Diagnosis and rescue of malignant hyperthermia induced by anesthesia during radical surgery in a cervical cancer patient using the National Remote Emergency System: A case report.

RATIONALE: Malignant hyperthermia (MH) is a rare yet serious medical complication that typically arises following general anesthesia or the administration of specific anesthetics. Due to the infrequency of MH, anesthesiologists often lack sufficient expertise in identifying and managing it, leading to misdiagnosis and inappropriate treatment. There is an urgent need to enhance the diagnosis and management of MH through the utilization of relevant tools. PATIENT CONCERNS: In this case, a 52-year-old woman underwent radical cervical cancer surgery under general anesthesia, with no family or significant medical history. She experienced a gradual increase in end-tidal carbon dioxide (ETCO2) to a maximum of 75 mm Hg and a rise in body temperature from 36.5 to 37.5 °C in a very short period, as well as a blood gas analysis showing a pH of 7.217. DIAGNOSIS: The anesthesiologist immediately used The WeChat applet-based National Remote Emergency System for Malignant Hyperthermia (MH-NRES), and the score was 40, which indicated that the patient was very likely to have MH. INTERVENTIONS: We immediately discontinued sevoflurane and switched total intravenous anesthesia to maintain general anesthesia, with a rapid intravenous infusion of dantrolene sodium. OUTCOMES: The ETCO2 and the temperature quickly dropped to normal, followed by successful completion of the surgery, and the patient was discharged 8 days after surgery. LESSONS: The experience can provide a basis use of MH-NRES and improve the ability of anesthesiologists to deal with intraoperative MH as well as increase the survival probability of patients.

Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts.

Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient ß-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.

Each year, more than 300,000 people experience cardiac arrest or sudden cardiac death. Sudden cardiac death is caused by irregular heartbeats known as ventricular tachycardia or ventricular fibrillation, which prevent the heart from pumping blood. During a regular heart rhythm, the heart muscles contract and relax, regulated by a coordinated rise and fall of calcium ions within heart cells. In the cells of diseased hearts, on the other hand, calcium leaks out of a compartment known as the sarcoplasmic reticulum in an uncontrolled manner. This happens because an ion channel in the membrane of the sarcoplasmic reticulum known as ryanodine receptor 2 becomes hyperactive and releases calcium in an uncontrolled manner. This abnormal calcium release leads to irregular calcium waves, which can make the heart's electrical properties unstable, causing ventricular tachycardia, ventricular fibrillation and sudden cardiac death. Joshi et al. tested whether dantrolene, a molecule that blocks ryanodine receptor 2, can stop calcium leaks from the sarcoplasmic reticulum and prevent lethal arrhythmias and sudden cardiac death in failing hearts. To investigate this, Joshi et al. induced heart failure in guinea pigs that have abnormal heart calcium signalling similar to human heart failure, and then treated the animals with either dantrolene or a placebo. The results indicate that blocking ryanodine receptor 2 hyperactivity with dantrolene prevents lethal arrhythmias and sudden cardiac death by blocking calcium leaks and by preventing the instability of the electrical properties of the heart. Additionally, Joshi et al. found that dantrolene also improved the diseased heart's ability to pump adequate amounts of blood, allowing failing hearts to meet increased cardiovascular demands, and thereby improving the heart's overall function. The proposed studies come from a strong clinical need to improve bad outcomes in people who keep having fatal heart rhythm episodes despite getting the best medical care. Many heart failure patients are plagued by recurrent defibrillator shocks to abort sudden cardiac death from relentless lethal heart rhythms. These shocks are painful, injure the heart, and worsen the quality of life. Unfortunately, management options are extremely limited for these patients. The findings of Joshi et al. indicate that dantrolene may be a potential treatment for people with fatal heart rhythms who are at risk of sudden cardiac death and could have a positive impact on these people's quality of life. However, before this can happen, dantrolene will first have to be thoroughly tested to ensure effectivity and safety in humans. In any case, Joshi et al. have opened a new avenue in the search for medications to treat deadly arrhythmias and sudden cardiac death.

Oral Dantrolene Reduces Myalgia and Hyperckemia in a Child with RYR1-Related Exertional Myalgia/Rhabdomyolysis.

RYR1-related exertional myalgia/rhabdomyolysis (ERM) is an underrecognized condition, which can cause limiting muscle symptoms, and may account for more than one-third of undiagnosed rhabdomyolysis cases. Dantrolene has shown promising results in controlling muscle symptoms in individuals with ERM, however, its use in children remains poorly documented. This case report presents the successful treatment of a 5-year-old patient with ERM using oral dantrolene. The patient experienced notable improvements, including a reduction in the frequency and intensity of myalgia episodes, no hospitalizations due to rhabdomyolysis, a substantial decrease in creatine phosphokinase (CPK) levels, and enhanced performance on the 6-minute walk test. The use of dantrolene was well-tolerated, and no significant adverse effects were observed. This report adds to the existing evidence supporting the effectiveness of oral dantrolene in managing ERM, and, to the best of our knowledge, this is the first report of the use of dantrolene in a pediatric patient for controlling anesthesia-independent muscle symptoms.

Suspected Malignant Hyperthermia in a Brain-Dead Donor During Anesthesia for Organ Procurement Surgery: A Case Report.

We report an unusual case of highly suspected malignant hyperthermia after inducing anesthesia in a brain-dead 18-year-old male patient undergoing organ procurement surgery. The patient was administered desflurane (3 vol%) and rocuronium bromide (50 mg) to induce and maintain general anesthesia. He experienced hypercapnia and tachycardia within 5 minutes of anesthesia induction; however, his body temperature rapidly rose only after 15 minutes. The volatile anesthetic was discontinued, and dantrolene was administered at a low dose (1 mg/kg) to avert possible hepatotoxic effects on the donor liver. Fortunately, the clinical course of the brain-dead donor until the organs were harvested and the liver transplantation outcome of the recipient was favorable. A comprehensive understanding of the pathophysiology of brain death, organ transplantation, and malignant hyperthermia is essential to respond promptly and appropriately. Based on our experience, low-dose dantrolene may be clinically used in brain-dead donors while accounting for its potential hepatotoxic effects.

Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms.

Dantrolene is an intra-cellularly acting skeletal muscle relaxant used for the treatment of the rare genetic disorder, malignant hyperthermia (MH). In most cases, MH susceptibility is caused by dysfunction of the skeletal ryanodine receptor (RyR1) harboring one of nearly 230 single-point MH mutations. The therapeutic effect of dantrolene is the result of a direct inhibitory action on the RyR1 channel, thus suppressing aberrant Ca2+ release from the sarcoplasmic reticulum. Despite the almost identical dantrolene-binding sequence exits in all three mammalian RyR isoforms, dantrolene appears to be an isoform-selective inhibitor. Whereas RyR1 and RyR3 channels are competent to bind dantrolene, the RyR2 channel, predominantly expressed in the heart, is unresponsive. However, a large body of evidence suggests that the RyR2 channel becomes sensitive to dantrolene-mediated inhibition under certain pathological conditions. Although a consistent picture of the dantrolene effect emerges from in vivo studies, in vitro results are often contradictory. Hence, our goal in this perspective is to provide the best possible clues to the molecular mechanism of dantrolene's action on RyR isoforms by identifying and discussing potential sources of conflicting results, mainly coming from cell-free experiments. Moreover, we propose that, specifically in the case of the RyR2 channel, its phosphorylation could be implicated in acquiring the channel responsiveness to dantrolene inhibition, interpreting functional findings in the structural context.

Dantrolene Significantly Improves Cerebral Blood Flow in a Rat Model of Hemorrhagic Vasospasms.

INTRODUCTION: A cerebral vasospasm (CVSP) is a potent vasoconstriction of the cerebral vasculature and the primary cause of morbidity and mortality following a subarachnoid hemorrhage. The middle cerebral artery (MCA) is commonly affected by CVSPs. Concomitant administration of dantrolene and nimodipine synergistically reduces vasospasms in aortic rings from Sprague Dawley rats. To determine if the effects observed in the systemic vasculature extend to the cerebral circulation, we investigated the effect of intravenous administration of dantrolene (2.5 mg/kg) and nimodipine (1 mg/kg and 2 mg/kg) on MCA blood flow velocity (BFV) 7 days after the induction of CVSPs. METHODS: Vasospasms were induced by bathing the left common carotid artery with autologous whole blood. Age-matched sham rats were used as controls. BFV, mean arterial pressure (MAP), and heart rate (HR) were measured with a PeriFlux 5000 Laser Doppler System, and a CODA non-invasive blood pressure system, before and after administering the drugs. Morphometric evaluations were also performed to assess vascular alterations. RESULTS: BFV was reduced by 37% with dantrolene alone (n = 6, p ≤ 0.05) and by 27% with 2 mg/kg nimodipine (n = 6, p < 0.05), while it was not affected by 1 mg/kg nimodipine. The combination of 1 mg/kg nimodipine with dantrolene, however, decreased BFV by 35% (from 435.70 ± 21.53 to 284.30 ± 23.13 perfusion units, n = 7, p ≤ 0.05). A similar reduction (31%) was obtained with dantrolene and 2 mg/kg nimodipine (from 536.00 ± 32.61 to 367.80 ± 40.93 perfusion units, n = 6, p ≤ 0.05). Neither MAP nor HR was affected by dantrolene or nimodipine alone. The combination of dantrolene with 2 mg/kg nimodipine, however, decreased MAP and increased HR. Furthermore, 7 days after the induction of vasospasms, lumen area of the left common carotid artery decreased, whereas media thickness and the wall-to-lumen ratio increased when compared to contralateral controls. The latter finding suggests that vascular remodeling was present at this stage. CONCLUSION: Altogether, our results indicate that 2.5 mg/kg dantrolene significantly reduces BFV in the MCA without altering systemic hemodynamic parameters to a similar extent than the highest dose of nimodipine or the combination of dantrolene and the lowest dose of nimodipine. Therefore, dantrolene may provide a promising alternative to lower the risk, or partially revert, CVSP.

Dantrolene and ryanodine receptors in COVID-19: The daunting task and neglected warden.

Dantrolene (DTN) is a ryanodine receptor (RyR) antagonist that inhibits Ca2+ release from stores in the sarcoplasmic reticulum. DTN is mainly used in the management of malignant hyperthermia. RyRs are highly expressed in immune cells and are involved in different viral infections, including severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), because Ca2+ is necessary for viral replication, maturation and release. DTN can inhibit the proliferation of SARS-CoV-2, indicating its potential role in reducing entry and pathogenesis of SARS-CoV-2. DTN may increase clearance of SARS-CoV-2 and promote coronavirus disease 2019 (COVID-19) recovery by shortening the period of infection. DTN inhibits N-methyl-D-aspartate (NMDA) mediated platelets aggregations and thrombosis. Therefore, DTN may inhibit thrombosis and coagulopathy in COVID-19 through suppression of platelet NMDA receptors. Moreover, DTN has a neuroprotective effect against SARS-CoV-2 infection-induced brain injury through modulation of NMDA receptors, which are involved in excitotoxicity, neuronal injury and the development of neuropsychiatric disorders. In conclusion, DTN by inhibiting RyRs may attenuate inflammatory disorders in SARS-CoV-2 infection and associated cardio-pulmonary complications. Therefore, DNT could be a promising drug therapy against COVID-19. Preclinical and clinical studies are warranted in this regards.

Design, synthesis, and evaluation of hydrazones as dual inhibitors of ryanodine receptors and acetylcholinesterases for Alzheimer's disease.

Alzheimer's disease (AD) implicates neuronal loss, plaque and neurofibrillary tangle formation, and disturbed neuronal Ca2+ homeostasis, which leads to severe dementia, memory loss, as well as thinking and behavioral perturbations that could ultimately lead to death. Calcium dysregulation and low acetylcholine levels are two main mechanisms implicated in Alzheimer's disease progression. Simultaneous inhibition of calcium oscillations (store overload-induced Ca2+ release [SOICR]) and acetylcholinesterase (AChE) by a single molecule may bring a new breath of hope for AD treatment. Here, we described some dantrolene derivatives as dual inhibitors of the ryanodine receptor and AChE. Two series of acylhydrazone/sulfonylhydrazone derivatives with aromaticgroup were designed and synthesized. In this study, the target compounds were evaluated for their ability to inhibit SOICR and AChE in vitro, using dantrolene and donepezil as positive controls. Compound 22a exhibited excellent and balanced inhibitory potency against SOICR (inhibition (%) = 90.1, IC50 = 0.162 µM) and AChE (inhibition (%) = 93.5, IC50 = 0.372 µM). Docking simulations showed that several preferred compounds could bind to the active sites of both the proteins, further validating the rationality of the design strategy. Potential therapeutic effects in AD were evaluated using the Barnes maze and Morris water maze tests, which demonstrated that compound 22a significantly improved memory and cognitive behavior in AD model mice. Moreover, it was also found that compound 22a could enhance synaptic strength by measuring hippocampal long-term potentiation (LTP) in brain slices. These results suggested that the introduction of a sulfonyl-hydrazone scaffold and aromatic substitution to dantrolene derivatives provided a useful template for the development of potential chemical entities against AD.

Malignant hyperthermia in maxillofacial surgery: Literature review supported by case presentation.

OBJECTIVE: Malignant hyperthermia (MH) is characterized by a state of hypermetabolism after exposure to halogenated inhalational anesthetics or succinylcholine. The aims of this study were to carry out an updated review on the subject and report an illustrative case of MH in urgent maxillofacial surgery. MATERIAL AND METHODS: A search of the PubMed/MEDLINE database using the keyword "malignant hyperthermia" was performed including articles published over the last 11 years in English, Spanish or Portuguese. Exclusion criteria were similar presentations but not associated with MH and cases not related to the use of anesthetic drugs as a trigger of the condition. CASE REPORT: A 45-year-old man (75 kg, ASA status IE) with a negative family history for neuromuscular diseases, victim of a car accident with a facial fracture, underwent surgery under balanced general anesthesia and developed signs of MH 4 h after anesthesia induction. In our patient, the causative agent was sevoflurane and the diagnosis of MH was confirmed, subsequently, by muscle biopsy. RESULTS/DISCUSSION: Overall, 44 cases of MH were found. According to the recent literature, MH shows a male predilection (3:1) and the mean age of patients is 32.2 ± 22.2 years. The most frequently cited causative agents were sevoflurane (30.5%), isoflurane (22.2%), and sevoflurane + succinylcholine (13.8%). The most common clinical indicators included hypercarbia (88.8%), hyperthermia (86.1%), and tachycardia (63.8%). Dantrolene was administered in 24 cases. The outcome was favorable in 31 cases (86.1%). The in vitro muscle contracture test (IVCT) was performed in only 15 patients and all of them tested positive. In our patient, the causative agent was sevoflurane and the diagnosis of MH was confirmed by muscle biopsy. CONCLUSION: The mortality from MH is still high and an early clinical diagnosis and specific treatment with dantrolene are necessary for a favorable outcome. A complete understanding will allow better management of patients with MH. At present, the best management is to identify susceptible patients and to avoid triggering agents, combined with vigilant monitoring.

Stabilizing cardiac ryanodine receptor with dantrolene treatment prevents left ventricular remodeling in pressure-overloaded heart failure mice.

Dantrolene (DAN) directly binds to cardiac ryanodine receptor 2 (RyR2) through Leu601-Cys620 in the N-terminal domain and subsequently inhibits diastolic Ca2+ leakage through RyR2. We previously reported that therapy using RyR2 V3599K mutation, which inhibits diastolic Ca2+ leakage by enhancing calmodulin (CaM) binding ability to RyR2, prevents left ventricular (LV) remodeling in transverse aortic constriction (TAC) heart failure. Here, we examined whether chronic administration of DAN prevents LV remodeling in TAC heart failure via the same mechanism as genetic therapy. A pressure-overloaded hypertrophy mouse model was developed using TAC. Wild-type (WT) mice were divided into three groups: sham-operated mice (Sham group), TAC mice (TAC group), and TAC mice treated with DAN (TAC-DAN group, 20 mg/kg/day, i.p.). They were then followed up for 8 weeks. The survival rate was higher in the TAC-DAN group (83%) than in the TAC group (49%), and serial echocardiography studies and pathological tissue analysis showed that LV remodeling was significantly prevented in the TAC-DAN group compared to the TAC group. An increase in the diastolic Ca2+ spark frequency and a decrease in the binding affinity of CaM to RyR2 were observed at 8 weeks in the TAC group but not in the TAC-DAN group. Stabilization of RyR2 with DAN prevented LV remodeling and improved survival after TAC by enhancing CaM binding to RyR2 and inhibiting RyR2-mediated diastolic Ca2+ leakage.

Should rocuronium and sugammadex replace succinylcholine for airway emergencies in class B ambulatory anesthesia settings?

INTRODUCTION: In class B surgical facilities, where only oral or intravenous (IV) sedation is employed without the administration of volatile anesthetics, laryngospasm is among the most common airway complications. However, these facilities generally do not stock succinylcholine to avoid the cost of storing dantrolene for the treatment of malignant hyperthermia (MH). High dose IV rocuronium with sugammadex reversal has been suggested as an alternative to succinylcholine for airway emergencies. The aim of this paper was to evaluate the clinical utility, patient safety, and financial implications of replacing succinylcholine with rocuronium and sugammadex in lieu of stocking dantrolene in class B facilities. EVIDENCE ACQUISITION: A systematic review of the literature concerning neuromuscular blockade for airway emergencies in class B settings in adult patients was conducted. The MEDLINE and EMBASE databases were searched for published studies from January 1, 1990, to October 1, 2021. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system was used to assess the certainty of evidence. EVIDENCE SYNTHESIS: The search strategy yielded 1124 articles. After review, 107 articles were included, with 49 graded as "strong" evidence to provide recommendations for the posed questions. CONCLUSIONS: The use of succinylcholine in isolation without volatile agents has a low incidence of triggering MH. Laryngospasm is a common airway emergency that requires immediate treatment to avoid morbidity and mortality. Both succinylcholine and rocuronium-sugammadex provide adequate treatment of airway emergencies and rapid return of spontaneous ventilation, but succinylcholine has a superior economic and clinical profile.

Dantrolene for muscle rigidity in progressive supranuclear palsy.

Progressive supranuclear palsy is a degenerative neurological condition with a high level of associated motor symptom burden manifesting in poor postural reflexes, bradykinesia, dystonia and stiffness in the body core and neck. In the light of a paucity in literature exploring pain management in neurodegenerative diseases, the below case report describes the use of dantrolene to successfully relieve distressing widespread dystonia and muscle rigidity refractory to non-pharmacological and pharmacotherapy. To our knowledge, this is the first reported case of dantrolene use for the treatment of refractory muscle rigidity pain in neurodegenerative conditions.

Intravenous dantrolene in hypermetabolic syndromes: a survey of the U.S. Veterans Health Administration database.

BACKGROUND: Intravenous dantrolene is often prescribed for hypermetabolic syndromes other than the approved indication of malignant hyperthermia (MH). To clarify the extent of and indications for dantrolene use in conditions other than MH, we sought to document current practices in the frequency, diagnoses, clinical characteristics and outcomes associated with dantrolene treatment in critical care settings. METHODS: Inpatients receiving intravenous dantrolene from October 1, 2004 to September 30, 2014 were identified retrospectively in the U.S. Veterans Health Administration national database. Extracted data included; diagnoses of hypermetabolic syndromes; triggering drugs; dantrolene dosages; demographics; vital signs; laboratory values; in-hospital mortality; complications; and lengths of stay. Frequency and mortality of patients who did not receive dantrolene were obtained in selected diagnoses for exploratory comparisons. RESULTS: Dantrolene was administered to 304 inpatients. The most frequent diagnoses associated with dantrolene treatment were neuroleptic malignant syndrome (NMS; N = 108, 35.53%) and sepsis (N = 47, 15.46%), with MH accounting for only 13 (4.28%) cases. Over half the patients had psychiatric comorbidities and received psychotropic drugs before dantrolene treatment. Common clinical findings in patients receiving dantrolene included elevated temperature (mean ± SD; 38.7 ± 1.3 °C), pulse (116.33 ± 22.80/bpm), respirations (27.75 ± 9.58/min), creatine kinase levels (2,859.37 ± 6,646.88 IU/L) and low pO2 (74.93 ± 40.16 mmHg). Respiratory, renal or cardiac failure were common complications. Mortality rates in-hospital were 24.01% overall, 7.69% in MH, 20.37% in NMS and 42.55% in sepsis, compared with mortality rates in larger and possibly less severe groups of unmatched patients with MH (5.26%), NMS (6.66%), or sepsis (41.91%) who did not receive dantrolene. CONCLUSIONS: In over 95% of cases, dantrolene administration was associated with diagnoses other than MH in critically-ill patients with hypermetabolic symptoms and medical and psychiatric comorbidities. Exploratory survey data suggested that the efficacy and safety of dantrolene in preventing mortality in hypermetabolic syndromes other than MH remain uncertain. However, randomized and controlled studies using standardized criteria between groups matched for severity are essential to guide practice in using dantrolene.

Ryanodine receptor 1-mediated Ca2+ signaling and mitochondrial reprogramming modulate uterine serous cancer malignant phenotypes.

BACKGROUND: Uterine serous cancer (USC) is the most common non-endometrioid subtype of uterine cancer, and is also the most aggressive. Most patients will die of progressively chemotherapy-resistant disease, and the development of new therapies that can target USC remains a major unmet clinical need. This study sought to determine the molecular mechanism by which a novel unfavorable prognostic biomarker ryanodine receptor 1 (RYR1) identified in advanced USC confers their malignant phenotypes, and demonstrated the efficacy of targeting RYR1 by repositioned FDA-approved compounds in USC treatment. METHODS: TCGA USC dataset was analyzed to identify top genes that are associated with patient survival or disease stage, and can be targeted by FDA-approved compounds. The top gene RYR1 was selected and the functional role of RYR1 in USC progression was determined by silencing and over-expressing RYR1 in USC cells in vitro and in vivo. The molecular mechanism and signaling networks associated with the functional role of RYR1 in USC progression were determined by reverse phase protein arrays (RPPA), Western blot, and transcriptomic profiling analyses. The efficacy of the repositioned compound dantrolene on USC progression was determined using both in vitro and in vivo models. RESULTS: High expression level of RYR1 in the tumors is associated with advanced stage of the disease. Inhibition of RYR1 suppressed proliferation, migration and enhanced apoptosis through Ca2+-dependent activation of AKT/CREB/PGC-1α and AKT/HK1/2 signaling pathways, which modulate mitochondrial bioenergetics properties, including oxidative phosphorylation, ATP production, mitochondrial membrane potential, ROS production and TCA metabolites, and glycolytic activities in USC cells. Repositioned compound dantrolene suppressed USC progression and survival in mouse models. CONCLUSIONS: These findings provided insight into the mechanism by which RYR1 modulates the malignant phenotypes of USC and could aid in the development of dantrolene as a repurposed therapeutic agent for the treatment of USC to improve patient survival.

Donating Dantrolene: Development and Implementation of a Malignant Hyperthermia Program in a Scarce Resource Setting.

Intravenous dantrolene is the first-line treatment of malignant hyperthermia (MH), however, it is not always accessible in lower-middle income countries (LMICs). Facilities in the United States are in a transition period where dantrolene is being replaced with Ryanodex, therefore, there is an opportunity for excess dantrolene to be utilized in LMICs where neither dantrolene nor Ryanodex exist. Thirty-six vials of recently expired, unused dantrolene were obtained for a hospital in a LMIC and an MH program was developed in conjunction with the Lao Friends Hospital for Children (LFHC) anesthesia providers, LFHC liaison, LFHC leadership team, and an expert in the field of MH. Components of the MH program included developing a facility-specific protocol, treatment guidelines, supply list, and educational tools. A designated MH drawer was also created in preparation for an MH event. By procuring dantrolene and implementing an MH program in a facility where no MH protocol, treatment guidelines, supply list, or educational tools existed, LFHC is better equipped to handle a potentially lethal scenario.

Dantrolene, a stabilizer of the ryanodine receptor, prevents collagen-induced arthritis.

Dantrolene inhibits Ca2+ leakage from destabilized ryanodine receptors and therefore may serve as a therapeutic agent against endoplasmic reticulum stress-associated diseases. However, its effectiveness in treating autoimmune diseases remains unclear. Here, we investigated the effect of dantrolene on collagen-induced arthritis (CIA) in mice. Oral administration of dantrolene resulted in significantly lower arthritic scores in both male and female CIA mice than in the control mice. Micro-computed tomographic and histological analyses showed that dantrolene suppressed bone and chondral destruction. The serum levels of anti-type II collagen (CII) IgG were positively correlated with the arthritic scores (r = 0.704, p < 0.01). In addition, the serum levels of anti-CII IgG were significantly lower in the dantrolene group than in the control group (p < 0.05). These results demonstrate that oral administration of dantrolene to CIA mice inhibits the production of serum anti-CII IgG and consequently prevents arthritis. Therefore, dantrolene may be a potential anti-rheumatic drug.

Neuroleptic Malignant Syndrome with Adrenal Insufficiency After BNT162b2 COVID-19 Vaccination in a Man Taking Valproate: A Case Report.

BACKGROUND Considering the ongoing coronavirus disease 2019 (COVID-19) pandemic, sufficient information about common and serious adverse events is needed to rapidly distribute COVID-19 vaccines worldwide. We report a case of neuroleptic malignant syndrome (NMS) with adrenal insufficiency after initial vaccination with Pfizer/BioNTech BNT162b2. CASE REPORT A 48-year-old man presented to the Emergency Department with fever and an altered mental status 7 days after receiving the first dose of the BNT162b2 COVID-19 vaccine. The patient had a history of end-stage renal disease and epilepsy treated with valproate. He was diagnosed with NMS based on the clinical findings of hyperthermia, muscular rigidity, and an elevated creatine kinase level. Additionally, a reduction in the response of cortisol to adrenocorticotropic hormone (ACTH) stimulation was observed in the rapid ACTH stimulation test. The patient was treated with dantrolene, bromocriptine, and hydrocortisone, and he responded well to treatment. Dantrolene and bromocriptine were tapered off over 4 weeks. Hydrocortisone was also tapered, and the patient was discharged on oral hydrocortisone (30 mg). CONCLUSIONS The present case suggests a possible link between the BNT162b2 COVID-19 vaccine and NMS with adrenal insufficiency based on the temporal relationship between vaccine administration and disease onset, although the patient was taking valproate, a potential cause of NMS. Having a high level of suspicion is important because the diagnosis of NMS with adrenal insufficiency is often challenging due to non-specific clinical manifestations. However, this case does not negate the utility of vaccination because these complications are extremely rare and can be treated with early diagnosis and proper management.

Malignant hyperthermia in Mazovia Province - are we adequately prepared?

INTRODUCTION: Malignant hyperthermia (MH) is a life-threatening syndrome caused by sudden skeletal muscle hypermetabolism in response to inhalation anaesthetics and depolarising relaxants. The estimated incidence of MH is between 1 : 10,000 and 1 : 250,000 anaesthetic procedures. In Poland the incidence of MH is unknown. Dantrolene is imported as a life-saving drug and temporally authorised for sale. The aim of the study is to assess the incidence of MH and access to dantrolene in the Mazovia Province. METHODS: Anonymous questionnaires were sent to anaesthesia departments in the Mazovia Province after prior contact by phone and e-mail. The survey was approved by the local ethical review board. RESULTS: Completed surveys were received from 60 respondents which represents 72% of anaesthesiology departments in Mazovia. In the last 5 years there have been 4 episodes of MH in the Mazovia Province. Three patients survived the MH crisis. In a centre that did not have access to dantrolene, the patient died. Dantrolene is found only in 11 (18.3%) anaesthesiology departments in Mazovia. Only 6 (10%) hospitals are able to administer dantrolene within 5 minutes of suspecting MH crisis, while 5 centres may receive it after a few days. Only 38% of units have an algorithm for dealing with MH crisis in the operating theatres. CONCLUSIONS: MH is rare, but if untreated, it can be fatal. Therefore prompt diagnosis and treatment are crucial to avoid fatal outcome. Every centre using inhalational anaesthetics and/or succinylcholine should have dantrolene. To ensure the safety of our patients, we must be better prepared.