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British Journal of Anaesthesia Jul 2023Most patients with malignant hyperthermia susceptibility diagnosed by the in vitro caffeine-halothane contracture test (CHCT) develop excessive force in response to...
BACKGROUND
Most patients with malignant hyperthermia susceptibility diagnosed by the in vitro caffeine-halothane contracture test (CHCT) develop excessive force in response to halothane but not caffeine (halothane-hypersensitive). Hallmarks of halothane-hypersensitive patients include high incidence of musculoskeletal symptoms at rest and abnormal calcium events in muscle. By measuring sensitivity to halothane of myotubes and extending clinical observations and cell-level studies to a large group of patients, we reach new insights into the pathological mechanism of malignant hyperthermia susceptibility.
METHODS
Patients with malignant hyperthermia susceptibility were classified into subgroups HH and HS (positive to halothane only and positive to both caffeine and halothane). The effects on [Ca] of halothane concentrations between 0.5 and 3 % were measured in myotubes and compared with CHCT responses of muscle. A clinical index that summarises patient symptoms was determined for 67 patients, together with a calcium index summarising resting [Ca] and spontaneous and electrically evoked Ca events in their primary myotubes.
RESULTS
Halothane-hypersensitive myotubes showed a higher response to halothane 0.5% than the caffeine-halothane hypersensitive myotubes (P<0.001), but a lower response to higher concentrations, comparable with that used in the CHCT (P=0.055). The HH group had a higher calcium index (P<0.001), but their clinical index was not significantly elevated vs the HS. Principal component analysis identified electrically evoked Ca spikes and resting [Ca] as the strongest variables for separation of subgroups.
CONCLUSIONS
Enhanced sensitivity to depolarisation and to halothane appear to be the primary, mutually reinforcing and phenotype-defining defects of halothane-hypersensitive patients with malignant hyperthermia susceptibility.
Topics: Humans; Malignant Hyperthermia; Halothane; Calcium; Muscle Fibers, Skeletal; Disease Susceptibility; Caffeine; Muscle Contraction
PubMed: 36792386
DOI: 10.1016/j.bja.2023.01.008 -
Innovations in Clinical Neuroscience Nov 2019Clozapine-induced agranulocytosis, malignant hyperthermia (MH), statin-induced myopathy, and neuroleptic malignant syndrome (NMS) are all serious drug reactions with... (Review)
Review
Clozapine-induced agranulocytosis, malignant hyperthermia (MH), statin-induced myopathy, and neuroleptic malignant syndrome (NMS) are all serious drug reactions with significant overlap in terms of clinical symptomatology. The use of clozapine can lead to neutropenia, as well as the development of NMS; thus, it seemed logical to explore a possible common genetic background for the development of these two adverse effects. Furthermore, due to the overwhelming clinical resemblance between NMS, MH, and statin-induced myopathy, we decided specifically to search for a common genetic background in the development of these conditions. We searched the PubMed, OMIM, WikiGenes, Medline, and Google Scholar databases to identify articles pertinent to our subject published over the last 30 years. Articles were reviewed according to our inclusion/exclusion criteria, and irrelevant articles were excluded. In our exploration for a common genetic background between clozapine-induced agranulocytosis, MH, NMS, and statin-induced myopathy, we identified the SLCO1B1 gene, which was common to three of these four conditions (MH, statin-induced myopathy, and clozapine-induced agranulocytosis). Although we did not find a gene common among NMS and the other conditions, the overlap of clinical symptoms between NMS, MH, and statin-induced myopathy did not allow us to rule out the possibility of a common factor, in terms of genetic predisposition, between these conditions. Future studies can aid to fill in the gaps of knowledge in terms of any genetic linkage between these three conditions and the mechanism of their associations.
PubMed: 32082940
DOI: No ID Found -
Journal of Nursing Care QualityMalignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder triggered by certain anesthetic agents. There is currently no standardized preoperative...
BACKGROUND
Malignant hyperthermia (MH) is a potentially lethal pharmacogenetic disorder triggered by certain anesthetic agents. There is currently no standardized preoperative screening tool utilized to identify MH-susceptible individuals.
LOCAL PROBLEM
This quality improvement (QI) project aimed to enhance preoperative screening for MH susceptibility (MHS) by implementing an evidence-based screening tool for surgical patients at 2 sites.
METHODS
This prospective descriptive QI project evaluated the success of implementing an MHS screening tool preoperatively and its impact on the anesthesia plan.
INTERVENTIONS
Anesthesia professionals included the screening tool in their preoperative interview for surgical patients so that positively screened patients could receive MH prevention measures.
RESULTS
A total of 95 patients at site A and 234 patients at site B were screened using the MH tool, a cumulative total of 21 patients were positively screened, and 1 anesthetic plan was altered.
CONCLUSIONS
This MHS screening tool has the potential to prevent MH episodes when used consistently by staff.
Topics: Humans; Malignant Hyperthermia; Prospective Studies
PubMed: 34799529
DOI: 10.1097/NCQ.0000000000000610 -
Brazilian Journal of Anesthesiology... 2023Malignant Hyperthermia (MH) is a pharmacogenetic disorder triggered by halogenated anesthesia agents/succinylcholine and characterized by hypermetabolism crisis during... (Observational Study)
Observational Study
BACKGROUND
Malignant Hyperthermia (MH) is a pharmacogenetic disorder triggered by halogenated anesthesia agents/succinylcholine and characterized by hypermetabolism crisis during anesthesia, but also by day-to-day symptoms, such as exercise intolerance, that may alert the health professional.
OBJECTIVE
The study aimed to analyze the incidence of fatigue in MH susceptible patients and the variables that can impact perception of fatigue, such as the level of routine physical activity and depression.
METHODS
A cross-sectional observational study was carried out with three groups ... 22 patients susceptible to MH (positive in vitro muscle contracture test), 13 non-susceptible to MH (negative in vitro muscle contracture test) and 22 controls (no history of MH). Groups were assessed by a demographic/clinical questionnaire, a fatigue severity scale (intensity, specific situations, psychological consequences, rest/sleep response), and the Beck depression scale. Subgroups were re-assessed with the Baecke habitual physical exercise questionnaire (occupational physical activity, leisure physical exercise, leisure/locomotion physical activity).
RESULTS
There were no significant differences among the three groups regarding fatigue intensity, fatigue related to specific situations, psychological consequences of fatigue, fatigue response to resting/sleeping, depression, number of active/sedentary participants, and the mean time and characteristics of habitual physical activity. Nevertheless, unlike the control sub-group, the physically active MH-susceptible subgroup had a higher fatigue response to resting/sleeping than the sedentary MH susceptible subgroup (respectively, 5.9.ß...ß1.9 vs. 3.9.ß...ß2, t-test unpaired, p.ß<.ß0.05).
CONCLUSION
We did not detect subjective fatigue in MH susceptible patients, although we reported protracted recovery after physical activity, which may alert us to further investigation requirements.
Topics: Humans; Malignant Hyperthermia; Halothane; Cross-Sectional Studies; Depression; Contracture; Exercise; Disease Susceptibility
PubMed: 34626754
DOI: 10.1016/j.bjane.2021.07.038 -
EJIFCC Jun 2021Malignant hyperthermia is a pharmacogenetic disorder. It manifests as a hypercatabolic skeletal muscle syndrome linked to inhaled volatile anesthetics or depolarizing...
Malignant hyperthermia is a pharmacogenetic disorder. It manifests as a hypercatabolic skeletal muscle syndrome linked to inhaled volatile anesthetics or depolarizing muscle relaxants. Its clinical signs and symptoms are tachycardia, hyperthermia, hypercapnia, acidosis, muscle rigidity, rhabdomyolysis, hyperkalemia, arrhythmia and renal failure. Mortality without specific treatment is 80% and decreases to 5% with the use of dantrolene sodium. This article presents the case of a 39-year-old patient admitted to the Intensive Care Unit for malignant hyperthermia after surgery for septoplasty plus turbinoplasty.
PubMed: 34421497
DOI: No ID Found -
Journal of Neuromuscular Diseases 2023Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been...
BACKGROUND
Variants in RYR1, the gene encoding the ryanodine receptor-1, can give rise to a wide spectrum of neuromuscular conditions. Muscle imaging abnormalities have been demonstrated in isolated cases of patients with a history of RYR1-related malignant hyperthermia (MH) susceptibility.
OBJECTIVE
To provide insights into the type and prevalence of muscle ultrasound abnormalities and muscle hypertrophy in patients carrying gain-of-function RYR1 variants associated with MH susceptibility and to contribute to delineating the wider phenotype, optimizing the diagnostic work-up and care for MH susceptible patients.
METHODS
We performed a prospective cross-sectional observational muscle ultrasound study in patients with a history of RYR1-related MH susceptibility (n = 40). Study procedures included a standardized history of neuromuscular symptoms and a muscle ultrasound assessment. Muscle ultrasound images were analyzed using a quantitative and qualitative approach and compared to reference values and subsequently subjected to a screening protocol for neuromuscular disorders.
RESULTS
A total of 15 (38%) patients had an abnormal muscle ultrasound result, 4 (10%) had a borderline muscle ultrasound screening result, and 21 (53%) had a normal muscle ultrasound screening result. The proportion of symptomatic patients with an abnormal result (11 of 24; 46%) was not significantly higher compared to the proportion of asymptomatic patients with an abnormal ultrasound result (4 of 16; 25%) (P = 0.182). The mean z-scores of the biceps brachii (z = 1.45; P < 0.001), biceps femoris (z = 0.43; P = 0.002), deltoid (z = 0.31; P = 0.009), trapezius (z = 0.38; P = 0.010) and the sum of all muscles (z = 0.40; P < 0.001) were significantly higher compared to 0, indicating hypertrophy.
CONCLUSIONS
Patients with RYR1 variants resulting in MH susceptibility often have muscle ultrasound abnormalities. Frequently observed muscle ultrasound abnormalities include muscle hypertrophy and increased echogenicity.
Topics: Humans; Cross-Sectional Studies; Genetic Predisposition to Disease; Malignant Hyperthermia; Muscle, Skeletal; Mutation; Prospective Studies; Ryanodine Receptor Calcium Release Channel; Ultrasonography
PubMed: 37154182
DOI: 10.3233/JND-230018 -
Current Pharmaceutical Design 2022Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and... (Review)
Review
Variants in the ryanodine receptor-1 gene (RYR1) have been associated with a wide range of neuromuscular conditions, including various congenital myopathies and malignant hyperthermia (MH). More recently, a number of RYR1 variants, mostly MH-associated, have been demonstrated to contribute to rhabdomyolysis events not directly related to anesthesia in otherwise healthy individuals. This review focuses on RYR1-related rhabdomyolysis in the context of several clinical presentations (i.e., exertional rhabdomyolysis, exertional heat illnesses and MH), and conditions involving a similar hypermetabolic state, in which RYR1 variants may be present (i.e., neuroleptic malignant syndrome and serotonin syndrome). The variety of triggers that can evoke rhabdomyolysis, on their own or in combination, as well as the number of potentially associated complications, illustrates that this is a condition relevant to several medical disciplines. External triggers include but are not limited to strenuous physical exercise, especially if unaccustomed or performed under challenging environmental conditions (e.g., high ambient temperature or humidity), alcohol/illicit drugs, prescription medication (in particular statins, other anti-lipid agents, antipsychotics and antidepressants) infection, or heat. Amongst all patients presenting with rhabdomyolysis, genetic susceptibility is present in a proportion, with RYR1 being one of the most common genetic causes. Clinical clues for a genetic susceptibility include recurrent rhabdomyolysis, creatine kinase (CK) levels above 50 times the upper limit of normal, hyperCKemia lasting for 8 weeks or longer, drug/medication doses insufficient to explain the rhabdomyolysis event, and positive family history. For the treatment or prevention of RYR1-related rhabdomyolysis, the RYR1 antagonist dantrolene can be administered, both in the acute phase or prophylactically in patients with a history of muscle cramps and/or recurrent rhabdomyolysis events. Aside from dantrolene, several other drugs are being investigated for their potential therapeutic use in RYR1-related disorders. These findings offer further therapeutic perspectives for humans, suggesting an important area for future research.
Topics: Exercise; Genetic Predisposition to Disease; Humans; Malignant Hyperthermia; Mutation; Rhabdomyolysis; Ryanodine Receptor Calcium Release Channel
PubMed: 34348614
DOI: 10.2174/1381612827666210804095300 -
Experimental Biology and Medicine... Apr 2022The isolated tissue bath research methodology was first developed in 1904. Since then, it has been recognized as an important tool in pharmacology and physiology... (Review)
Review
The isolated tissue bath research methodology was first developed in 1904. Since then, it has been recognized as an important tool in pharmacology and physiology research, including investigations into neuromuscular disorders. The tissue bath is still used routinely as the instrument for performing the "gold standard" test for clinical diagnosis of malignant hyperthermia susceptibility - the caffeine-halothane contracture test. Our research group has utilized this tool for several decades for a range of research studies, and we are currently one of four North American diagnostic centers for determining susceptibility for malignant hyperthermia. This review provides a brief summary of some of the historical uses of the tissue bath. Important experimental considerations for the operation of the tissue bath are further described. Finally, we discuss the different studies our group has performed using isolated tissue baths to highlight the broad potential applications.
Topics: Baths; Caffeine; Humans; In Vitro Techniques; Laboratories; Malignant Hyperthermia; Muscle Contraction; Research Design; Translational Research, Biomedical
PubMed: 35068214
DOI: 10.1177/15353702211070535 -
Neuromuscular Disorders : NMD Dec 2023Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these...
Malignant hyperthermia is a pharmacogenetic disorder triggered by halogenated anesthetic agents in genetically predisposed individuals. Approximately 70 % of these individuals carry mutations in RYR1, the gene encoding the ryanodine receptor calcium channel of skeletal muscle. In this study, we performed functional analysis of 5 RYR1 variants identified in members from 8 families who had been diagnosed by the IVCT. Of the 68 individuals enrolled in the study, 43 were diagnosed as MHS, 23 as MHN, and 2 individuals were not tested. Here we demonstrate that the 5 RyR1 variants cause hypersensitivity to RyR1 agonist-mediated calcium release. According to the EMHG scoring matrix these five genetic variants can be classified as follows: c.8638G>A (p.E2880K) and c.11314C>T (p.R3772W) likely pathogenic, c.11416G>A (p.G3806R), c.14627A>G (p.K4876R) and c.14813T>C (p.I4938T), pathogenic (RefSeq NM_000540.3). We propose that the newly functionally characterized RYR1 variants, be included in the panel of variants to be used for the molecular diagnosis of MHS.
Topics: Humans; Calcium; Genetic Predisposition to Disease; Malignant Hyperthermia; Muscle, Skeletal; Mutation; Ryanodine Receptor Calcium Release Channel
PubMed: 37996280
DOI: 10.1016/j.nmd.2023.10.019 -
Journal of Anaesthesiology, Clinical... 2020Malignant hyperthermia susceptibility (MHS) and the associated condition malignant hyperthermia (MH) are rare but well-known disorders in the field of anesthesiology....
Malignant hyperthermia susceptibility (MHS) and the associated condition malignant hyperthermia (MH) are rare but well-known disorders in the field of anesthesiology. MHS is usually determined by a history of a family member developing a positive episode during general anesthesia and then confirmed by an invasive caffeine halothane contracture test (CHCT). More recently, within the context of MH as a pharmacogenetic disorder, the question of whether or not MHS can be principally genetically determined is of high importance as knowledge of detailed pathogenesis may prevent against its largely invariable lethality if untreated. Thus, in this brief report, genetic terms, as well as updates in the genetics of MHS, will be reviewed in order to better understand both the condition and the current research.
PubMed: 33840940
DOI: 10.4103/joacp.JOACP_360_19