RESUMO
BACKGROUND AND PURPOSE: Patients with neuromuscular conditions are at increased risk of suffering perioperative complications related to anaesthesia. There is currently little specific anaesthetic guidance concerning these patients. Here, we present the European Neuromuscular Centre (ENMC) consensus statement on anaesthesia in patients with neuromuscular disorders as formulated during the 259th ENMC Workshop on Anaesthesia in Neuromuscular Disorders. METHODS: International experts in the field of (paediatric) anaesthesia, neurology, and genetics were invited to participate in the ENMC workshop. A literature search was conducted in PubMed and Embase, the main findings of which were disseminated to the participants and presented during the workshop. Depending on specific expertise, participants presented the existing evidence and their expert opinion concerning anaesthetic management in six specific groups of myopathies and neuromuscular junction disorders. The consensus statement was prepared according to the AGREE II (Appraisal of Guidelines for Research & Evaluation) reporting checklist. The level of evidence has been adapted according to the SIGN (Scottish Intercollegiate Guidelines Network) grading system. The final consensus statement was subjected to a modified Delphi process. RESULTS: A set of general recommendations valid for the anaesthetic management of patients with neuromuscular disorders in general have been formulated. Specific recommendations were formulated for (i) neuromuscular junction disorders, (ii) muscle channelopathies (nondystrophic myotonia and periodic paralysis), (iii) myotonic dystrophy (types 1 and 2), (iv) muscular dystrophies, (v) congenital myopathies and congenital dystrophies, and (vi) mitochondrial and metabolic myopathies. CONCLUSIONS: This ENMC consensus statement summarizes the most important considerations for planning and performing anaesthesia in patients with neuromuscular disorders.
Assuntos
Anestesia , Anestésicos , Doenças Musculares , Doenças Neuromusculares , Doenças da Junção Neuromuscular , Humanos , CriançaRESUMO
BACKGROUND: Malignant hyperthermia (MH) is a potentially lethal disorder triggered by certain anesthetics. Mutations in the ryanodine receptor 1 (RYR1) gene account for about half of MH cases. Discordance between the low incidence of MH and a high prevalence of mutations has been attributed to incomplete penetrance, which has not been quantified yet. The authors aimed to examine penetrance of MH-diagnostic RYR1 mutations and the likelihood of mutation carriers to develop MH, and to identify factors affecting severity of MH clinical expression. METHODS: In this multicenter case-control study, data from 125 MH pedigrees between 1994 and 2017 were collected from four European registries and one Canadian registry. Probands (survivors of MH reaction) and their relatives with at least one exposure to anesthetic triggers, carrying one diagnostic RYR1 mutation, were included. Penetrance (percentage of probands among all genotype-positive) and the probability of a mutation carrier to develop MH were obtained. MH onset time and Clinical Grading Scale score were used to assess MH reaction severity. RESULTS: The overall penetrance of nine RYR1 diagnostic mutations was 40.6% (93 of 229), without statistical differences among mutations. Likelihood to develop MH on exposure to triggers was 0.25 among all RYR1 mutation carriers, and 0.76 in probands (95% CI of the difference 0.41 to 0.59). Penetrance in males was significantly higher than in females (50% [62 of 124] vs. 29.7% [30 of 101]; P = 0.002). Males had increased odds of developing MH (odds ratio, 2.37; 95% CI, 1.36 to 4.12) despite similar levels of exposure to trigger anesthetics. Proband's median age was 12 yr (interquartile range 6 to 32.5). CONCLUSIONS: Nine MH-diagnostic RYR1 mutations have sex-dependent incomplete penetrance, whereas MH clinical expression is influenced by patient's age and the type of anesthetic. Our quantitative evaluation of MH penetrance reinforces the notion that a previous uneventful anesthetic does not preclude the possibility of developing MH.
Assuntos
Predisposição Genética para Doença/genética , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/genética , Mutação/genética , Penetrância , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Adulto JovemRESUMO
BACKGROUND: The blood/gas partition coefficient of a certain volatile anesthetic is of clinical importance because it determines its velocity of uptake into and elimination from the body of a patient and thus its pharmacokinetic behavior. To date, the blood/gas partition coefficients of isoflurane, sevoflurane, and desflurane have been measured in small numbers of subjects or in particular study groups, for example, healthy volunteers, patients experiencing a common kind of disease, or mothers immediately after giving birth. The objective of this study was to determine the blood/gas partition coefficients of these volatile anesthetics at 37°C in a larger clinically relevant and adult patient population. Furthermore, we tested whether age, gender, body mass index, hemoglobin concentration, or hematocrit had an influence on the coefficients. METHODS: Blood samples were taken from 120 fasting operative patients with ASA physical status I to III and aged 19 to 86 years. All subjects were randomly enrolled in study groups for the separate determinations of the blood/gas partition coefficients of isoflurane (n = 41), sevoflurane (n = 41), and desflurane (n = 38) by headspace gas chromatography. To check the quality of the measurements, we determined the distilled water/gas partition coefficients of those anesthetics and compared them with previously published values. RESULTS: We found a blood/gas partition coefficient of 1.45 ± 0.12 (mean ± SD) for isoflurane, 0.74 ± 0.06 for sevoflurane, and 0.57 ± 0.04 for desflurane. Values of this study are 5.07%, 12.12%, and 7.55% higher for isoflurane, sevoflurane, and desflurane, respectively, than the previously published mean values (all P ≤ 0.001). There were only trends for small correlations between the blood/gas partition coefficient of isoflurane and hemoglobin concentration (Pearson r = 0.32; P = 0.041) and hematocrit (r = 0.37; P = 0.016). We found no other potentially significant correlations of the partition coefficients with patient age, body mass index, hemoglobin concentration, or hematocrit (all remaining P > 0.069). Furthermore, the coefficients did not differ significantly between female and male patients. The evaluation of the distilled water/gas partition coefficients of isoflurane (0.59 ± 0.04), sevoflurane (0.37 ± 0.04), and desflurane (0.27 ± 0.03) proved the validity of the gas chromatography method used in this study. CONCLUSIONS: The blood/gas partition coefficients of the modern volatile anesthetics, in particular, those of sevoflurane and desflurane, may be higher than that has been hitherto reported. Therefore, their uptake and elimination may occur more slowly in some patients than has been supposed. The blood/gas partition coefficients of isoflurane, sevoflurane, and desflurane measured in this study appear to be representative because they were determined in a clinically and numerically relevant patient cohort.
Assuntos
Anestésicos Inalatórios/sangue , Gasometria/estatística & dados numéricos , Isoflurano/análogos & derivados , Éteres Metílicos/sangue , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Desflurano , Feminino , Hematócrito , Hemoglobinas/metabolismo , Humanos , Isoflurano/sangue , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sevoflurano , Fatores Sexuais , Adulto JovemAssuntos
Canais de Cálcio/genética , Hipertermia Maligna/diagnóstico , Hipertermia Maligna/genética , Mutação , Miopatias Congênitas Estruturais/diagnóstico , Síndrome Maligna Neuroléptica/diagnóstico , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Fatores Etários , Biópsia , Canais de Cálcio Tipo L , Dantroleno/administração & dosagem , Diagnóstico Diferencial , Frequência do Gene , Humanos , Incidência , Hipertermia Maligna/tratamento farmacológico , Hipertermia Maligna/epidemiologia , Miopatias Congênitas Estruturais/genética , Síndrome Maligna Neuroléptica/genética , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Valor Preditivo dos Testes , Mapeamento por Restrição , Fatores de Risco , Análise de Sequência de DNARESUMO
In this article, we analyze myopathies with cores, for which an association to malignant hyperthermia (MH) has been suggested. We discuss the clinical features, the underlying genetic defects, subsequent effects on cellular calcium metabolism, and in vitro muscle responses to MH triggers. We describe in detail central core disease, multiminicore disease, and nemaline rod myopathy. We categorize the diseases according to the affected proteins and discuss the risk for MH, which is high or theoretically possible when the calcium-conducting proteins are affected.
Assuntos
Anestesia/efeitos adversos , Hipertermia Maligna/etiologia , Músculo Esquelético/metabolismo , Doenças Musculares/complicações , Cálcio/metabolismo , Predisposição Genética para Doença , Humanos , Hipertermia Maligna/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/genética , Doenças Musculares/metabolismo , Mutação , Miopatias da Nemalina/complicações , Miopatia da Parte Central/complicações , Fenótipo , Medição de Risco , Fatores de Risco , Canal de Liberação de Cálcio do Receptor de Rianodina/genéticaRESUMO
Malignant hyperthermia (MH) is a pharmacogenetic disorder with an autosomal dominant inheritance. During exposure to triggering agents as volatile anaesthetics, affected individuals may develop a potentially fatal hypermetabolic syndrome caused by excessive calcium release from the sarcoplasmic reticulum in skeletal muscle. More than 60 MH associated mutations were found in the gene of skeletal muscle ryanodine receptor (RyR1), but only some of them have been functionally characterized. Primary human myotubes were cultured from carriers of RyR1 mutations in exon 44 (Ala2350Thr, Arg2355Trp, Gly2375Ala) and from MH non-susceptible individuals. Investigation of calcium homeostasis with the calcium sensitive probe Fura 2 showed a higher sensitivity to the ryanodine receptor agonists 4-chloro-m-cresol, caffeine and halothane for the myotubes derived from the mutation carriers as compared to those of the control group. The presence of RyR1 mutations with impact on calcium homeostasis emphasizes the functional significance of exon 44.
Assuntos
Éxons , Hipertermia Maligna/genética , Fibras Musculares Esqueléticas/metabolismo , Mutação , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Adulto , Idoso , Anestésicos/farmacologia , Biópsia , Cafeína/farmacologia , Cálcio/metabolismo , Células Cultivadas , Estimulantes do Sistema Nervoso Central/farmacologia , Criança , Pré-Escolar , Cresóis/farmacologia , Relação Dose-Resposta a Droga , Saúde da Família , Fungicidas Industriais/farmacologia , Fura-2/metabolismo , Halotano/farmacologia , Humanos , Técnicas In Vitro , Masculino , Hipertermia Maligna/fisiopatologia , Pessoa de Meia-Idade , Biologia Molecular , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/citologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologiaAssuntos
Hipertermia Maligna/genética , Hipertermia Maligna/fisiopatologia , Adolescente , Criança , DNA/genética , Feminino , Humanos , Técnicas In Vitro , Hipertermia Maligna/diagnóstico , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/efeitos dos fármacos , Canal de Liberação de Cálcio do Receptor de Rianodina/genéticaRESUMO
Malignant hyperthermia susceptibility (MHS) and central core disease (CCD) have been shown to result from missense mutations in the ryanodine receptor gene of the skeletal muscle (RYR1). A 15-year-old patient who had spondylocostal dysostosis (SCD) developed an MH crisis during general anesthesia. The patient was characterized phenotypically by block vertebrae, vertebral fusion, short neck and thorax, fused ribs, craniofacial abnormalities, spina bifida occulta, and a diaphragmatic defect closed surgically in early infancy. The diagnosis MH susceptible (MHS) was confirmed by the in vitro contracture test (IVCT) on a muscle biopsy. Surprisingly, the histopathological investigation revealed the presence of CCD too. Molecular genetic investigation of the RYR1 gene was performed to search for known MH-related mutations. Cluster regions of the RYR1 gene, in which mutations have already been found, were examined by direct automated sequencing. In addition to the diagnosis MHS and CCD we were able to identify a novel RYR1 mutation in exon 46: 7358ATC > ACC, resulting in an Ile2453Thr substitution. This mutation was also present in the mother, in whom MH disposition and CCD were determined by muscle investigations. We suggest that the newly identified RYR1 mutation is closely associated with MH and CCD. A probable causative role of the RYR1 gene in SCD patients should be assessed by further genetic investigations.
Assuntos
Disostoses/genética , Hipertermia Maligna/patologia , Mutação , Miopatia da Parte Central/patologia , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Sequência de Bases , Cafeína/farmacologia , DNA/química , DNA/genética , Análise Mutacional de DNA , Disostoses/patologia , Disostoses/fisiopatologia , Saúde da Família , Feminino , Genótipo , Halotano/farmacologia , Humanos , Masculino , Hipertermia Maligna/complicações , Contração Muscular/efeitos dos fármacos , Anormalidades Musculoesqueléticas/complicações , Anormalidades Musculoesqueléticas/genética , Miopatia da Parte Central/complicações , Linhagem , Fenótipo , Mutação PuntualRESUMO
Central core disease (CCD) is a congenital disorder of skeletal muscle that is characterised histologically by typical central cores in type 1 skeletal muscle fibres. This disease is associated with malignant hyperthermia susceptibility and has been linked to the gene of skeletal muscle ryanodine receptor RYR1. In this study, we present a family with the spontaneous occurrence of the RYR1 Ile2453Thr mutation. Affected individuals were diagnosed as susceptible to malignant hyperthermia in the in vitro contracture test (IVCT) and showed histological signs of CCD. Myotubes were derived from the index patient. The calcium homeostasis in response to the ryanodine receptor agonist 4-chloro-m-cresol (4CmC) was investigated by calcium imaging using the Ca(2+)-sensitive fluorescent probe FURA 2. In the myotubes derived from the mutation carrier, the EC(50) of 4CmC was reduced to 94 micro as compared to 201 microM in a control group of 16 individuals non-susceptible to malignant hyperthermia. In the myotubes of the non-affected family members, the EC(50) was found within the same range as that of the control group. The reduction of EC(50) indicates a facilitated calcium release from sarcoplasmic reticulum in the myotubes of the index patient suggesting that the RYR1 Ile2453Thr mutation is pathogenic for the malignant hyperthermia susceptibility and CCD of the two affected individuals.
Assuntos
Cálcio/metabolismo , Cresóis/farmacologia , Fibras Musculares Esqueléticas/metabolismo , Mutação , Miopatia da Parte Central/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Retículo Sarcoplasmático/metabolismo , Adolescente , Adulto , Idoso , Criança , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Hipertermia Maligna/genética , Fibras Musculares Esqueléticas/efeitos dos fármacos , LinhagemRESUMO
BACKGROUND: The ryanodine receptor of the skeletal muscle (RYR1) seems to be of outstanding importance in the pathogenesis of malignant hyperthermia (MH). It has been shown that point mutations in the RYR1 gene are strongly associated with the MH phenotype. A correctly determined phenotype is the basic prerequisite for adequate genetic MH screening. In this study we examined only those MH susceptible patients for the presence of potential RYR1 mutations who showed strong pathological muscle responses in the in vitro contracture test (IVCT). METHODS: A total of 56 MHS index patients who complied with the following IVCT criteria were included in the molecular genetic investigation: Contracture forces > or =4 mN at a caffeine concentration of 2.0 mmol/l and > or =8 mN at a halothane concentration of 0.44 mmol/l. DNA sequences of exons 2, 6, 9, 11, 12, 14, 15, 17, 39, 40, 45, 46, 102 of the RYR1 gene were analysed by the direct sequencing technique. Furthermore, if an MH mutation was identified in an index patient, all relatives were screened for their family specific RYR1 defect. RESULTS: In 39 index patients an RYR1 mutation was detected: Arg163Cys (n = 2), Asp166Asn (n = 1), Gly341Arg (n = 2), Arg401His (n = 2), Arg614Cys (n = 12), Asp2129Glu (n = 1),Vol2168Met (n = 1), Thr2206Met (n = 9), Ala2428Thr (n = 1), Gly2434Arg (n = 2), Arg2435His (n = 1), Arg2452Trp (n = 1), Arg2454His (n = 4). Three new RYR1 mutations were identified. We found a potential MH mutation in a further 130 relatives of the 39 index patients. Thirty-seven individuals were classified as MHS exclusively by molecular genetic techniques and did not have to undergo the IVCT. CONCLUSIONS: The ascertained high rate of successful MH mutation screening (69.64%) is obviously associated with the more clearly defined MHS diagnosis in the IVCT. According to the EMHG guidelines for the molecular genetic detection of MH susceptibility, a positive MH disposition could be determined in numerous persons by a less invasive technique.