-
Cells Aug 2022Calsequestrin 1 (CASQ1) and Ryanodine receptor 1 (RYR1) are two of the main players in excitation-contraction (EC) coupling. CASQ1-knockout mice and mice carrying a...
Calsequestrin 1 (CASQ1) and Ryanodine receptor 1 (RYR1) are two of the main players in excitation-contraction (EC) coupling. CASQ1-knockout mice and mice carrying a mutation in RYR1 (Y522S) linked to human malignant hyperthermia susceptibility (MHS) both suffer lethal hypermetabolic episodes when exposed to halothane (MHS crises) and to environmental heat (heat stroke, HS). The phenotype of Y522S is more severe than that of CASQ1-null mice. As MHS and HS are hypermetabolic responses, we studied the metabolism of adult CASQ1-null and Y522S mice using wild-type (WT) mice as controls. We found that CASQ1-null and Y522S mice have increased food consumption and higher core temperature at rest. By indirect calorimetry, we then verified that CASQ1-null and Y522S mice show an increased oxygen consumption and a lower respiratory quotient (RQ). The accelerated metabolism of CASQ1-null and Y522S mice was also accompanied with a reduction in body fat. Moreover, both mouse models displayed increased oxygen consumption and a higher core temperature during heat stress. The results collected suggest that metabolic rate, oxygen consumption, and body temperature at rest, all more elevated in Y522S than in CASQ1-null mice, could possibly be used as predictors of the level of susceptibility to hyperthermic crises of mice (and possibly humans).
Topics: Animals; Basal Metabolism; Calcium-Binding Proteins; Calsequestrin; Heat Stroke; Humans; Malignant Hyperthermia; Mice; Mice, Knockout; Oxygen Consumption; Ryanodine Receptor Calcium Release Channel
PubMed: 36010545
DOI: 10.3390/cells11162468 -
Orphanet Journal of Rare Diseases May 2007Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy.... (Review)
Review
Central core disease (CCD) is an inherited neuromuscular disorder characterised by central cores on muscle biopsy and clinical features of a congenital myopathy. Prevalence is unknown but the condition is probably more common than other congenital myopathies. CCD typically presents in infancy with hypotonia and motor developmental delay and is characterized by predominantly proximal weakness pronounced in the hip girdle; orthopaedic complications are common and malignant hyperthermia susceptibility (MHS) is a frequent complication. CCD and MHS are allelic conditions both due to (predominantly dominant) mutations in the skeletal muscle ryanodine receptor (RYR1) gene, encoding the principal skeletal muscle sarcoplasmic reticulum calcium release channel (RyR1). Altered excitability and/or changes in calcium homeostasis within muscle cells due to mutation-induced conformational changes of the RyR protein are considered the main pathogenetic mechanism(s). The diagnosis of CCD is based on the presence of suggestive clinical features and central cores on muscle biopsy; muscle MRI may show a characteristic pattern of selective muscle involvement and aid the diagnosis in cases with equivocal histopathological findings. Mutational analysis of the RYR1 gene may provide genetic confirmation of the diagnosis. Management is mainly supportive and has to anticipate susceptibility to potentially life-threatening reactions to general anaesthesia. Further evaluation of the underlying molecular mechanisms may provide the basis for future rational pharmacological treatment. In the majority of patients, weakness is static or only slowly progressive, with a favourable long-term outcome.
Topics: Cardiomyopathy, Hypertrophic; Child, Preschool; Diagnosis, Differential; Genetic Testing; Humans; Infant; Infant, Newborn; Malignant Hyperthermia; Muscle, Skeletal; Mutation; Myopathy, Central Core; Physical Therapy Modalities; Prognosis; Ryanodine Receptor Calcium Release Channel
PubMed: 17504518
DOI: 10.1186/1750-1172-2-25 -
IUBMB Life Dec 2019Malignant hyperthermia is a pharmacogenetic disorder, which is an uncommon but frequently fatal intricacy of inhalation anesthesia in man. It causes a quick rise in body... (Review)
Review
Malignant hyperthermia is a pharmacogenetic disorder, which is an uncommon but frequently fatal intricacy of inhalation anesthesia in man. It causes a quick rise in body temperature to highly irreversible levels, which causes death in around three of four cases. The trigger anesthetics cause an anomalous, continued ascent in myoplasmic calcium levels. Possible mechanisms by which continuous release of sodium, calcium from skeletal muscle plasma membrane and sarcoplasmic reticulum stores respectively can produce the profound hyperthermia are discussed.
Topics: Anesthesia; Anesthetics; Calcium; Dantrolene; Humans; Malignant Hyperthermia; Muscle, Skeletal; Sodium-Calcium Exchanger; TRPC Cation Channels
PubMed: 31381266
DOI: 10.1002/iub.2138 -
Pharmacogenomics Jan 2020Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.'... (Review)
Review
Pharmacogenetics, the genetic influence on the interpersonal variability in drug response, has enabled tailored pharmacotherapy and emerging 'personalized medicine.' Although oncology spearheaded the clinical implementation of personalized medicine, other specialties are rapidly catching up. In anesthesia, classical examples of genetically mediated idiosyncratic reactions have been long known (e.g., malignant hyperthermia and prolonged apnea after succinylcholine). The last two decades have witnessed an expanding body of pharmacogenetic evidence in anesthesia. This review highlights some of the prominent pharmacogenetic associations studied in anesthesia and pain management, with special focus on pediatric anesthesia.
Topics: Anesthesia; Anesthesiology; Apnea; Child; Child, Preschool; Humans; Malignant Hyperthermia; Pain; Pain Management; Pediatrics; Precision Medicine; Succinylcholine
PubMed: 31849281
DOI: 10.2217/pgs-2019-0108 -
Boletin Medico Del Hospital Infantil de... 2020Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile...
BACKGROUND
Malignant hyperthermia syndrome is a hereditary pharmacogenetic disorder of skeletal muscle characterized by hypermetabolic state related to the exposure of volatile anesthetic gases or depolarizing muscle relaxants. It is an infrequent entity that occurs in genetically predisposed individuals, with a very low incidence in pediatrics (1 in 10,000-15,000 anesthetic procedures).
CASE REPORT
We report a case of malignant hyperthermia related to exposure to sevoflurane during adenoidectomy surgery in a 6-year-old female. The patient presented with tachycardia, hypercapnia, and hyperthermia, requiring two successive doses of dantrolene sodium administration, with an adequate response to the treatment.
CONCLUSIONS
Malignant hyperthermia syndrome is a rare condition in pediatric patients that should be detected in early stages since it is essential to initiate the treatment as soon as possible.
Topics: Adenoidectomy; Anesthetics, Inhalation; Child; Dantrolene; Female; Humans; Malignant Hyperthermia; Sevoflurane
PubMed: 33186346
DOI: 10.24875/BMHIM.20000047 -
Anesthesiology Jan 2019Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia...
BACKGROUND
Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.
METHODS
The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given.
RESULTS
Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities.
CONCLUSIONS
Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used.
Topics: Humans; Dantrolene; Databases, Factual; Malignant Hyperthermia; Muscle Relaxants, Central; Neuromuscular Depolarizing Agents; Succinylcholine
PubMed: 30550426
DOI: 10.1097/ALN.0000000000002490 -
Canadian Journal of Surgery. Journal... Oct 2002Malignant hyperthermia is a potentially fatal genetic myopathy that presents when the patient is under anesthesia. It manifests as a hypermetabolic state involving... (Review)
Review
Malignant hyperthermia is a potentially fatal genetic myopathy that presents when the patient is under anesthesia. It manifests as a hypermetabolic state involving tachycardia, hypercarbia, base deficit, rigidity and fever. Many of the hallmark traits of an acute malignant hyperthermic crisis overlap with signs and symptoms of an emergent abdominal condition. Historically, there has been a reluctance in local community hospitals to manage patients known to be susceptible to malignant hyperthemia, and this is a source of frustration for many families in which there is a history of this condition. This article outlines the diagnosis and management of an acute malignant hyperthermic crisis from the viewpoint of a community general surgeon and provides a review of the management of patients known to be susceptible to this condition in the surgeon's elective and emergent practice.
Topics: Anesthetics, Inhalation; Biopsy; Dantrolene; General Surgery; Genetic Predisposition to Disease; Humans; Malignant Hyperthermia; Monitoring, Physiologic; Muscle Relaxants, Central; Muscle, Skeletal; Neuromuscular Nondepolarizing Agents
PubMed: 12387544
DOI: No ID Found -
Anesthesia and Analgesia Nov 2011Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle... (Review)
Review
Malignant hyperthermia (MH) is a complex pharmacogenetic disorder of muscle metabolism. To more closely examine the complexities of MH and other related muscle disorders, the Malignant Hyperthermia Association of the United States (MHAUS) recently sponsored a scientific conference at which an interdisciplinary group of experts gathered to share new information and ideas. In this Special Article, we highlight key concepts and theories presented at the conference along with exciting new trends and challenges in MH research and patient care.
Topics: Calcium; Heat Stroke; Homeostasis; Humans; Malignant Hyperthermia; Muscle, Skeletal; Muscular Diseases; Patient Care; Patient Safety; Research
PubMed: 21709147
DOI: 10.1213/ANE.0b013e318222af2e -
Anesthesiology Jun 2014
Topics: Ambulatory Surgical Procedures; Anesthetics; Dantrolene; Humans; Malignant Hyperthermia
PubMed: 24710219
DOI: 10.1097/ALN.0000000000000256 -
Anesthesiology Jun 2022The introduction of next-generation sequencing into the diagnosis of neuromuscular disorders has resulted in an increased number of newly identified RYR1 variants. The...
BACKGROUND
The introduction of next-generation sequencing into the diagnosis of neuromuscular disorders has resulted in an increased number of newly identified RYR1 variants. The hypothesis was that there is an increased referral of patients to malignant hyperthermia units without a personal/family history of adverse anesthetic events suspected to be malignant hyperthermia. This retrospective multicenter cohort study evaluates patient referral indications and outcomes for those without a history of an adverse anesthetic event.
METHODS
Patients referred between 2010 and 2019 to the malignant hyperthermia units in Antwerp, Belgium; Lund, Sweden; Nijmegen, The Netherlands; and Toronto, Ontario, Canada were included. Previously tested patients and relatives of previously tested patients were excluded. Data collection included demographics, referral details, muscle contracture, and genetic testing results including Rare Exome Variant Ensemble Learner scores. Referral indications were categorized into those with a personal/family history of adverse anesthetic event and other indications including exertional and/or recurrent rhabdomyolysis, RYR1 variant(s) detected in diagnostic testing in the neuromuscular clinic without a specific diagnosis (in a family member), diagnosed RYR1-related myopathy (in a family member), idiopathically elevated resting creatine kinase values, exertional heat stroke, and other.
RESULTS
A total of 520 medical records were included, with the three most frequent referral indications as follows: personal history of an adverse anesthetic event (211 of 520; 40.6%), family history of an adverse anesthetic event (115 of 520; 22.1%), and exertional and/or recurrent rhabdomyolysis (46 of 520; 8.8%). The proportion of patients referred without a personal/family history of an adverse anesthetic event increased to 43.6% (133 of 305) between 2015 and 2019 compared to 28.4% (61 of 215) in 2010 to 2014 (P < 0.001). Patients with a personal/family history of an adverse anesthetic event were more frequently diagnosed as malignant hyperthermia-susceptible (133 of 220; 60.5%) than those without (47 of 120; 39.2%; P < 0.001). Due to missing data, 180 medical records were excluded.
CONCLUSIONS
The proportion of patients referred to malignant hyperthermia units without a personal/family history of an adverse anesthetic event has increased, with 39.2% (47 of 120) diagnosed as malignant hyperthermia-susceptible.
Topics: Anesthetics; Cohort Studies; Disease Susceptibility; High-Throughput Nucleotide Sequencing; Humans; Malignant Hyperthermia; Referral and Consultation; Rhabdomyolysis; Ryanodine Receptor Calcium Release Channel
PubMed: 35285867
DOI: 10.1097/ALN.0000000000004199