Malignant Hyperthermia Susceptibility Research Articles

Relative Affinities of General Anesthetics for Experimentally Identified Binding Sites in Ryanodine Receptors (RyR1)

Malignant hyperthermia (MH) is a pharmacogenetic disorder that manifests as a hypermetabolic response to certain anesthetic agents (halothane, isoflurane, sevoflurane, desflurane, succinylcholine). A defective or disordered Calcium ion channel, ryanodine receptor 1 (RyR1), located in the sarcoplasmic reticulum (SR) membrane, underlies MH susceptibility. RyR1, the largest known ion channel, is responsible for the rapid release of Ca2+ ions from SR into the cytoplasm, a key event that triggers skeletal muscle contraction. It has a homotetrameric organization and approximately 5000 residues in each protomer. There are a large number (>100) of known mutations in RyR1 or its binding partners which are associated with MH sensitivity. In the presence of a triggering agent and an MH-causative mutation, the channel may be biased open, allowing uncontrolled Ca2+ release, generating an extreme metabolic load. In order to understand how MH is triggered mechanistically by anesthetics, we use molecular dynamics simulations to study experimentally-identified binding sites in specific domains of the channel and alchemical free energy perturbation calculations to evaluate binding configurations and affinities. We computationally refine residue-level binding sites identified by photoaffinity labeling for selected anesthetic ligands on RyR1. We further evaluate MH-causative mutations that may precipitate an increase or decrease in the binding affinity of anesthetic molecules to RyR1. Evaluating and comparing binding sites of MH-causative anesthetics, in wild-type and mutated RyR1, helps us understand combinations of an RYR1 mutation and a bound anesthetic configuration that bias an open conformation of the channel and trigger MH.

Identification and Functional Analysis of RYR1 Variants in a Family with a Suspected Myopathy and Associated Malignant Hyperthermia

The ryanodine receptor 1 (RyR1) is a major skeletal muscle calcium release channel located in the sarcoplasmic reticulum and involved in excitation-contraction coupling. Variants in the gene encoding RyR1 have been linked to a range of neuromuscular disorders including myopathies and malignant hyperthermia (MH). We have identified three RYR1 variants (c.1983 G>A, p.Trp661*; c.7025A>G, p.Asn2342Ser and c.2447 C>T, p.Pro816Leu) in a family with a suspected myopathy and associated malignant hyperthermia susceptibility. We used calcium release assays to functionally characterise these variants in a recombinant system. Site-directed mutagenesis was used to introduce each variant separately into the human RYR1 cDNA. HEK293-T cells were transfected with the recombinant constructs and calcium release assays were carried out using 4-chloro-m-cresol (4-CmC) as the RyR1 agonist to investigate the functional consequences of each variant. RYR1 c.1983 G>A, p.Trp661* resulted in a non-functional channel, c.7025A>G, p.Asn2342Ser in a hypersensitive channel and c.2447 C>T, p.Pro816Leu in a hypersensitive channel at higher concentrations of 4-CmC. The p.Trp661* RYR1 variant should be considered as a risk factor for myopathies. The p.Asn2342Ser RYR1 variant, when expressed as a compound heterozygote with a nonsense mutation on the second allele, is likely to result in MH-susceptibility. The role of the p.Pro816Leu variant in MH remains unclear.

Prevalence of malignant hyperthermia diagnosis in obstetric patients in the United States, 2003 to 2014

BackgroundThe cost-benefit of stocking dantrolene in maternity units for treating malignant hyperthermia (MH) has been recently questioned because of the low incidence of MH crisis in the general population and the low utilization of general anesthesia in obstetrics. However, no study has examined the prevalence of MH susceptibility in obstetrics. This study aimed to assess the prevalence of MH diagnosis and associated factors in obstetric patients.MethodsData for this study came from the National Inpatient Sample from 2003 to 2014, a 20% nationally representative sample of discharge records from community hospitals. A diagnosis of MH due to anesthesia was identified using the International Classification of Diseases, Ninth Revision, Clinical Modification code 995.86. MH prevalence was estimated according to the delivery mode and patient and hospital characteristics.ResultsDuring the 12-year study period, 47,178,322 delivery-related discharges [including 15,175,127 (32.2%) cesarean deliveries] were identified. Of them, 215 recorded a diagnosis of MH, yielding a prevalence of 0.46 per 100,000 [95% confidence interval (CI), 0.40 to 0.52]. The prevalence of MH diagnosis in cesarean deliveries was 0.81 per 100,000 (95% CI, 0.67 to 0.97), compared with 0.29 per 100,000 (95% CI, 0.23 to 0.35) in vaginal deliveries (P < 0.001). Multivariable logistic regression revealed that cesarean delivery was associated with a significantly increased risk of MH diagnosis [adjusted rate ratio (aOR) 2.88; 95% CI, 2.19 to 3.80]. Prevalence of MH diagnosis was lower in Hispanics than in non-Hispanic whites (aOR 0.47; 95% CI, 0.29 to 0.76) and higher in the South than in the Northeast census regions (aOR 2.44; 95% CI, 1.50 to 3.96).ConclusionThe prevalence of MH-susceptibility is about 1 in 125,000 in cesarean deliveries, similar to the prevalence reported in non-obstetrical surgery inpatients. The findings of this study suggest that stocking dantrolene in maternity units is justified.

Genetics of Malignant Hyperthermia: A Brief Update.

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.

The current status of malignant hyperthermia.

Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.

Don\u2019t stress: a case report of regional anesthesia as the primary anesthetic for gynecologic surgery in a patient with mitochondrial myopathy and possible malignant hyperthermia susceptibility

BackgroundWe aim to describe the evaluation and management of a patient with the uncommon combination of both mitochondrial myopathy and possible malignant hyperthermia susceptibility as an important source of information and as a valuable example of the role of regional anesthesia for patients with these diagnoses.Case presentationA 24 year old woman with a history of possible mitochondrial myopathy and possible malignant hyperthermia susceptibility presented for gynecologic surgery. Surgery was well tolerated with combined spinal epidural anesthesia as well as sedation with midazolam, ketamine, and fentanyl.ConclusionsAnesthetic management of patients with mitochondrial myopathy is challenging, made even more so with concurrent malignant hyperthermia susceptibility. This case adds an example to the literature of employing regional anesthesia as a safe approach to this complex care.

Significance of Asymptomatic Hyper Creatine-Kinase Emia.

Whether asymptomatic hyper-CKemia (AHCE) should prompt a thorough work-up for muscle disease or not is controversially discussed. This review aims at summarizing and discussing recent findings concerning the cause, frequency, evolution, and work-up of conditions manifesting as AHCE and normal or abnormal electromyography (EMG) respectively muscle biopsy. Systematic PubMed search. There are numerous primary (hereditary) and acquired myopathies that manifest with permanent, recurrent, or temporary AHCE with/without myopathic EMG or muscle biopsy. AHCE particularly occurs at onset of these conditions, which include dystrophinopathies, myotilinopathies, calpainopathy, caveolinopathy, dysferlinopathy, central core disease, multicore disease, desminopathy, MD1, MD2, hypoPP, malignant hyperthermia susceptibility, Pompe disease, McArdle disease, myoadenylate deaminase-deficiency, CPT2-deficiency, mitochondrial disorders, or myopathy with tubular aggregates. Most likely, other primary myopathies manifest with AHCE as well, without having been reported. Patients with AHCE should be taken seriously and repeated CK determination must be conducted. If hyper-CKemia is persisting or recurrent, these patients should undergo an EMG and eventually muscle biopsy. If noninformative, genetic work-up by a panel or whole exome sequencing should be initiated, irrespective of the family history. Patients with AHCE should avoid excessive exercise, require sufficient hydration, require counseling with regard to the risk of malignant hyperthermia, and should inform anesthesiologists and surgeons about their condition before elective surgery. Recurrent AHCE should be taken seriously and managed with conventional work-up. If noninformative, genetic work-up should follow irrespective of the family history.

Excessive Accumulation of Ca2 + in Mitochondria of Y522S-RYR1 Knock-in Mice: A Link Between Leak From the Sarcoplasmic Reticulum and Altered Redox State.

Mice (Y522S or YS), carrying a mutation of the sarcoplasmic reticulum (SR) Ca2+ release channel of skeletal muscle fibers (ryanodine receptor type-1, RyR1) which causes Ca2+ leak, are a widely accepted and intensively studied model for human malignant hyperthermia (MH) susceptibility. Since the involvement of reactive oxygen species (ROS) and of mitochondria in MH crisis has been previously debated, here we sought to determine Ca2+ uptake in mitochondria and its possible link with ROS production in single fibers isolated from flexor digitorum brevis (FDB) of YS mice. We found that Ca2+ concentration in the mitochondrial matrix, as detected with the ratiometric FRET-based 4mtD3cpv probe, was higher in YS than in wild-type (WT) fibers at rest and after Ca2+ release from SR during repetitive electrical stimulation or caffeine administration. Also mitochondrial ROS production associated with contractile activity (detected with Mitosox probe) was much higher in YS fibers than in WT. Importantly, the inhibition of mitochondrial Ca2+ uptake achieved by silencing MCU reduced ROS accumulation in the matrix and Ca2+ release from SR. Finally, inhibition of mitochondrial ROS accumulation using Mitotempo reduced SR Ca2+ release in YS fibers exposed to caffeine. The present results support the view that mitochondria take up larger amounts of Ca2+ in YS than in WT fibers and that mitochondrial ROS production substantially contributes to the increased caffeine-sensitivity and to the enhanced Ca2+ release from SR in YS fibers.

Malignant Hyperthermia - Diagnosis in Practice

Testing for malignant hyperthermia (MH) susceptibility is usually performed either in relatives of MH susceptible persons or in patients with an MH suspicious clinical event. There are two diagnostic options: muscle biopsy with in-vitro contracture testing and molecular genetic diagnosis. Patients with familial MH mutations are usually tested genetically. A genetic screening can be performed in clinical events with a high pretest probability. MH susceptibility can be confirmed by presence of a diagnostic MH mutation. Absence of MH mutations cannot exclude MH. The only option to exclude MH susceptibility is contracture testing.

Bayesian modeling to predict malignant hyperthermia susceptibility and pathogenicity of RYR1, CACNA1S and STAC3 variants.

Aim: Identify variants in RYR1, CACNA1S and STAC3, and predict malignant hyperthermia (MH) pathogenicity using Bayesian statistics in individuals clinically treated as MH susceptible (MHS). Materials & methods: Whole exome sequencing including RYR1, CACNA1S and STAC3 performed on 64 subjects with: MHS; suspected MH event or first-degree relative; and MH negative. Variant pathogenicity was estimated using in silico analysis, allele frequency and prior data to calculate Bayesian posterior probabilities. Results: Bayesian statistics predicted CACNA1S variant p.Thr1009Lys and RYR1 variants p.Ser1728Phe and p.Leu4824Pro are likely pathogenic, and novel STAC3 variant p.Met187Thr has uncertain significance. Nearly a third of MHS subjects had only benign variants. Conclusion: Bayesian method provides new approach to predict MH pathogenicity of genetic variants.

Risk-Stratifying Patients at an Increased Risk of Malignant Hyperthermia: Improving Safety by Expanding Beyond Classic Tenets

Malignant hyperthermia (MH) is classically described as an autosomal dominant myopathy involving type 1 ryanodine receptor (RYR1), which predisposes affected individuals to potentially life-threatening sequela when exposed to volatile anesthetics or depolarizing skeletal muscle relaxants, such as succinylcholine. In cases where malignant hyperthermia or anesthetic induced rhabdomyolysis (AIR) is triggered, significant morbidity and often mortality can result. In an ambulatory anesthetic setting, family history of malignant hyperthermia and history of anesthetic-related events is typically utilized to screen out susceptible individuals. Furthermore, in cases where suspicion of increased risk for MH susceptibility is present, volatile agents and depolarizing muscle relaxants are avoided, per recommendations of Malignant Hyperthermia Association of US. However, MH phenotype has been found to be inherited with incomplete penetrance and variable expression. Investigations into the molecular genetics of MH have revealed over 400 different variants in the RYR1 gene, with fewer than 40 variants that have been functionally characterized. Exome studies have suggested that the incidence of RYR1 variants in general population is as high as 1 in 2000-3000 persons. These data suggest that potential for triggering malignant hyperthermia is much greater than previously estimated, even if a fulminant reaction is not encountered. Estimates based on genomic analysis call for increased index of suspicion in patient selection for ambulatory anesthesia, compelling for improved risk stratification, as well as improved level of preparedness to treat malignant hyperthermia. This is especially pertinent for providers that administer anesthesia to pediatric populations, as pediatric patients have been documented to exhibit MH/AIR response in the absence of volatile anesthetic exposure.

Anesthesia for muscle biopsy to test susceptibility to malignant hyperthermia

IntroductionMalignant hyperthermia is an autosomal dominant pharmacogenetic disorder, characterized by hypermetabolic crisis triggered by halogenated anesthetics and/or succinylcholine. The standard method for diagnosing malignant hyperthermia susceptibility is the in vitro muscle contracture test in response to halothane-caffeine, which requires muscle biopsy under anesthesia. We describe a series of anesthetic procedures without triggering agents in malignant hyperthermia, comparing peripheral nerve block and subarachnoid anesthesia. MethodWe assessed the anesthetic record charts of 69 patients suspected of malignant hyperthermia susceptibility who underwent muscle biopsy for in vitro muscle contracture in the period of 7 years. Demographic data, indication for malignant hyperthermia investigation, in vitro muscle contracture test results, and surgery/anesthesia/recovery data were analyzed. ResultsSample with 34±13.7 years, 60.9% women, 65.2% of in vitro muscle contracture test positive. Techniques used: peripheral nerve blocks — lateral femoral and femoral cutaneous, latency 65±41min — (47.8%); subarachnoid anesthesia (49.3%), and total venous anesthesia (1.4%). There was 39.4% failure of peripheral nerve block and 11.8% of subarachnoid anesthesia. Adverse events (8.7%) occurred only with subarachnoid blockade (bradycardia, nausea, and transient neurological syndrome). All patients remained in the post-anesthesia care unit until discharge. Age and weight were significantly higher in patients with blockade failure (ROC cut-off point of 23.5 years and 59.5kg) and blockade failure was more frequent in the presence of increased idiopathic creatine kinase. ConclusionAnesthesia with non-triggering agents has been shown to be safe in patients with malignant hyperthermia susceptibility. Variables such as age, weight, and history of increased idiopathic creatine kinase may be useful in selecting the anesthetic technique for this group of patients.

Anomalous Kv 7 channel activity in human malignant hyperthermia syndrome unmasks a key role for H2 S and persulfidation in skeletal muscle.

Human malignant hyperthermia (MH) syndrome is induced by volatile anaesthetics and involves increased levels of cystathionine β-synthase (CBS)-derived H2 S within skeletal muscle. This increase contributes to skeletal muscle hypercontractility. Kv 7 channels, expressed in skeletal muscle, may be a molecular target for H2 S. Here, we have investigated the role of Kv 7 channels in MH. Skeletal muscle biopsies were obtained from MH-susceptible (MHS) and MH-negative (MHN) patients. Immunohistochemistry, RT-PCR, Western blot, and in vitro contracture test (IVCT) were carried out. Development and characterization of primary human skeletal muscle cells (PHSKMC) and evaluation of cell membrane potential were also performed. The persulfidation state of Kv 7 channels and polysulfide levels were measured. Kv 7 channels were similarly expressed in MHN and MHS biopsies. The IVCT revealed an anomalous contractility of MHS biopsies following exposure to the Kv 7 channel opener retigabine. Incubation of negative biopsies with NaHS, prior to retigabine addition, led to an MHS-like positive response. MHS-derived PHSKMC challenged with retigabine showed a paradoxical depolarizing effect, compared with the canonical hyperpolarizing effect. CBS expression and activity were increased in MHS biopsies, resulting in a major polysulfide bioavailability. Persulfidation of Kv 7.4 channels was significantly higher in MHS than in MHN biopsies. In skeletal muscle of MHS patients, CBS-derived H2 S induced persulfidation of Kv 7 channels. This post-translational modification switches the hyperpolarizing activity into depolarizing. This mechanism can contribute to the pathological skeletal muscle hypercontractility typical of MH syndrome. This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc.

Anestesia durante biópsia muscular para teste de suscetibilidade à hipertermia maligna

IntroductionMalignant hyperthermia is an autosomal dominant pharmacogenetic disorder, characterized by hypermetabolic crisis triggered by halogenated anesthetics and/or succinylcholine. The standard method for diagnosing malignant hyperthermia susceptibility is the in vitro muscle contracture test in response to halothane‐caffeine, which requires muscle biopsy under anesthesia. We describe a series of anesthetic procedures without triggering agents in malignant hyperthermia, comparing peripheral nerve block and subarachnoid anesthesia. MethodWe assessed the anesthetic record charts of 69 patients suspected of malignant hyperthermia susceptibility who underwent muscle biopsy for in vitro muscle contracture in the period of 7 years. Demographic data, indication for malignant hyperthermia investigation, in vitro muscle contracture test results, and surgery/anesthesia/recovery data were analyzed. ResultsSample with 34±13.7 years, 60.9% women, 65.2% of in vitro muscle contracture test positive. Techniques used: peripheral nerve blocks — lateral femoral and femoral cutaneous, latency 65±41minutes — (47.8%); subarachnoid anesthesia (49.3%), and total venous anesthesia (1.4%). There was 39.4% failure of peripheral nerve block and 11.8% of subarachnoid anesthesia. Adverse events (8.7%) occurred only with subarachnoid blockade (bradycardia, nausea, and transient neurological syndrome). All patients remained in the post‐anesthesia care unit until discharge. Age and weight were significantly higher in patients with blockade failure (ROC cut‐off point of 23.5 years and 59.5kg) and blockade failure was more frequent in the presence of increased idiopathic creatine kinase. ConclusionAnesthesia with non‐triggering agents has been shown to be safe in patients with malignant hyperthermia susceptibility. Variables such as age, weight, and history of increased idiopathic creatine kinase may be useful in selecting the anesthetic technique for this group of patients.

Permeabilised skeletal muscle reveals mitochondrial deficiency in malignant hyperthermia-susceptible individuals

BackgroundIndividuals genetically susceptible to malignant hyperthermia (MH) exhibit hypermetabolic reactions when exposed to volatile anaesthetics. Mitochondrial dysfunction has previously been associated with the MH-susceptible (MHS) phenotype in animal models, but evidence of this in human MH is limited. MethodsWe used high resolution respirometry to compare oxygen consumption rates (oxygen flux) between permeabilised human MHS and MH-negative (MHN) skeletal muscle fibres with or without prior exposure to halothane. A substrate-uncoupler-inhibitor titration protocol was used to measure the following components of the electron transport chain under conditions of oxidative phosphorylation (OXPHOS) or after uncoupling the electron transport system (ETS): complex I (CI), complex II (CII), CI+CII and, as a measure of mitochondrial mass, complex IV (CIV). ResultsBaseline comparisons without halothane exposure showed significantly increased mitochondrial mass (CIV, P=0.021) but lower flux control ratios in CI+CII(OXPHOS) and CII(ETS) of MHS mitochondria compared with MHN (P=0.033 and 0.005, respectively) showing that human MHS mitochondria have a functional deficiency. Exposure to halothane triggered a hypermetabolic response in MHS mitochondria, significantly increasing mass-specific oxygen flux in CI(OXPHOS), CI+CII(OXPHOS), CI+CII(ETS), and CII(ETS) (P=0.001–0.012), while the rates in MHN samples were unaltered by halothane exposure. ConclusionsWe present evidence of mitochondrial dysfunction in human MHS skeletal muscle both at baseline and after halothane exposure.

Myalgia with the presence of pathologic EMG correlates with perimysial inflammatory infiltrates

ObjectiveWe aimed to define normal numbers of inflammatory cells in muscle biopsies and to identify the predictive value of isolated muscle pain and increased creatine kinase regarding the diagnosis of myositis.MethodsWe analyzed muscle biopsies of 71 patients using immunostains for CD3+, CD4+, CD8+, CD68+, major histocompatibility complex class I, perforin, and myeloid-related protein (MRP) 8. Patients were categorized as follows—group 1: myalgia without further clinical or laboratory abnormalities (n = 24); group 2: asymptomatic elevation of creatine kinase (hyperCKemia, n = 26); group 3: myalgia and pathologic EMG findings (n = 9); and group 4: otherwise healthy controls who had malignant hyperthermia susceptibility testing (n = 12).ResultsIn the normal muscle biopsy specimens from group 4, mean endomysial macrophage (CD68+) density was 21.7 ± 5.6/mm2, and perimysial density was 13.0 ± 5.6/mm2. Numbers of T-lymphocytes (CD3+) were 5 ± 3.5 endomysially and 2.2 ± 3.9/mm2 perimysially. This was not different from groups 1 and 2. Only group 3 patients had increased mean numbers of perimysial macrophages (24.1 ± 6.3/mm2; p = 0.0005), CD3+ (7.6 ± 4.9/mm2; p = 0.0056), and CD8+ T-lymphocytes (5.4 ± 3.1/mm2; p = 0.0008) and displayed the activation marker MRP8 in all cases. Although inflammatory cells were increased in the perimysium in group 3, histology did not fulfill the criteria for dermatomyositis, polymyositis, or inclusion body myositis.ConclusionsNormal muscle contains a considerable number of macrophages and T-lymphocytes. Muscle biopsy is likely to detect inflammatory changes in patients with myalgia or hyperCKemia only if pathologic EMG findings are present.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes.

The identification in a patient of 1 of the 50 variants in the RYR1 or CACNA1S genes reviewed here should lead to a presumption of malignant hyperthermia susceptibility (MHS). MHS can lead to life-threatening reactions to potent volatile anesthetic agents or succinylcholine. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for the use of these agents in patients with these RYR1 or CACNA1S variants (updates at https://cpicpgx.org/guidelines and www.pharmgkb.org).

Profile of malignant hyperthermia susceptibility reports confirmed with muscular contracture test in Brazil

Background and objectivesMalignant hyperthermia is an autosomal dominant hypermetabolic pharmacogenetic syndrome, with a mortality rate of 10%–20%, which is triggered by the use of halogenated inhaled anesthetics or muscle relaxant succinylcholine. The gold standard for suspected susceptibility to malignant hyperthermia is the in vitro muscle contracture test in response to halothane and caffeine. The determination of susceptibility in suspected families allows the planning of safe anesthesia without triggering agents for patients with known susceptibility to malignant hyperthermia by positive in vitro muscle contracture test. Moreover, the patient whose suspicion of malignant hyperthermia was excluded by the in vitro negative muscle contracture test may undergo standard anesthesia. Susceptibility to malignant hyperthermia has a variable manifestation ranging from an asymptomatic subject presenting a crisis of malignant hyperthermia during anesthesia with triggering agents to a patient with atrophy and muscle weakness due to central core myopathy. The aim of this study is to analyze the profile of reports of susceptibility to malignant hyperthermia confirmed with in vitro muscle contracture test. MethodAnalysis of the medical records of patients with personal/family suspicion of malignant hyperthermia investigated with in vitro muscle contracture test, after given written informed consent, between 1997 and 2010. ResultsOf the 50 events that motivated the suspicion of malignant hyperthermia and family investigation (sample aged 27±18 years, 52% men, 76% white), 64% were investigated for an anesthetic malignant hyperthermia crisis, with mortality rate of 25%. The most common signs of a malignant hyperthermia crisis were hyperthermia, tachycardia, and muscle stiffness. Susceptibility to malignant hyperthermia was confirmed in 79.4% of the 92 relatives investigated with the in vitro muscle contracture test. ConclusionThe crises of malignant hyperthermia resembled those described in other countries, but with frequency lower than that estimated in the country.

A follow-up survey of total intravenous anesthesia usage in children in the U.K. and Ireland.

Total intravenous anesthesia usage in children remains relatively unpopular in the UK and Ireland. A postal survey by Hill et al in 2008 indicated that only 26% of Consultants used a propofol infusion at least once a month. Following an increase in teaching and training opportunities in pediatric total intravenous anesthesia in the UK, we repeated the survey among Consultant members of Association of Paediatric Anaesthetists of Great Britain and Ireland and Society for Intravenous Anaesthesia, to see if this had affected total intravenous anesthesia usage in children and how practice may have changed. We used an anonymous online survey sent to Association of Paediatric Anaesthetists of Great Britain and Ireland and Society for Intravenous Anaesthesia members. A total of 291 responses were analyzed. Total intravenous anesthesia was the default method of anesthesia in 8% of respondents and a further 46% used total intravenous anesthesia at least monthly. Overall total intravenous anesthesia usage had increased in the past year in 53%. The main indications were malignant hyperthermia susceptibility, and postoperative nausea and vomiting. Ear/nose/throat surgery was the most popular surgical specialty. The main reasons for not using total intravenous anesthesia were that it was too "fiddly" and lack of confidence in the user. Most respondents used propofol in combination with remifentanil. Over 80% used propofol target-controlled infusion. The potential for propofol-related infusion syndrome concerned many, with 74% limiting infusion duration as a result. Bispectral Index was not used routinely by the majority of anesthetists. Even though most anesthetists did not use total intravenous anesthesia routinely, 98% felt they would be confident to anesthetize an malignant hyperpyrexia-positive patient using the technique. This survey has shown that although total intravenous anesthesia is not the default anesthetic technique for most anesthetists, overall usage in children has more than doubled in the past 10years, with many happy to use it in a wide variety of patients and procedures.

Masseter muscle rigidity and the role of DNA analysis to confirm malignant hyperthermia susceptibility.

Malignant hyperthermia (MH) is an uncommon, autosomal dominant disorder of skeletal muscle, triggered by inhalational anaesthetics or depolarizing muscle relaxants. Masseter muscle rigidity (MMR) can be regarded as potentially a preceding sign for an MH reaction. Susceptibility to MH can be determined by the in vitro contracture test (IVCT) or DNA analysis where a familial variant is known. Our aims were to review patients with MMR, where IVCT and DNA analysis had been undertaken, to determine if DNA analysis could be used as an initial screening tool for MH susceptibility, and, by reviewing standard monitored variables (SMVs), to determine if any clinical characteristics could be used to differentiate between MMR patients who are MH susceptible (MHS) and those who are not. Patients with MMR were identified from the Palmerston North Hospital MH Reactions Database. IVCT and DNA analysis results were documented. DNA testing was performed retrospectively in the majority of patients as many patients had presented before DNA analysis was available. Forty-one patients were analysed. Fourteen were DNA positive/IVCT positive and six DNA positive only (48% in total), seven were IVCT positive/DNA negative and 14 were IVCT normal. Increased creatine kinase (>18,000 units/L) was consistent with MH susceptibility. Severity of MMR was not linked to MH susceptibility. This study confirmed that DNA analysis can be used as a first-line test for MH susceptibility in patients presenting with MMR (consistent with European MH Group recommendations). Creatine kinase was the only SMV that was significantly different between MHS and MH normal individuals.