestive of rate of temperature increase; Epstein et al, 1999); geographical region (Be...…”

Malignant hyperthermia susceptibility in patients with exertional rhabdomyolysis: a retrospective cohort study and updated systematic review

“…18,21 The remaining RYR1 variants were rare variants of unknown significance (VUS) and several neutral polymorphisms (Table 2). [17][18][19][20][21][22][23][24][25][26][27][28][29] There were five CACNA1S variants, p.Arg498His, p.Ser516Leu, p.Ser606Asn, p.Arg683Cys, p.Thr852Met, identified in this cohort. These rare variants (minor allele frequency\1%) are of unknown significance and have not been reported in association with MH.…”