Propofol binds and inhibits skeletal muscle ryanodine receptor 1.

BACKGROUND: As the primary Ca2+ release channel in skeletal muscle sarcoplasmic reticulum (SR), mutations in type 1 ryanodine receptor (RyR1) or its binding partners underlie a constellation of muscle disorders, including malignant hyperthermia (MH). In patients with MH mutations, triggering agents including halogenated volatile anaesthetics bias RyR1 to an open state resulting in uncontrolled Ca2+ release, increased sarcomere tension, and heat production. Propofol does not trigger MH and is commonly used for patients at risk of MH. The atomic-level interactions of any anaesthetic with RyR1 are unknown. METHODS: RyR1 opening was measured by [3H]ryanodine binding in heavy SR vesicles (wild type) and single-channel recordings of MH mutant R615C RyR1 in planar lipid bilayers, each exposed to propofol or the photoaffinity ligand analogue m-azipropofol (AziPm). Activator-mediated wild-type RyR1 opening as a function of propofol concentration was measured by Fura-2 Ca2+ imaging of human skeletal myotubes. AziPm binding sites, reflecting propofol binding, were identified on RyR1 using photoaffinity labelling. Propofol binding affinity to a photoadducted site was predicted using molecular dynamics (MD) simulation. RESULTS: Both propofol and AziPm decreased RyR1 opening in planar lipid bilayers (P<0.01) and heavy SR vesicles, and inhibited activator-induced Ca2+ release from human skeletal myotube SR. Several putative propofol binding sites on RyR1 were photoadducted by AziPm. MD simulation predicted propofol KD values of 55.8 µM and 1.4 µM in the V4828 pocket in open and closed RyR1, respectively. CONCLUSIONS: Propofol demonstrated direct binding and inhibition of RyR1 at clinically plausible concentrations, consistent with the hypothesis that propofol partially mitigates MH by inhibition of induced Ca2+ flux through RyR1.

Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review.

Malignant hyperthermia susceptibility (MHS) designates individuals at risk of developing a hypermetabolic reaction triggered by halogenated anaesthetics or the depolarising neuromuscular blocking agent suxamethonium. Over the past few decades, beyond the operating theatre, myopathic manifestations impacting daily life are increasingly recognised as a prevalent phenomenon in MHS patients. At the request of the European Malignant Hyperthermia Group, we reviewed the literature and gathered the opinion of experts to define MHS-related myopathy as a distinct phenotype expressed across the adult lifespan of MHS patients unrelated to anaesthetic exposure; this serves to raise awareness about non-anaesthetic manifestations, potential therapies, and management of MHS-related myopathy. We focused on the clinical presentation, biochemical and histopathological findings, and the impact on patient well-being. The spectrum of symptoms of MHS-related myopathy encompasses muscle cramps, stiffness, myalgias, rhabdomyolysis, and weakness, with a wide age range of onset mainly during adulthood. Histopathological analysis can reveal nonspecific abnormalities suggestive of RYR1 involvement, while metabolic profiling reflects altered energy metabolism in MHS muscle. Myopathic manifestations can significantly impact patient quality of life and lead to functional limitations and socio-economic burden. While currently available therapies can provide symptomatic relief, there is a need for further research into targeted treatments addressing the underlying pathophysiology. Counselling early after establishing the MHS diagnosis, followed by multidisciplinary management involving various medical specialties, is crucial to optimise patient care.

Thiopentone-based total intravenous anaesthesia for a patient with carnitine palmitoyltransferase II deficiency and malignant hyperthermia susceptibility.

In this case report, we discuss the use of a thiopentone infusion for the maintenance of anaesthesia in a patient with confirmed malignant hyperthermia susceptibility and carnitine palmitoyltransferase 2 deficiency. The concurrence of both diagnoses precluded the use of both propofol-based total intravenous anaesthesia and volatile inhalational anaesthesia. This patient had been anaesthetised previously with a triple infusion regimen of thiopentone, midazolam and remifentanil and this was a unique opportunity to compare the two instances. Electroencephalogram-based depth of anaesthesia monitoring was in routine use by the time of the second anaesthetic, and thus, the thiopentone infusion could be adjusted accordingly, resulting in a more rapid emergence time. We hope that this case may serve as an example of suitable anaesthetic alternative should both propofol infusion and inhalational anaesthesia not be an option.

Combining stress inoculation with virtual reality simulation training of malignant hyperthermia.

BACKGROUND: Limited research has been conducted on how healthcare simulation can mitigate clinician stress. Stress exposure training (SET) has been shown to decrease stress's impact on performance. Combining SET with virtual reality (VR) simulation training has not yet been explored in the context of stress inoculation. The primary purpose of this pilot study was to determine if a VR module could induce stress. The secondary purpose was to determine if repeated exposure to stressors could decrease stress response in a simulated environment. METHODS: Medical students were recruited to partake in VR simulation modules aimed at treatment of malignant hyperthermia (MH). Those in the SET group were exposed to stressful stimuli during training modules, while those in the Control group were not. Both groups then completed a Test Module with the presence of stressful stimuli. Objective and subjective indicators of stress were measured after each module. RESULTS: Both groups indicated increases in perceived stress and module stressfulness after Training Module 1 and decreases after Training Module 2. After the Test Module, the Control group experienced significant elevation in perceived stress (p = .05), and the SET group had a significant decrease in perceived module stressfulness (p < .05). Both groups had a decrease in perceived competence after Training Module 1 (p < .001) and an increase after Training Module 2 (p < .001), with the SET group having significant elevation after the Test Module (p < .01). Both groups found the VR module to be feasible as a teaching tool. Objectively, the SET group showed an upward trend in electrodermal activity (EDA) from the Tutorial to Test Modules (p < .05), with the Control group showing a decrease after Training Module 2 (p = .05) and an increase after the Test Module (p < .01). CONCLUSIONS: A VR module targeting treatment of MH successfully induced stress and was regarded favorably by participants. Those in the SET group perceived less stress and more competence after the Test Module than those in the Control. Findings suggest that repeated exposure to stressors through VR may desensitize participants from future stress in a simulated environment.

Individuals and Families Affected by RYR1-Related Diseases: The Patient/Caregiver Perspective.

Background and objective: Pathogenic variants of RYR1, the gene encoding the principal sarcoplasmic reticulum calcium release channel (RyR1) with a crucial role in excitation-contraction coupling, are among the most common genetic causes of non-dystrophic neuromuscular disorders. We recently conducted a questionnaire study focusing on functional impairments, fatigue, and quality of life (QoL) in patients with RYR1-related diseases (RYR1-RD) throughout the recognized disease spectrum. In this previous questionnaire study the medical perspective was taken, reflective of a study protocol designed by neurologists and psychologists. With this present study we wanted to specifically address the patient perspective. Methods: Together with affected individuals, family members, and advocates concerned with RYR1-RD, we developed an online patient survey that was completed by 227 patients or their parents/other caretakers (143 females and 84 males, 0-85 years). We invited 12 individuals, representing most of the patient group based on age, sex, race, and type and severity of diagnosis, to share their personal experiences on living with a RYR1-RD during an international workshop in July 2022. Data were analyzed through a mixed-methods approach, employing both a quantitative analysis of the survey results and a qualitative analysis of the testimonials. Results: Data obtained from the combined quantitative and qualitative analyses provide important insights on six topics: 1) Diagnosis; 2) Symptoms and impact of the condition; 3) Physical activity; 4) Treatment; 5) Clinical research and studies; and 6) Expectations. Conclusions: Together, this study provides a unique patient perspective on the RYR1-RD spectrum, associated disease impact, suitable physical activities and expectations of future treatments and trials, and thus, offers an essential contribution to future research.

Turn Up the Heat: A Case Report of Malignant Hyperthermia During Ambulatory Surgery.

Malignant hyperthermia is a rare complication of general anesthesia involving the uncontrolled release of calcium when exposed to triggers such as depolarizing muscle relaxants or volatile anesthetics. It presents as a hypercatabolic skeletal muscle syndrome that results in tachycardia, hyperthermia, hypercapnia, muscle rigidity, acidosis, rhabdomyolysis, and hyperkalemia. This report presents the case of a 67-year-old female without a personal or family history of complications with anesthesia who experienced malignant hyperthermia during an elective hysterectomy. The patient was given multiple doses of dantrolene, with the ultimate resolution of her symptoms several days after surgery. She was discharged one week after surgery.

Malignant hyperthermia in a paediatric patient; managed successfully without dantrolene: a case report.

Introduction: Malignant hyperthermia (MH) is a potentially life-threatening pharmacogenetic syndrome triggered by volatile anaesthetics, succinylcholine, and stress such as vigorous exercise. Case presentation: The authors describe a case of an 8-year-old male who presented with classical symptoms of MH after induction of general anaesthesia and symptomatic treatment was done successfully due to the unavailability of Dantrolene. Discussion: Definitive diagnosis of MH can be done based on a contracture test in fresh muscle biopsy in the presence of halothane and caffeine. In the absence of muscle biopsy and genetic testing, diagnosis for MH can be done based on MH scoring. Conclusion: Anesthesiologists should be made aware that proper symptomatic management can also save the life of a patient. Also, strong advocacy should be done to ensure the availability of Dantrolene and further strengthen lab facilities to confirm diagnosis to facilitate diagnosis and management in the future.

Anesthesia Spearheading Perioperative Safety Efforts in a Patient with Inclusion Body Myositis: A Case Report.

Anesthesiologists have been at the forefront of initiatives addressing perioperative patient safety. As anesthesia has no direct therapeutic benefit, its risk must be minimized. At times the surgery is simple but the patient's condition complicates anesthetic management, increasing the risk for complications. This report describes the anesthetic management of an adult patient diagnosed with inclusion body myositis (IBM), a rare inflammatory degenerative myopathy, who initially presented with decreased motor function in both lower and upper extremities causing him to be bedbound for two years. Due to the progression of his disease, he eventually developed dysphagia, hence he was scheduled for esophagoscopy, cricopharyngeal Botox injection, and percutaneous endoscopic gastrostomy. As patients with IBM are at risk for exaggerated sensitivity to neuromuscular blockers and respiratory compromise, anesthesia was at the helm of a multidisciplinary team approach. The perioperative management centered on preoperative optimization, prevention of aspiration, avoidance of anesthetics that may trigger malignant hyperthermia, and prevention of postoperative pulmonary complication. The hospital course was uncomplicated and the patient was discharged well after one day. This report emphasizes how improvements in resources, technology, and healthcare delivery, especially in anesthesia, help prevent perioperative adverse events.

Anaesthetic management of a parturient with hypokalaemic periodic paralysis for caesarean section: A case report and review of the literature.

A 32-year-old multigravida woman, with known familial hypokalaemic periodic paralysis, underwent spinal anaesthesia for an elective lower segment caesarean section. There are several case reports in the literature discussing the optimal anaesthetic technique. In the past there has not been an emphasis on aggressive and early potassium replacement. A target level to commence replacement of potassium at 4.0 mmol/L or less is proposed. Careful preoperative preparation, frequent perioperative monitoring and early potassium replacement resulted in no perioperative episodes of weakness in this case, in contrast with other case reports where potassium was either not monitored or not replaced early enough, resulting in postoperative attacks. Another factor to consider in hypokalaemic periodic paralysis is the avoidance of triggers, including certain medications. Misoprostol was used in this instance to avoid potential electrolyte derangements from other uterotonics.

Caution for psychiatrists: malignant hyperthermia risks with the anesthetic agent succinylcholine (Suxamethonium) during electroconvulsive therapy.

BACKGROUND: Malignant hyperthermia is a potentially lethal condition triggered by specific anesthetic drugs, especially a depolarizing muscle relaxant of succinylcholine (Suxamethonium). Despite the frequent use of succinylcholine with electroconvulsive therapy (ECT), there has been no reported case of potentially lethal malignant hyperthermia following ECT. In addition, the time interval between the administration of succinylcholine and the onset of malignant hyperthermia has not been outlined in the context of ECT. CASE PRESENTATION: We present the case of a 79-year-old woman suffering from severe depression, who experienced severe malignant hyperthermia due to succinylcholine administration during an ECT session. She presented with a high fever of 40.2 °C, tachycardia of 140/min, hypertension with a blood pressure exceeding 200 mmHg, significant muscle rigidity, and impaired consciousness. These symptoms emerged two hours after ECT, which occurred in a psychiatric ward rather than an operating room, and reached their peak in less than 24 h. She was given 60 mg of dantrolene, which quickly reduced the muscular rigidity. Subsequently, she received two additional doses of 20 mg and 60 mg of dantrolene, which brought her fever down to 36.2 °C and completely eased her muscle rigidity within two days after ECT. CONCLUSIONS: This is the first reported case of potentially lethal malignant hyperthermia after ECT. In addition, it highlights the delayed onset of malignant hyperthermia following an ECT procedure, emphasizing the necessity for psychiatrists to recognize its onset even after the treatment. In the light of potentially lethal consequences of malignant hyperthermia, it is critically important for psychiatrists to closely monitor both intraoperative and postoperative patient's vital signs and characteristic physical presentations, promptly identify any symptomatic emergence, and treat it immediately with dantrolene.

Treatment and nursing care of a patient diagnosed with malignant hyperthermia after general anesthesia: a case report.

Malignant hyperthermia (MH), characterized by severe myoclonus, pyrexia, tachycardia, hypertension, elevated muscle enzymes, and hypercapnia, often occurs in patients with congenital deformities or genetic disorders. Although the reported incidence rate is as low as 1:5000 to 1:100,000, patients with MH exhibit rapid aggravation and an elevated mortality rate. Thus, MH is associated with substantial perioperative risk. Successful treatment of patients with MH largely depends on early diagnosis and timely effective treatment. This clinical report provides a detailed description of a patient with newly diagnosed MH who developed a rapid rise in body temperature, end-tidal carbon dioxide, and heart rate during maxillary osteotomy. After successful rescue, the patient recovered smoothly during the postoperative period, indicating the importance of intraoperative monitoring, early diagnosis, effective treatment, and postoperative monitoring. This case is expected to serve as a reference for future interventions and healthcare practices in managing other patients with MH.

Case Report of the Use of an Intravascular Cooling Device in the Management of Malignant Hyperthermia.

Malignant hyperthermia (MH) is a rare, life-threatening condition caused by alterations in skeletal muscle calcium channels inherited through an autosomal dominant pattern. The use of specific agents in anesthesia such as inhaled anesthetics and succinylcholine can precipitate a hyperthermic crisis. Patients experience a rapid increase in muscle rigidity, secondary to skeletal muscle calcium dysregulation, leading to acute rhabdomyolysis and possible hyperthermia. Providers must have a high index of suspicion of this disease process because early diagnosis is critical to mortality reduction. Management centers around removal of the offending agent, dantrolene, and supportive care including cooling if hyperthermic. Intravascular cooling devices have been used in thermodynamic regulation after cardiac arrest and have shown to be more effective than dermal cooling techniques; however, they have not been well described in other disease processes. The following case report is the first to describe a patient suffering from MH to undergo invasive intravenous cooling in order to counteract the effects of this life-threatening disease.

Perioperative Management of Paraneoplastic Necrotizing Myopathy in Thyroidectomy: A Case Report.

Perioperative management of patients with myopathies can be challenging due to the increased risk of malignant hyperthermia (MH) and anesthesia-induced rhabdomyolysis (AIR). However, currently, there is no evidence regarding the optimal anesthetic management for paraneoplastic necrotizing myopathy (PNM) (total intravenous anesthetic vs. volatile anesthetics). Here, I report a case where anesthesia was administered safely using volatile anesthetics. A 63-year-old female presented with PNM associated with papillary thyroid carcinoma, necessitating urgent thyroidectomy. The patient, previously diagnosed with anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibody-associated myopathy, exhibited progressive weakness and dysphagia, prompting suspicion of PNM. The patient's compromised respiratory status, attributed to tracheal compression by a large goiter, necessitated an urgent thyroidectomy. Anesthetic management considerations included the potential effect of HMGCR-M on respiratory muscles and the need for careful planning to mitigate postoperative complications. The patient underwent total thyroidectomy, left central compartment clearance, and tracheostomy. The surgery proceeded uneventfully, with meticulous monitoring and adjustment of anesthetic agents to maintain hemodynamic stability. Postoperatively, the patient recovered well, demonstrating complete resolution of neurological symptoms during a three-month follow-up. The case underscores the importance of recognizing paraneoplastic syndromes in the context of thyroid surgery and highlights potential challenges faced by anesthesiologists. Despite the lack of established safety data for anesthetic drugs in HMGCR-M necrotizing myopathy, the case demonstrates the successful use of sevoflurane and rocuronium.

Anesthetic Management of Patients With Morvan Syndrome: A Case Report and Literature Review.

Morvan syndrome is a rare condition distinguished by hyperactivity within the central, autonomic, and peripheral nervous systems. Due to the limited number of cases, this presents clinical challenges stemming from the scarcity of published literature. We present a successful anesthetic approach for a patient diagnosed with Morvan syndrome scheduled for elective major intra-thoracic surgery to remove metastases from a thymoma. The patient had previously undergone thymectomy, with the syndrome being diagnosed only one year after the surgery. Additionally, we conducted a literature review on the anesthetic management of this condition.

Perioperative Management in Neuromuscular Diseases: A Narrative Review.

Patients with neuromuscular diseases are particularly vulnerable in the perioperative period to the development of pulmonary and cardiac complications, or medication side effects. These risks could include hypoventilation, aspiration pneumonia, exacerbation of underlying cardiomyopathy, arrhythmias, adrenal insufficiency, prolonged neuromuscular blockade, issues related to thermoregulation, rhabdomyolysis, malignant hyperthermia, or prolonged mechanical ventilation. Interventions at each of the perioperative stages can be implemented to mitigate these risks. A careful pre-operative evaluation may help identify risk factors so that appropriate interventions are initiated, including cardiology consultation, pulmonary function tests, initiation of noninvasive ventilation, or implementation of preventive measures. Important intraoperative issues include positioning, airway and anesthetic management, and adequate ventilation. The postoperative period may require correction of electrolyte abnormalities, control of secretions with medications, manual or mechanical cough assistance, avoiding the risk of reintubation, judicious pain control, and appropriate medication management. The aim of this review is to increase awareness of the particular surgical challenges in this vulnerable population, and guide the clinician on the various evaluations and interventions that may result in a favorable surgical outcome.

Incidence of statin-associated muscle symptoms in patients taking statins with RYR1 or CACNA1S variants.

Background: Statins are commonly used medications. Variants in SLCO1B1, CYP2C9, and ABCG2 are known predictors of muscle effects when taking statins. More exploratory genes include RYR1 and CACNA1S, which can also be associated with disease conditions. Methods: Patients with pathogenic/likely pathogenic variants in RYR1 or CACNA1S were identified through an elective genomic testing program. Through chart review, patients with a history of statin use were assessed for statin-associated muscle symptoms (SAMS) along with collection of demographics and other known risk factors for SAMS. Results: Of the 23 patients who had a pathogenic or likely pathogenic RYR1 or CACNA1S variant found, 12 had previous statin use; of these, SAMS were identified in four patients. Conclusion: These data contribute to previous literature suggesting patients with RYR1 variants may have an increased SAMS risk. Additional research will be helpful in further investigating this relationship and providing recommendations.

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Malignant hyperthermia safety - A nationwide survey of publicly funded Swedish healthcare.

BACKGROUND: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder that can lead to a life-threatening reaction during general anaesthesia with triggering agents. Prompt life-saving treatment includes the immediate administration of the antidote dantrolene. This study investigated Swedish healthcare providers' awareness and adherence to guidelines and recommendations with respect to MH and whether adherence to safe MH-praxis varies with hospital care-complexity level and private versus public management form. METHOD: Agreements and procurement specifications between all 21 Swedish County Councils and privately run surgical care providers were reviewed alongside with questionnaire-aided collection of information from 62 publicly funded health care providers (both privately and publicly run). RESULTS: No procurement requirement specification or contract contained requirements on anaesthesia or aspects of MH. All publicly run hospitals stocked dantrolene and 28 out of 52 (54%) stocked the recommended amount. Seven out of nine (78%) of the privately run institutions stocked dantrolene, and one stocked the recommended amount. Publicly run hospitals adhered to recommendations to a greater extent than privately run institutions, both with respect to stocking of dantrolene (p = .02) and to stocking the recommended amount (p = .03). CONCLUSIONS: Contracts between Swedish county councils and private surgical care subcontractors rarely outline expectations of standards for the safe practice of anaesthesia such as preparedness to handle a life-threatening MH reaction. Among Swedish publicly funded anaesthesia providers there is room for improvement in adherence to the EMHG guideline on dantrolene availability. Publicly run hospitals seem to have better compliance with these recommendations than privately run institutions. Raising awareness about current guidelines is important to improve safety for known and unknown MH-susceptible individuals.

The Anesthesiologists' Perception of Malignant Hyperthermia and Availability of Dantrolene in China: A Cross-Sectional Survey.

Background: Malignant hyperthermia (MH) is a hypermetabolic syndrome with high mortality rates. Early detection and prompt intravenous administration of dantrolene are crucial for effective management of MH. However, there is currently a lack of comprehensive nationwide surveys on the availability of dantrolene and anesthesiologists' understanding of MH in China. Methods: A nationwide survey was conducted between January 2022 and June 2022. Online questionnaires on the cognition of MH among anesthesiologists in China were sent through social platforms to anesthesiologists in mainland China. Data regarding participants' perception of MH-related knowledge, availability of domestic dantrolene, and reported MH cases were collected in this study. Results: Responses were collected from a total of 11,354 anesthesiologists representing 31 provinces across the Chinese mainland. Among the 11 scoring questions, the highest accuracy rates were observed for the question regarding therapeutic drugs for MH (99.3%) and the characteristics of MH (98.0%). Conversely, the question pertaining to the earliest clinical signs of MH had the lowest accuracy rate (23.5%). Significant variations were observed in the scores among different professional titles (P=0.003), academic degree (P<0.001), hospital classification (P<0.001), and urban hierarchy (P<0.001). Of the respondents, 919 (8.1%) anesthesiologists reported dantrolene availability in their hospitals, and 631 (5.6%) indicated unclear. A total of 136 hospitals in this survey reported at least one previous case of MH. Conclusion: Mainland China faces challenges such as insufficient experience in diagnosing and treating MH, as well as difficulty in obtaining dantrolene. To improve the public awareness of MH, it is imperative to establish and promote a refined MH training system. Additionally, a streamlined and rapid dantrolene linkage emergency system should be implemented to ensure prompt access to the drug.

Remimazolam-based total intravenous anesthesia in a patient with a confirmed diagnosis of malignant hyperthermia: a case report.

BACKGROUND: Malignant hyperthermia (MH) is a rare, life-threatening disorder of calcium homeostasis in skeletal muscle cells that is triggered by volatile anesthetics and succinylcholine, leading to a hypermetabolic reaction. The pathogenic ryanodine receptor 1 (RYR1) gene variant is critical. Patients susceptible to MH should avoid triggering agents, and total intravenous anesthesia (TIVA) is preferred. Remimazolam is safe in patients with suspected MH. CASE PRESENTATION: We present the first case of remimazolam treatment in a genetically confirmed patient with MH without MH development. A 72-year-old man with a family history of MH underwent remimazolam-based TIVA. After informed consent was obtained, a muscle biopsy and genetic testing were performed. Intraoperatively and postoperatively, the patient exhibited no signs of MH. An enhanced function of the RYR1 channel into releasing calcium was indicated, and the genetic testing revealed a pathogenic variant of RYR1. CONCLUSIONS: Remimazolam-based TIVA is safe in patients confirming the diagnosis of MH.