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Nature Communications Jun 2022Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors...
Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in ASPH, a gene encoding junctin, a regulator of excitation-contraction coupling. We validated the pathogenicity of these variants using orthogonal pre-clinical models, CRISPR-edited C2C12 myotubes and transgenic zebrafish. In total, we demonstrate that ASPH variants represent a new cause of EHI and MH susceptibility.
Topics: Animals; Caffeine; Calcium-Binding Proteins; Heat Stress Disorders; Humans; Malignant Hyperthermia; Membrane Proteins; Mixed Function Oxygenases; Muscle Contraction; Muscle Fibers, Skeletal; Muscle Proteins; Zebrafish
PubMed: 35697689
DOI: 10.1038/s41467-022-31088-8 -
Neuromuscular Disorders : NMD Aug 2022Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle...
Malignant hyperthermia (MH) is a life-threatening reaction triggered by volatile anesthetics and succinylcholine. MH is caused by mutations in the skeletal muscle ryanodine receptor (RYR1) gene, as is rhabdomyolysis triggered by exertion and/or pyrexia. The discrepancy between the prevalence of risk genotypes and actual MH incidence remains unexplained. We investigated the role of pre-operative exercise and pyrexia as potential MH modifying factors. We included cases from 5 MH referral centers with 1) clinical features suggestive of MH, 2) confirmation of MH susceptibility on Contracture Testing (IVCT or CHCT) and/or RYR1 genetic testing, and a history of 3) strenuous exercise within 72 h and/or pyrexia >37.5 °C prior to the triggering anesthetic. Characteristics of MH-triggering agents, surgery and succinylcholine use were collected. We identified 41 cases with general anesthesias resulting in an MH event (GA+MH, n = 41) within 72 h of strenuous exercise and/or pyrexia. We also identified previous general anesthesias without MH events (GA-MH, n = 51) in the index cases and their MH susceptible relatives. Apart from pre-operative exercise and/or pyrexia, trauma and acute abdomen as surgery indications, emergency surgery and succinylcholine use were also more common with GA+MH events. These observations suggest a link between pre-operative exercise, pyrexia and MH.
Topics: Fever; Humans; Malignant Hyperthermia; Mutation; Preoperative Exercise; Ryanodine Receptor Calcium Release Channel; Succinylcholine
PubMed: 35738978
DOI: 10.1016/j.nmd.2022.06.003 -
Journal of Perianesthesia Nursing :... Aug 2022Malignant hypothermia (MH) is a potentially fatal hypermetabolic reaction of skeletal muscle. It is an autosomal dominant disorder that generally occurs in people with...
Malignant hypothermia (MH) is a potentially fatal hypermetabolic reaction of skeletal muscle. It is an autosomal dominant disorder that generally occurs in people with RYR1, CACNA1S, or STAC3 mutations. And these genetic abnormalities often cause the imperfection of calcium release channels of skeletal muscle. The incidence of MH among different racial groups across the world ranges from approximately 1:5,000-1:250,000, but there is no national statistic MH incidence in China. It is not clear whether there are racial or regional differences in the incidence, but patients under 18 years old may be more affected. MH can be triggered by anesthetics, or other stimuli, such as strenuous exercise, heat-stroke, and emotional stress. While viral infection, statins, hyperglycemia, and muscle metabolic dysfunctions might accelerate the onset of MH. The onset of MH is insidious and rapid, with the preclinical stage characterized by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature. Medical history, family history, clinical presentation, in vitro caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing are commonly diagnostic methods of MH. As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities. For symptomatic treatment, "5C principles" were summarized as an algorithm to guide clinicians.
Topics: Adolescent; Caffeine; China; Halothane; Humans; Malignant Hyperthermia; Mutation
PubMed: 35414440
DOI: 10.1016/j.jopan.2021.08.018 -
Skeletal Muscle Nov 2020The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1... (Review)
Review
The RYR1 gene, which encodes the sarcoplasmic reticulum calcium release channel or type 1 ryanodine receptor (RyR1) of skeletal muscle, was sequenced in 1988 and RYR1 variations that impair calcium homeostasis and increase susceptibility to malignant hyperthermia were first identified in 1991. Since then, RYR1-related myopathies (RYR1-RM) have been described as rare, histopathologically and clinically heterogeneous, and slowly progressive neuromuscular disorders. RYR1 variants can lead to dysfunctional RyR1-mediated calcium release, malignant hyperthermia susceptibility, elevated oxidative stress, deleterious post-translational modifications, and decreased RyR1 expression. RYR1-RM-affected individuals can present with delayed motor milestones, contractures, scoliosis, ophthalmoplegia, and respiratory insufficiency.Historically, RYR1-RM-affected individuals were diagnosed based on morphologic features observed in muscle biopsies including central cores, cores and rods, central nuclei, fiber type disproportion, and multi-minicores. However, these histopathologic features are not always specific to RYR1-RM and often change over time. As additional phenotypes were associated with RYR1 variations (including King-Denborough syndrome, exercise-induced rhabdomyolysis, lethal multiple pterygium syndrome, adult-onset distal myopathy, atypical periodic paralysis with or without myalgia, mild calf-predominant myopathy, and dusty core disease) the overlap among diagnostic categories is ever increasing. With the continuing emergence of new clinical subtypes along the RYR1 disease spectrum and reports of adult-onset phenotypes, nuanced nomenclatures have been reported (RYR1- [related, related congenital, congenital] myopathies). In this narrative review, we provide historical highlights of RYR1 research, accounts of the main diagnostic disease subtypes and propose RYR1-related disorders (RYR1-RD) as a unified nomenclature to describe this complex and evolving disease spectrum.
Topics: Animals; Humans; Neuromuscular Diseases; Phenotype; Ryanodine Receptor Calcium Release Channel; Terminology as Topic
PubMed: 33190635
DOI: 10.1186/s13395-020-00243-4 -
American Journal of Therapeutics Jul 2022
Topics: Atracurium; COVID-19; Humans; Malignant Hyperthermia; SARS-CoV-2
PubMed: 35802921
DOI: 10.1097/MJT.0000000000001453 -
Journal of Perianesthesia Nursing :... Feb 2022The purpose of this project was to prepare perioperative staff at a military ambulatory surgical center to respond to a malignant hyperthermia crisis effectively with...
PURPOSE
The purpose of this project was to prepare perioperative staff at a military ambulatory surgical center to respond to a malignant hyperthermia crisis effectively with the assistance the Stanford emergency manual cognitive aid.
DESIGN
This is an evidence-based practice improvement project.
METHODS
Multidisciplinary perioperative staff at a military ambulatory surgical center participated in an in-service about the Stanford emergency manual cognitive aid tool, and a simulation exercise was conducted to practice using the tool during a malignant hyperthermia crisis. Preproject and postproject implementation surveys were to used to measure staff perceptions of and willingness to use cognitive aids/emergency checklists during perioperative emergencies.
FINDINGS
Staff positive perception of and willingness to use the Stanford emergency manual cognitive aid improved after implementation of an education session and simulation exercise with the checklist tool.
CONCLUSIONS
Introduction of the Stanford emergency manual cognitive aid to multidisciplinary perioperative staff with an in-service and simulated malignant hyperthermia scenario improved staff perception of cognitive aid use during emergencies. Use of cognitive aid checklists during simulated perioperative emergencies was shown to reduce missed critical treatment steps.
Topics: Checklist; Cognition; Computer Simulation; Humans; Malignant Hyperthermia
PubMed: 34736836
DOI: 10.1016/j.jopan.2020.09.020 -
International Journal of Molecular... Mar 2022Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant... (Review)
Review
Fine temperature control is essential in homeothermic animals. Both hyper- and hypothermia can have deleterious effects. Multiple, efficient and partly redundant mechanisms of adjusting the body temperature to the value set by the internal thermostat exist. The neural circuitry of temperature control and the neurotransmitters involved are reviewed. The GABAergic inhibitory output from the brain thermostat in the preoptic area POA to subaltern neural circuitry of temperature control (Nucleus Raphe Dorsalis and Nucleus Raphe Pallidus) is a function of the balance between the (opposite) effects mediated by the transient receptor potential receptor TRPM2 and EP3 prostaglandin receptors. Activation of TRPM2-expressing neurons in POA favors hypothermia, while inhibition has the opposite effect. Conversely, EP3 receptors induce elevation in body temperature. Activation of EP3-expressing neurons in POA results in hyperthermia, while inhibition has the opposite effect. Agonists at TRPM2 and/or antagonists at EP3 could be beneficial in hyperthermia control. Activity of the neural circuitry of temperature control is modulated by a variety of 5-HT receptors. Based on the theoretical model presented the "ideal" antidote against serotonin syndrome hyperthermia appears to be an antagonist at the 5-HT receptor subtypes 2, 4 and 6 and an agonist at the receptor subtypes 1, 3 and 7. Very broadly speaking, such a profile translates in a sympatholytic effect. While a compound with such an ideal profile is presently not available, better matches than the conventional antidote cyproheptadine (used off-label in severe serotonin syndrome cases) appear to be possible and need to be identified.
Topics: Animals; Antidotes; Cyproheptadine; Hyperthermia; Hyperthermia, Induced; Hypothermia; Serotonin; Serotonin Syndrome; TRPM Cation Channels
PubMed: 35328784
DOI: 10.3390/ijms23063365 -
A&A Practice Jan 2021
Topics: Hemodynamics; Humans; Hyperthermia; Malignant Hyperthermia; Muscular Diseases; Ryanodine Receptor Calcium Release Channel
PubMed: 33512901
DOI: 10.1213/XAA.0000000000001377 -
BMJ Military Health Jun 2023The organisation of a military health system (MHS) differs from the civilian system due to the role of the armed forces, the unique nature of the supported population...
The organisation of a military health system (MHS) differs from the civilian system due to the role of the armed forces, the unique nature of the supported population and their occupational health requirements. A previously published review of the Military Medical Corps Worldwide Almanac demonstrated the value of a standardised framework for evaluation and comparison of MHSs. This paper proposes such a framework which highlights the unique features of MHSs not covered by health services research of national health systems. These include: national context and summary; organisational structure; firm base facilities, healthcare beneficiaries and medical research; operational capabilities, overseas deployments, collaborations and alliances; personnel including recruitment, training and education; and history and culture. This common framework can help facilitate international collaboration between military medical services including capability development, training exercises and mutual support during military operations. It can also inform national contributions to future editions of the Almanac.
Topics: Humans; Military Health Services; Delivery of Health Care; Military Personnel; Workforce; Biomedical Research
PubMed: 33619229
DOI: 10.1136/bmjmilitary-2020-001699 -
Children (Basel, Switzerland) Nov 2022Malignant Hyperthermia (MH) is a rare, hereditary, life-threatening disease triggered by volatile anesthetics and succinylcholine. Rarely, MH can occur after... (Review)
Review
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.
PubMed: 36360420
DOI: 10.3390/children9111692