RÉSUMÉ
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.
Sujet(s)
Anesthésie , Anesthésiques , Maladies musculaires , Maladies neuromusculaires , Maladies de la jonction neuromusculaire , Humains , EnfantRÉSUMÉ
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.
Sujet(s)
Prédisposition génétique à une maladie/génétique , Hyperthermie maligne/diagnostic , Hyperthermie maligne/génétique , Mutation/génétique , Pénétrance , Canal de libération du calcium du récepteur à la ryanodine/génétique , Adolescent , Adulte , Études cas-témoins , Enfant , Enfant d'âge préscolaire , Femelle , Humains , Mâle , Adulte d'âge moyen , Enregistrements , Jeune adulteRÉSUMÉ
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.
Sujet(s)
Anesthésiques par inhalation/sang , Gazométrie sanguine/statistiques et données numériques , Isoflurane/analogues et dérivés , Éthers méthyliques/sang , Adulte , Facteurs âges , Sujet âgé , Sujet âgé de 80 ans ou plus , Indice de masse corporelle , Desflurane , Femelle , Hématocrite , Hémoglobines/métabolisme , Humains , Isoflurane/sang , Mâle , Adulte d'âge moyen , Reproductibilité des résultats , Sévoflurane , Facteurs sexuels , Jeune adulteRÉSUMÉ
BACKGROUND: Cerebral vasospasm is one of the most serious complications after subarachnoid hemorrhage (SAH). The cerebral artery diameter is regulated by complex physiological mechanisms. Among them the regulation of intracellular calcium homeostasis seems to play a crucial role. Recent data suggest that ryanodine receptors (RYRs) are involved in regulating the luminal calcium concentration in vascular smooth muscle cells. In this gene association investigation, we studied the question as to whether variants in the gene for the ryanodine receptors subtype 1 (RYR1) are associated with symptomatic cerebral vasospasm following SAH. METHODS: After informed consent genomic DNA analysis was performed from a whole blood sample in 46 patients suffering from aneurysmal SAH. 16 Patients were affected by symptomatic vasospasm. The RYR1 gene was screened for possible genetic variants by means of direct sequencing. The association of these variants was correlated to the development of symptomatic vasospasm, which was confirmed by clinical examination combined with cerebral angiography, transcranial doppler sonography, or CT scan. RESULTS: Three different genetic RYR1 variants (c.5360C>T, c.6178G>T, and c.7244G>A) were identified in the study. The G/T genotype of RYR1 c.6178G>T was associated with an increased risk for development of symptomatic vasospasm (odds ratio 6.4; 95% CI 1.1-37.8; P = 0.04). CONCLUSION: Our pilot study suggests that RYRs are involved in the complex pathophysiology of vasospasm development following SAH. The potential role of RYR1 as a biomarker for prediction of cerebral vasospasm after SAH has to be confirmed in a larger clinical trial.
Sujet(s)
Allèles , Variation génétique/génétique , Canal de libération du calcium du récepteur à la ryanodine/génétique , Hémorragie meningée/génétique , Vasospasme intracrânien/génétique , Adulte , Femelle , Dépistage des porteurs génétiques , Prédisposition génétique à une maladie/génétique , Dépistage génétique , Génotype , Échelle de suivi de Glasgow , Humains , Mâle , Adulte d'âge moyen , Projets pilotes , Polymorphisme de nucléotide simple/génétique , Pronostic , Facteurs de risqueSujet(s)
Canaux calciques/génétique , Hyperthermie maligne/diagnostic , Hyperthermie maligne/génétique , Mutation , Myopathies congénitales structurales/diagnostic , Syndrome malin des neuroleptiques/diagnostic , Canal de libération du calcium du récepteur à la ryanodine/génétique , Facteurs âges , Biopsie , Canaux calciques de type L , Dantrolène/administration et posologie , Diagnostic différentiel , Fréquence d'allèle , Humains , Incidence , Hyperthermie maligne/traitement médicamenteux , Hyperthermie maligne/épidémiologie , Myopathies congénitales structurales/génétique , Syndrome malin des neuroleptiques/génétique , Réaction de polymérisation en chaîne , Polymorphisme de restriction , Valeur prédictive des tests , Cartographie de restriction , Facteurs de risque , Analyse de séquence d'ADNRÉSUMÉ
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.
Sujet(s)
Anesthésie/effets indésirables , Hyperthermie maligne/étiologie , Muscles squelettiques/métabolisme , Maladies musculaires/complications , Calcium/métabolisme , Prédisposition génétique à une maladie , Humains , Hyperthermie maligne/métabolisme , Muscles squelettiques/anatomopathologie , Muscles squelettiques/physiopathologie , Maladies musculaires/génétique , Maladies musculaires/métabolisme , Mutation , Myopathies némaline/complications , Myopathie à axe central/complications , Phénotype , Appréciation des risques , Facteurs de risque , Canal de libération du calcium du récepteur à la ryanodine/génétiqueRÉSUMÉ
BACKGROUND: Postoperative nausea and vomiting are unpleasant side effects of general anesthesia. Besides known risk factors (female gender, nonsmoker, history, and opioids), a genetic influence of the serotonin receptor system on the development of nausea and vomiting has repeatedly been proposed. In this pilot study, we therefore investigated the genes of the serotonin receptor subunits A and B (HTR3A and HTR3B) for genetic variants. METHODS: We included 95 patients who had suffered from postoperative vomiting (POV) after general anesthesia and 94 control patients. After DNA isolation, the entire HTR3A and HTR3B coding regions, the 5' flanking regions, and exon/intron boundaries were screened for genetic variants. Correlation of identified genetic variants with POV was determined by logistic regression. RESULTS: We identified 16 different variants in the HTR3A gene and 19 in the HTR3B gene. By using a multivariate logistic regression model that also included classical risk factors, the HTR3A variant c1377A>G was associated with a significantly higher risk (odds ratio [OR] 2.972; 95% confidence interval [CI] 1.466-6.021; P = 0.003) and the HTR3B variants c5+201_+202delCA (OR 0.421; 95% CI 0.257-0.69; P = 0.001) and c6-137C>T (OR 0.034; 95% CI 0.003-0.332; P = 0.004) were associated with a lower risk for POV. However, all significant genetic variants were located in noncoding regions of their gene. CONCLUSIONS: Genetic variations in the HTR3A and HTR3B gene seem to be associated with the individual risk of developing POV. How strong their influence is within the multifactorial genesis of POV needs to be investigated in additional studies with an appropriate sample size.
Sujet(s)
Polymorphisme génétique , Vomissements et nausées postopératoires/génétique , Récepteurs sérotoninergiques/génétique , Région 5' flanquante , Adolescent , Adulte , Sujet âgé , Sujet âgé de 80 ans ou plus , Études cas-témoins , Exons , Femelle , Fréquence d'allèle , Prédisposition génétique à une maladie , Humains , Introns , Modèles logistiques , Mâle , Adulte d'âge moyen , Odds ratio , Phénotype , Projets pilotes , Récepteurs sérotoninergiques 5-HT3 , Appréciation des risques , Facteurs de risque , Jeune adulteRÉSUMÉ
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.
Sujet(s)
Exons , Hyperthermie maligne/génétique , Fibres musculaires squelettiques/métabolisme , Mutation , Canal de libération du calcium du récepteur à la ryanodine/génétique , Adolescent , Adulte , Sujet âgé , Anesthésiques/pharmacologie , Biopsie , Caféine/pharmacologie , Calcium/métabolisme , Cellules cultivées , Stimulants du système nerveux central/pharmacologie , Enfant , Enfant d'âge préscolaire , Crésols/pharmacologie , Relation dose-effet des médicaments , Santé de la famille , Fongicides industriels/pharmacologie , Fura-2/métabolisme , Halothane/pharmacologie , Humains , Techniques in vitro , Mâle , Hyperthermie maligne/physiopathologie , Adulte d'âge moyen , Biologie moléculaire , Contraction musculaire/effets des médicaments et des substances chimiques , Contraction musculaire/génétique , Fibres musculaires squelettiques/effets des médicaments et des substances chimiques , Muscles squelettiques/cytologie , Muscles squelettiques/effets des médicaments et des substances chimiques , Muscles squelettiques/physiopathologieSujet(s)
Hyperthermie maligne/génétique , Hyperthermie maligne/physiopathologie , Adolescent , Enfant , ADN/génétique , Femelle , Humains , Techniques in vitro , Hyperthermie maligne/diagnostic , Contraction musculaire/effets des médicaments et des substances chimiques , Muscles squelettiques/effets des médicaments et des substances chimiques , Canal de libération du calcium du récepteur à la ryanodine/effets des médicaments et des substances chimiques , Canal de libération du calcium du récepteur à la ryanodine/génétiqueRÉSUMÉ
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.
Sujet(s)
Dysostoses/génétique , Hyperthermie maligne/anatomopathologie , Mutation , Myopathie à axe central/anatomopathologie , Canal de libération du calcium du récepteur à la ryanodine/génétique , Adolescent , Séquence nucléotidique , Caféine/pharmacologie , ADN/composition chimique , ADN/génétique , Analyse de mutations d'ADN , Dysostoses/anatomopathologie , Dysostoses/physiopathologie , Santé de la famille , Femelle , Génotype , Halothane/pharmacologie , Humains , Mâle , Hyperthermie maligne/complications , Contraction musculaire/effets des médicaments et des substances chimiques , Malformations de l'appareil locomoteur/complications , Malformations de l'appareil locomoteur/génétique , Myopathie à axe central/complications , Pedigree , Phénotype , Mutation ponctuelleRÉSUMÉ
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.
Sujet(s)
Calcium/métabolisme , Crésols/pharmacologie , Fibres musculaires squelettiques/métabolisme , Mutation , Myopathie à axe central/génétique , Canal de libération du calcium du récepteur à la ryanodine/génétique , Réticulum sarcoplasmique/métabolisme , Adolescent , Adulte , Sujet âgé , Enfant , Femelle , Prédisposition génétique à une maladie , Humains , Mâle , Hyperthermie maligne/génétique , Fibres musculaires squelettiques/effets des médicaments et des substances chimiques , PedigreeRÉSUMÉ
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.