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Hypothesized overlapping mechanisms observed in awake cases of MH leading to EHS-like symptoms. Exposure to haloalkane anesthetics triggers Ca²⁺ release within the myofibers. Sustained contractions and heat production cause hyperthermia. Skeletal muscle rigidity may lead to rhabdomyolysis (i.e. skeletal muscle breakdown) with myoglobin leakage, which contributes to multi-organ injury. RyR1 ryanodine receptor 1, SkM skeletal muscle

Hypothesized overlapping mechanisms observed in awake cases of MH leading to EHS-like symptoms. Exposure to haloalkane anesthetics triggers Ca²⁺ release within the myofibers. Sustained contractions and heat production cause hyperthermia. Skeletal muscle rigidity may lead to rhabdomyolysis (i.e. skeletal muscle breakdown) with myoglobin leakage, which contributes to multi-organ injury. RyR1 ryanodine receptor 1, SkM skeletal muscle

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Exertional heat stroke (EHS) and malignant hyperthermia (MH) are life-threatening conditions, triggered by different environmental stimuli that share several clinical symptoms and pathophysiological features. EHS manifests during physical activity normally, but not always, in hot and humid environments. MH manifests during exposure to haloalkane an...

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... In perioperative settings, rhabdomyolysis also arises during propofol infusion syndrome in otherwise healthy patients after prolonged propofol administration, despite a potential risk in patients with mitochondrial myopathy [10]. Non-pharmacological rhabdomyolysis could be triggered by physical (trauma, crush-syndrome, burns, electrocution, seizures, compression, and compartment syndrome), chemical (toxins, alcohol, carbon monoxide or cyanide poisonings, heroin, and cocaine), and biological factors (hypoxia, infections, polymyositis, dermatomyositis, and thyroid disorders) [11]. AIR is presented by a diverse clinical picture, ranging from life-threatening hyperkalemia, with cardiac arrest, acute renal failure, and compartment syndrome, to asymptomatically increased CK, electrolyte, and enzyme imbalances [7,8,12]. ...
... A variety of drugs could induce rhabdomyolysis in the perioperative settings, such as neuroleptics, antihistamines, corticosteroids, statins, anti-lipid drugs, alcohol, and substance abuse drugs (heroin, cocaine) [7,16]. Among the non-anesthetic causes are thermal or radiation body exposure, intensive physical activity, infection, emotional stress, caffeine, hyperglycemia, and muscle metabolic dysfunction [8,9,11,14]. Patients with comorbid neuromuscular diseases [14] are also at increased risk. ...
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BACKGROUND Malignant hyperthermia (MH) and anesthesia-induced rhabdomyolysis (AIR) are rare, yet life-threatening complications that need prompt therapeutic actions and logistic preparedness for treatment success. Both conditions are triggered by general anesthetics, particularly volatiles and depolarizing muscle relaxants. In comparison with MH, which is an inherited pharmacogenomic disease of calcium channel receptor subpopulation and arises only after trigger exposure, AIR has been described mostly in patients with muscular dystrophies. In perioperative settings, rhabdomyolysis is also observed during propofol infusion syndrome, neuroleptic malignant syndrome, and cocaine, heroin, and alcohol intoxication. Despite their diverse etiology, the main clinical manifestations of MH and AIR overlap: a hypermetabolic state, hyperpyrexia, hypercarbia, acute renal failure, and hyperkalemia progressing to cardiac arrest, making the therapeutic approach to the patient extremely difficult. CASE REPORT We present an unenviable and challenging clinical scenario of an obligatory general anesthesia with endotracheal intubation in a patient with difficult airways for breast conserving onco-surgery with simultaneous targeted intraoperative 20 Gy irradiation. The case was complicated even further by coincident suspicious clinical presentation of a mild and self-limited hypercarbia, together with a protracted rhabdomyolysis, without hyperpyrexia. Given the atypical and scarce clinical presentation leading to diagnosis uncertainty of MH or AIR, which was proved only after receiving the genetic results, dantrolene was not administered, and the patient underwent successful supportive treatment. CONCLUSIONS The study points to the diagnostic dilemma – crisis event MH or AIR – and raises issues about possible preoperative preventive measures and treatment options in patients with an uncertain diagnosis. Keywords: Dantrolene; Hyperthermia; Rhabdomyolysis; Succinylcholine
... Among active-duty soldiers, those with a prior serious EHI event had four-fold greater odds of experiencing a mild EHI event and those with a prior mild EHI had a 1.8-fold greater risk of having a serious EHI event at a future date (109). Malignant hyperthermia trait has recently been suggested as a predisposing factor for exertional hyperthermia, but this is controversial, and more research is needed (110). ...
Article
Mass participation events include endurance events ( e.g. , marathon, triathlon) and/or competitive tournaments ( e.g. , baseball, tennis, football (soccer) tournaments). Event management requires medical administrative and participant care planning. Medical management provides safety advice and care at the event that accounts for large numbers of participants, anticipated injury and illness, variable environment, repeated games or matches, and mixed age groups of varying athletic ability. This document does not pertain to the care of the spectator.
... However, these data come from case reports. Whether dantrolene treatment is beneficial for EHS still requires randomized, controlled clinical studies [70]. ...
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Neurodegenerative diseases (NDs) refer to a group of diseases in which slow, continuous cell death is the main pathogenic event in the nervous system. Most NDs are characterized by cognitive dysfunction or progressive motor dysfunction. Treatments of NDs mainly target alleviating symptoms, and most NDs do not have disease-modifying drugs. The pathogenesis of NDs involves inflammation and apoptosis mediated by mitochondrial dysfunction. Dantrolene, approved by the US Food and Drug Administration, acts as a RyRs antagonist for the treatment of malignant hyperthermia, spasticity, neuroleptic syndrome, ecstasy intoxication and exertional heat stroke with tolerable side effects. Recently, dantrolene has also shown therapeutic effects in some NDs. Its neuroprotective mechanisms include the reduction of excitotoxicity, apoptosis and neuroinflammation. In summary, dantrolene can be considered as a potential therapeutic candidate for NDs.
... Notable exceptions exist such as highly trained athletes engaged in strenuous exercise may be susceptible to exertional heat stroke (EHS) even within the TNZ, leading to increased mortality risk [18]. Additionally, individuals with genetic variants affecting calcium metabolism, predisposing them to malignant hyperthermia (MH) may develop EHS during exercise indicating that the TNZ is not universally a safe or low-risk thermal environment [19][20][21][22]. ...
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The increasing use of time-series analyses in exploring the relationship between daily ambient temperature and mortality has expanded our understanding of the potential health impacts of climate change. However, it raises significant concerns about the risk of overinterpretation and misattribution of statistical findings. This review examines the methodological assumptions and interpretation pitfalls prevalent in current research on ambient temperature-mortality associations. Extremely elevated ambient temperatures are well-known to elicit physiological stress and increase mortality risk; however, there is no physiological evidence for lethality risk within normal ambient temperature ranges. Despite this, many studies attribute mortality risks across the entire ambient temperature-mortality curve, including normal range ambient temperatures, thus oversimplifying complex underlying physiological processes. Overinterpretation may lead to inaccurate assessments and misguided public health policies. We caution against the tendency to extrapolate results from extreme heat conditions to milder, more typical summer ambient temperature ranges. We advocate for an interdisciplinary approach that combines physiological, clinical, and epidemiological perspectives, with a strong emphasis on the role of behavioral thermoregulation and socio-economic factors to link normal range ambient temperatures with mortality. We recommend analyses centered on excess mortality during defined heatwave periods, and to incorporate heat stress biomarkers to substantiate causal claims for temperatures below heatwaves threshold. A careful approach to interpreting ambient temperature-mortality associations is crucial for formulating evidence-based public health policies.
... Among active-duty soldiers, those with a prior serious EHI event had four-fold greater odds of experiencing a mild EHI event and those with a prior mild EHI had a 1.8-fold greater risk of having a serious EHI event at a future date (109). Malignant hyperthermia trait has recently been suggested as a predisposing factor for exertional hyperthermia, but this is controversial, and more research is needed (110). ...
Article
Mass participation events include endurance events (e.g., marathon, triathlon) and/or competitive tournaments (e.g., baseball, tennis, football (soccer) tournaments). Event management requires medical administrative and participant care planning. Medical management provides safety advice and care at the event that accounts for large numbers of participants, anticipated injury and illness, variable environment, repeated games or matches, and mixed age groups of varying athletic ability. This document does not pertain to the care of the spectator.
... It has been demonstrated that overheating alone can trigger fatal MH in susceptible experimental piglets, thus supporting the association between MHS and heat stroke in humans and between MHS and sudden infant death syndrome, which may be due to overheating [18]. Some patients with environmental heat stroke have been found to have histories or family histories of MH or an association among MH-related genetic defects [26][27][28][29]. A rare case of a non-anesthetic, stress-induced hyperpyrexia death was described in a 12-year-old male who experienced an MH crisis during a humerus fracture operation and 8 months later presented MH followed by sudden death after exertion [27]. ...
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Malignant hyperthermia is a rare but life-threatening pharmacogenetic disorder triggered by exposure to specific anesthetic agents. Although this occurrence could affect virtually any patient during the perioperative time, the pediatric population is particularly vulnerable, and it has a five-fold higher incidence in children compared to adults. In the last few decades, synergistic efforts among leading anesthesiology, pediatrics, and neurology associations have produced new evidence concerning the diagnostic pathway, avoiding unnecessary testing and limiting false diagnoses. However, a personalized approach and an effective prevention policy focused on clearly recognizing the high-risk population, defining perioperative trigger-free hospitalization, and rapid activation of supportive therapy should be improved. Based on epidemiological data, many national scientific societies have produced consistent guidelines, but many misconceptions are common among physicians and healthcare workers. This review shall consider all these aspects and summarize the most recent updates.
... Interestingly, a link between RYR1 variants, exercise-induced rhabdomyolysis and a lowered MH threshold has been recently postulated [71]. However, another paper examining a possible link between MH Susceptibility and EHS found the data to be lacking [72]. Altogether, the complex interaction of intrinsic and extrinsic risk factors requires further research to elucidate the underlying mechanism leading to EHS/ERM. ...
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Introduction Exertional heat stroke (EHS) is a medical emergency, occurring when the body generates more heat than it can dissipate, and frequently associated with exertional rhabdomyolysis (ERM). In the present study we aimed to (I) identify clinical features and risk factors, (II) describe current prehospital management, (III) investigate long-term outcomes including the impact on mental health, and review the guidance received during restarting activities. We hope that our approach will improve individual and organizational heat illness preparedness, and improve follow-up care. Methods We performed a prospective online survey and retrospective medical record review among athletes and military personnel with an episode of EHS/ERM in the Netherlands between 2010 and 2020. We evaluated prehospital management, risk factors, clinical features and long-term outcomes at 6 and 12 months after the event, including mental health symptoms. Furthermore, we investigated what guidance participants received during follow-up, and assessed the patients’ perspective on these outcomes. Results Sixty participants were included, 42 male (70%) and 18 female (30%), of which 47 presented with EHS (78%) and 13 with ERM (22%). Prehospital management was inconsistent and in the majority of participants not conducted according to available guidelines. Self-reported risk factors included not feeling well-acclimatized to environmental heat (55%) and peer pressure (28%). Self-reported long-term symptoms included muscle symptoms at rest (26%) or during exercise (28%), and neurological sequelae (11%). Validated questionnaires (CIS, HADS and SF-36) were indicative of severe fatigue (30%) or mood/anxiety disorders (11%). Moreover, 90% expressed a lack of follow-up care and that a more frequent and intensive follow-up would have been beneficial for their recovery process. Conclusion Our findings indicate major inconsistencies in the management of patients with EHS/ERM, emphasizing the compelling need for implementing standardized protocols. Based on the results of long-term outcome measures, we recommend to counsel and evaluate every patient not only immediately after the event, but also in the long-term.
... Among active-duty soldiers, those with a prior serious EHI event had four-fold greater odds of experiencing a mild EHI event and those with a prior mild EHI had a 1.8-fold greater risk of having a serious EHI event at a future date (109). Malignant hyperthermia trait has recently been suggested as a predisposing factor for exertional hyperthermia, but this is controversial, and more research is needed (110). ...
Article
Full-text available
Exertional heat stroke is a true medical emergency with potential for organ injury and death. This consensus statement emphasizes that optimal exertional heat illness management is promoted by a synchronized chain of survival that promotes rapid recognition and management, as well as communication between care teams. Health care providers should be confident in the definitions, etiologies, and nuances of exertional heat exhaustion, exertional heat injury, and exertional heat stroke. Identifying the athlete with suspected exertional heat stroke early in the course, stopping activity (body heat generation), and providing rapid total body cooling are essential for survival, and like any critical life-threatening situation (cardiac arrest, brain stroke, sepsis), time is tissue. Recovery from exertional heat stroke is variable and outcomes are likely related to the duration of severe hyperthermia. Most exertional heat illnesses can be prevented with the recognition and modification of well-described risk factors ideally addressed through leadership, policy, and on-site health care.
... EHS and ERM occur more often in patients with known or not yet diagnosed myopathy, especially RYR1-related myopathies, without any pharmacological trigger. The link between MH, EHS and ERM is not well explored yet, but it is reasonable to assume that EHS and ERM patients might be at an increased risk for MH, and vice versa [30,[62][63][64][65]. ...
Article
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Malignant Hyperthermia (MH) is a rare, hereditary, life-threatening disease triggered by volatile anesthetics and succinylcholine. Rarely, MH can occur after non-pharmacological triggers too. MH was detected more often in children and young adults, which makes this topic very important for every pediatric specialist, both anesthesiologists and intensivists. MH crisis is a life-threatening severe hypermetabolic whole-body reaction. Triggers of MH are used in pediatric intensive care unit (PICU) as well, volatile anesthetics in difficult sedation, status asthmaticus or epilepticus, and succinylcholine still sometimes in airway management. Recrudescence or delayed onset of MH crisis hours after anesthesia was previously described. MH can also be a cause of rhabdomyolysis and hyperpyrexia in the PICU. In addition, patients with neuromuscular diseases are often admitted to PICU and they might be at risk for MH. The most typical symptoms of MH are hypercapnia, tachycardia, hyperthermia, and muscle rigidity. Thinking of the MH as the possible cause of deterioration of a patient’s clinical condition is the key to early diagnosis and treatment. The sooner the correct treatment is commenced, the better patient´s outcome. This narrative review article aims to summarize current knowledge and guidelines about recognition, treatment, and further management of MH in PICU.
... The sample is then treated with halothane or caffeine and fluctuations in muscle tone are measured. [26][27][28][29] The most important symptoms are hyperthermia, tachycardia, arrhythmia, rhabdomyolysis, metabolic and respiratory acidosis, cyanosis, lactic acidosis, coagulopathy, hyperkalemia, and renal failure. [1,25] In the initial stage, there is a rapid decrease in the amount of ATP, which results in increased CO2 production, respiratory acidosis, increased body temperature and increased demand for oxygen. ...
... [25] Anesthesiologists are required to recognize the signals indicating the onset of MH and to make an accurate and prompt diagnosis. [26,31] In practically all cases, the first symptoms of MH develop already in the operating room (tachycardia, tachypnea). Nevertheless, MH may also occur in the initial postoperative period. ...
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Malignant hyperthermia (MH) is a relatively rare, but potentially lethal genetic disorder. That disease is characterized by hypermetabolic response of the skeletal muscles caused by exposure to triggering agents e.g. volatile anesthetics or depolarizing neuromuscular blockers. The object of this article was to review and assess the most recent published works about the epidemiology, etiology, pathomechanism, therapy of the MH and the new advances in all these fields. Authors scrutinized PubMed and Google Scholar using keywords: malignant hyperthermia, volatile anesthetics, ryanodine receptor mutation. In addition to this, the references of chosen articles were manually scoured for supplementary applicable articles. The literature was selected on the basis of a general medicine readership and prioritized clinical practice guidelines, systematic reviews and case reports. The references include the latest reports on malignant hyperthermia, apart from works of historical importance. Available treatment methods consist mainly of pharmacotherapy, symptomatic treatment and monitoring of vital parameters. Dantrolene is a first-choice drug in initial treatment of MH and is considered the only specific antidote. In spite of the constant advances in the areas of medicine there is still much to be discovered about MH. Further studies are necessary, as the amount of credible evidence is not adequate.