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Contains fulltext : 287509.pdf (Publisher’s version ) (Open Access) 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.

ZusammenfassungDie maligne Hyperthermie ist eine seltene, in der Regel subklinische metabolische Myopathie, die zu einer lebensbedrohlichen metabolischen Entgleisung führen kann. Um im Falle einer notwendigen Anästhesie eine Gefährdung der Betroffenen zu vermeiden, müssen im Vorfeld entsprechende Vorkehrungen getroffen werden. Gerade bei einer Schwangerschaft stellt dies den Anästhesisten vor erheblichen Herausforderungen.Durch die Europäische Maligne Hyperthermie Gruppe wurde im Mai 2019 eine Richtlinie zum Vorgehen bei einer gesicherten oder vermuteten Disposition zur malignen Hyperthermie und einer Schwangerschaft publiziert. Der vorliegende Artikel fasst die Empfehlungen zusammen und beschreibt mögliche Vorgehensweisen bei der Betreuung von schwangeren Patientinnen mit einer MH-Veranlagung.

Malignant hyperthermia is a potentially fatal condition, in which genetically predisposed individuals develop a hypermetabolic reaction to potent inhalation anaesthetics or succinylcholine. Because of the rarity of malignant hyperthermia and ethical limitations, there is no evidence from interventional trials to inform the optimal perioperative management of patients known or suspected with malignant hyperthermia who present for surgery. Furthermore, as the concentrations of residual volatile anaesthetics that might trigger a malignant hyperthermia crisis are unknown and manufacturers' instructions differ considerably, there are uncertainties about how individual anaesthetic machines or workstations need to be prepared to avoid inadvertent exposure of susceptible patients to trigger anaesthetic drugs. The present guidelines are intended to bundle the available knowledge about perioperative management of malignant hyperthermia-susceptible patients and the preparation of anaesthesia workstations. The latter aspect includes guidance on the use of activated charcoal filters. The guidelines were developed by members of the European Malignant Hyperthermia Group, and they are based on evaluation of the available literature and a formal consensus process. The most crucial recommendation is that malignant hyperthermia-susceptible patients should receive anaesthesia that is free of triggering agents. Providing that this can be achieved, other key recommendations include avoidance of prophylactic administration of dantrolene; that preoperative management, intraoperative monitoring, and care in the PACU are unaltered by malignant hyperthermia susceptibility; and that malignant hyperthermia patients may be anaesthetised in an outpatient setting.

Summary Faced with a malignant hyperthermia crisis, the immediate access to sufficient dantrolene is essential to achieve the best possible outcome for the patient. However, malignant hyperthermia crises are rare, and there may be administrative pressures to limit the amount of dantrolene stocked or, in some countries, not to stock dantrolene at all. There are no published guidelines to support anaesthetic departments in their effort to ensure availability of sufficient dantrolene for the management of malignant hyperthermia crises. After a literature review that confirmed a lack of clinical trials to inform this guideline, we undertook a formal consensus development process, in which 25 members of the European Malignant Hyperthermia Group participated. The consensus process used a modified web-based Delphi exercise, in which participants rated the appropriateness of statements that covered the dosing regimen for dantrolene in a malignant hyperthermia crisis, the types of facility that should stock dantrolene, and the amount of dantrolene that should be stocked. The resulting guidelines are based on available evidence and the opinions of international malignant hyperthermia experts representing a large group of malignant hyperthermia laboratories from around the world. Key recommendations include: the dosing regimen of dantrolene should be based on actual body weight, dantrolene should be available wherever volatile anaesthetics or succinylcholine are used, and 36 vials of dantrolene should be immediately available with a further 24 vials available within 1 h.

Contains fulltext : 248839.pdf (Publisher’s version ) (Closed access)

ZusammenfassungDie maligne Hyperthermie (MH) ist eine subklinische, autosomal-dominant vererbte, pharmakogenetische Erkrankung der Skelettmuskulatur, die durch alle klinisch eingesetzten volatilen Anästhetika (Sevofluran, Desfluran, Isofluran) und das depolarisierende Muskelrelaxans Succinylcholin bei disponierten Patienten ausgelöst werden kann. Durch die Einführung von Dantrolen konnte die Sterblichkeit von vorher über 80% auf deutlich unter 10% reduziert werden. Zur initialen Therapie einer MH wird ein Bolus von 2,5 mg/kg Dantrolen bezogen auf das tatsächliche Patientengewicht verabreicht. Abhängig vom klinischen Verlauf muss dieser gegebenenfalls wiederholt werden. Teilweise sind wiederholte Dantrolen-Gaben bis 10 mg/kg/24 h für eine erfolgreiche Behandlung notwendig. Um im Notfall zeitnah therapeutische Maßnahmen einleiten zu können, wird in der deutschen S1-Leitlinie von 2018 die Bevorratung von 36 – 48 Ampullen Dantrolen 20 mg empfohlen. In Bereichen, in denen konsequent keine MH-Triggersubstanzen eingesetzt werden, kann auf eine Dantrolen-Vorhaltung verzichtet werden. Die Herstellung der injektionsfertigen Lösung ist aufgrund der schlechten Löslichkeit der Dantrolen-Trockensubstanz zeit- und personalintensiv. Ryanodex, eine nanokristalline Suspension von Dantrolen-Natrium, kann deutlich schneller gelöst werden und könnte bei der Therapie der MH eine effizientere Alternative darstellen.

ZusammenfassungDie maligne Hyperthermie ist ein heterogenes klinisches Syndrom, bei dem es nach Exposition mit volatilen Anästhetika und/oder dem depolarisierenden Muskelrelaxans Succinylcholin zu einer gesteigerten Stoffwechselaktivität der Skelettmuskulatur mit zum Teil lebensbedrohlichen systemischen Auswirkungen auf Herz-Kreislauf-Funktionen, Körpertemperatur und Säure-Basen-Haushalt kommt. Der Beitrag gibt einen aktuellen Überblick über dieses seltene Krankheitsbild.

Purpose of review Major trauma remains one of the leading causes of death worldwide with traumatic brain injury and uncontrolled traumatic bleeding as the main determinants of fatal outcome. Interestingly, the therapeutic approach to trauma-associated bleeding and coagulopathy shows differences between geographic regions, that are reflected in different guidelines and protocols. Recent findings This article summarizes main principles in coagulation diagnostics and compares different strategies for treatment of massive hemorrhage after trauma in different regions of the world. How would a bleeding trauma patient be managed if they got hit by the bus in the United States, United Kingdom, Germany, Switzerland, Austria, Denmark, Australia, or in Japan? Summary There are multiple coexistent treatment standards for trauma-induced coagulopathy in different countries and different trauma centers. Most of them initially follow a protocol-based approach and subsequently focus on predefined clinical and laboratory targets.

Malignant hyperthermia is a rare, subclinical pharmacogenetic syndrome leading to potentially life-threatening skeletal muscle hypermetabolism. Providing a safe and trigger-free anesthesia in predisposed individuals is essential to avoid serious harm to the patient. Especially the management of malignant hyperthermia predisposition in the context of pregnancy poses a huge challenge to the attending anesthesiologist. In May 2019 the European Malignant Hyperthermia Group published a guideline on malignant hyperthermia during pregnancy. The article summarizes and discusses the recommendations and provides practical advice for treatment of pregnant women or their fetus with known or suspected susceptibility to malignant hyperthermia.

Bei einer 59-jahrigen Frau, die sich eine perforierende Bulbusverletzung des rechten Auges zugezogen hatte, wurde durch den Notarzt eine Narkose mit Propofol, Fentanyl und dem depolarisierenden Muskelrelaxans Succinylcholin eingeleitet. Die Narkose wurde praklinisch und bis kurz nach der operativen Versorgung mit einer kontinuierlichen Propofol- und Remifentanilinfusion aufrechterhalten. Postoperativ fiel eine isolierte Rhabdomyolyse mit einem Anstieg der Kreatinkinase >20.000 U/l auf. Etwa 4 Monate nach dem akuten Ereignis konnte bei der Patientin eine maligne Hyperthermie(MH)-Veranlagung mittels In-vitro-Kontrakturtest sowie Nachweis der kausalen MH-Mutation p.Val4849Ile im Exon 101 des Ryanodinrezeptorgens bestatigt werden. Aufgrund der variablen Auspragung bleiben MH-Verlaufe haufig lange unerkannt. Warnsymptome, wie unspezifische Tachykardien oder ein Masseterspasmus nach Succinylcholin, sollten auch praklinisch Anlass geben, differenzialdiagnostisch an eine MH zu denken. Bei einer errechneten genetischen Pravalenz von 1:2000–3000 ist davon auszugehen, dass auch in der Praklinik gelegentlich Patienten behandelt werden, die eine bekannte oder bisher noch nicht nachgewiesene MH-Disposition aufweisen. Entwickelt ein Patient nach Exposition mit MH-Trigger-Substanzen Symptome einer MH, muss dieser zeitnah in ein Krankenhaus transportiert werden, um dort eine leitlinienkonforme Therapie zu initiieren, da praklinisch die lebensrettenden kausalen Masnahmen, u. a. aufgrund der fehlenden Dantrolenvorhaltung, nicht moglich sind.

Glahn KPE, Bendixen D, Girard T, Hopkins PM, Johannsen S, Ruffert H, Snoeck MM, Urwyler A (2020) Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines. Br J Anaesth. https://doi.org/10.1016/j.bja.2020.04.089 Article PubMed Google Scholar Hopkins PM, Ruffert H, Snoeck MM, Girard T, Glahn KPE, Ellis FR, Muller CR, Urwyler A, Bandschapp O, Gillies R, Glauber V, Heytens L, Islander G, Klingler W, Kraft B, Krivosic-Horber R, Pollock N, Schuster F, Silva H, Sorrentino V, Street N, Tegazzin V, Tzanova I (2015) European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility. Br J Anaesth 115:531–539 Article CAS Google Scholar Glahn KPE, Ellis FR, Halsall PJ, Muller CR, Snoeck MMJ, Urwyler A, Wappler F (2010) Recognizing and managing a malignant hyperthermia crisis: guidelines from the European Malignant Hyperthermia Group. Br J Anaesth 105:417–420 Article CAS Google Scholar Ibarra Moreno CA, Hu S, Kraeva N, Schuster F, Johannsen S, Rueffert H, Klingler W, Heytens L, Riazi S (2019) An assessment of penetrance and clinical expression of malignant hyperthermia in individuals carrying diagnostic ryanodine receptor 1 gene mutations. Anesthesiology 131:983–991 Article CAS Google Scholar Wolak S, Rucker B, Kohlschmidt N, Doetsch S, Bartsch O, Zechner U, Tzanova I (2014) Homozygote und „compound“-heterozygote RYR1-Mutationen: Neue Erkenntnisse zu Pravalenz und Penetranz der malignen Hyperthermie. Anaesthesist 63:643–650 Article CAS Google Scholar Download references Zentrum fur Maligne Hyperthermie, Klinik und Poliklinik fur Anasthesiologie und Intensivtherapie, Universitatsklinikum Leipzig AoR, Liebigstrase 20, 04103, Leipzig, Deutschland B. Bastian Zentrum fur Maligne Hyperthermie, Klinik fur Anasthesiologie und Intensivmedizin, Medizinische Hochschule Hannover, Hannover, Deutschland S. Heiderich Zentrum fur Maligne Hyperthermie, Klinik und Poliklinik fur Anasthesiologie, Intensivmedizin und Schmerztherapie, Universitatsklinikum Wurzburg, Wurzburg, Deutschland F. Schuster & S. Johannsen Klinik fur Anasthesie und Intensivmedizin, SRH Kliniken Landkreis Sigmaringen, Sigmaringen, Deutschland W. Klingler Klinik fur Anasthesie, Intensivmedizin und Schmerztherapie, Helios Klinik Schkeuditz, Schkeuditz, Deutschland H. Ruffert You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar Correspondence to B. Bastian. W. Klingler gibt an, dass die MH-Hotline von der Firma Norgine (Wettenberg, Deutschland) finanziell unterstutzt wird. B. Bastian, S. Heiderich, F. Schuster, S. Johannsen und H. Ruffert geben an, dass kein Interessenkonflikt besteht. Fur diesen Beitrag wurden von den Autoren keine Studien an Menschen oder Tieren durchgefuhrt. Fur die aufgefuhrten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Reprints and Permissions Bastian, B., Heiderich, S., Schuster, F. et al. Kommentar zur Leitlinie der European Malignant Hyperthermia Group zur Verfugbarkeit von Dantrolen fur die Behandlung der Malignen Hyperthermie. Anaesthesist (2020). https://doi.org/10.1007/s00101-020-00839-x Download citation Published: 16 September 2020 DOI: https://doi.org/10.1007/s00101-020-00839-x

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle presenting as a hypermetabolic response to potent volatile anesthetics such as sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine. Following introduction of the hydantoin derivative dantrolene, the previously high mortality of fulminant MH episodes could be reduced from 80% to less than 10%. For treatment of MH an initial intravenous bolus of 2.5 mg/kg dantrolene based on the actual body weight should be applied. If symptoms are not improving after the initial dose, up to 10 mg/kg dantrolene can be necessary within the first 24 h. In facilities where MH triggering anesthetics and depolarizing muscle relaxants are administered, at least 36 - 48 vials of dantrolene 20 mg should be stocked according to the recent German S1 guideline on MH. If none of these agents are ever used in the facility, the stockage of dantrolene is dispensable. Since dantrolene is not easily dissoluble, preparation requires time and manpower. Due to its pharmacological characteristics, ryanodex, a modern nanocrystalline dantrolene sodium suspension, might be a promising alternative in the treatment of MH.Die maligne Hyperthermie (MH) ist eine subklinische, autosomal-dominant vererbte, pharmakogenetische Erkrankung der Skelettmuskulatur, die durch alle klinisch eingesetzten volatilen Anästhetika (Sevofluran, Desfluran, Isofluran) und das depolarisierende Muskelrelaxans Succinylcholin bei disponierten Patienten ausgelöst werden kann. Durch die Einführung von Dantrolen konnte die Sterblichkeit von vorher über 80% auf deutlich unter 10% reduziert werden. Zur initialen Therapie einer MH wird ein Bolus von 2,5 mg/kg Dantrolen bezogen auf das tatsächliche Patientengewicht verabreicht. Abhängig vom klinischen Verlauf muss dieser gegebenenfalls wiederholt werden. Teilweise sind wiederholte Dantrolen-Gaben bis 10 mg/kg/24 h für eine erfolgreiche Behandlung notwendig. Um im Notfall zeitnah therapeutische Maßnahmen einleiten zu können, wird in der deutschen S1-Leitlinie von 2018 die Bevorratung von 36 – 48 Ampullen Dantrolen 20 mg empfohlen. In Bereichen, in denen konsequent keine MH-Triggersubstanzen eingesetzt werden, kann auf eine Dantrolen-Vorhaltung verzichtet werden. Die Herstellung der injektionsfertigen Lösung ist aufgrund der schlechten Löslichkeit der Dantrolen-Trockensubstanz zeit- und personalintensiv. Ryanodex, eine nanokristalline Suspension von Dantrolen-Natrium, kann deutlich schneller gelöst werden und könnte bei der Therapie der MH eine effizientere Alternative darstellen.

Malignant hyperthermia (MH) is a rare, heterogenic syndrome leading to potentially life-threatening skeletal muscle hypermetabolism following exposure to inhalational anesthetics and succinylcholine. In more than 50% of affected individuals a pathogenic variant in the RYR1 gene coding for the sarcoplasmic reticulum calcium channel is responsible for the underlying pathology of uncontrolled calcium liberation. While the genetic prevalence of MH is as high as 1 : 2750, the incidence of clinical MH reactions is considerably lower, suggesting a dominant pattern of inheritance with incomplete penetrance. During acute MH crisis presenting with characteristic symptoms like hypercarbia, tachycardia, acidosis, hyperthermia, generalized muscular rigidity and rhabdomyolysis, discontinuation of triggering agents and immediate treatment with dantrolene 2.5 mg/kg are vital therapeutic interventions to control the reaction. A predisposition to MH should be investigated in patients following a suspected MH crisis, in relatives from MH-families, after exertional or unexplained perioperative rhabdomyolysis and in patients with idiopathic hyper-CK-aemia. According to recent European guidelines, initial DNA screening is an alternative to muscle biopsy and in-vitro contracture testing, although in cases where no diagnostic variants are found, only contracture testing can safely exclude predisposition to MH.Die maligne Hyperthermie ist ein heterogenes klinisches Syndrom, bei dem es nach Exposition mit volatilen Anästhetika und/oder dem depolarisierenden Muskelrelaxans Succinylcholin zu einer gesteigerten Stoffwechselaktivität der Skelettmuskulatur mit zum Teil lebensbedrohlichen systemischen Auswirkungen auf Herz-Kreislauf-Funktionen, Körpertemperatur und Säure-Basen-Haushalt kommt. Der Beitrag gibt einen aktuellen Überblick über dieses seltene Krankheitsbild.

Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Halothane and caffeine induce excessive sarcoplasmic calcium liberation and skeletal muscle contracture in patients susceptible to malignant hyperthermia (MH) and are utilized for diagnosis in the in vitro contracture test. Intramuscular injection previously caused a marked local lactate increase in MH-susceptible but not in MH-nonsusceptible individuals in vivo. Using shear-wave elastography, this study evaluated localized changes in muscle stiffness after intramuscular injection of halothane and caffeine. Methods Microdialysis probes were placed into the gracilis muscle of 16 pigs (9 MH-susceptible and 7 MH-nonsusceptible). After local injection of either halothane or caffeine in different concentrations, changes of tissue elasticity surrounding the probe were examined by quantitative shear-wave elastography. Local lactate concentrations were analyzed spectrophotometrically. Results Ultrasound elastography detected a temporary increase in local muscle rigidity in MH-susceptible but not in MH-nonsusceptible pigs after 2.5 and 5 vol% halothane and after 10, 40, and 80 mM caffeine, whereas there were no differences in the control groups (median [interquartile range] for maximum effect after 5 vol% halothane: MH-susceptible: 97 [31 to 148] vs. MH-nonsusceptible: 5 [−6 to 18] kPa; P = 0.0006; maximum effect after 80 mM caffeine: 112 [64 to 174] vs. −3 [−6 to 35] kPa; P = 0.0002). These effects were seen rapidly within 5 min. Local lactate concentrations were higher in MH-susceptible versus nonsusceptible pigs after 1 and 2.5 vol% halothane and 10, 40, and 80 mM caffeine (2.5 vol% halothane: MH-susceptible: 2.8 [1.9 to 4.4] vs. MH-nonsusceptible: 0.6 [0.6 to 0.7] mmol/l; P < 0.0001; 80 mM caffeine: 5.2 [4.1 to 6.3] vs. 1.6 [1.2 to 2.4] mmol/l; P < 0.0001). After 10 vol% halothane, rigidity and lactate levels were increased in both MH-susceptible and MH-nonsusceptible animals. Conclusions This pilot study revealed shear-wave elastography as a suitable technique for real-time detection of altered tissue elasticity in response to pharmacologic stimulation. By considering the variability of these results, further test protocol optimization is required before elastography could serve as a minimally invasive MH diagnostic test.

Aside from the in vitro contracture test, genetic screening for causative RYR1 mutations is the established procedure to diagnose susceptibility to malignant hyperthermia (MH). However, currently only 34 out of more than 300 known RYR1 mutations have been confirmed to be causative for MH by experimental studies addressing their functional impact on intracellular calcium homeostasis. The RYR1 mutation p.Arg4737Trp has been recently detected in a German MH family. To evaluate the effects of that mutation on intracellular calcium handling, the response after stimulation with the RYR1 agonist 4-chloro-m-cresol was investigated in immortalized B lymphocytes containing the p.Arg4737Trp mutation and compared to the response of wild type RYR1 from unaffected family members and unrelated controls. Intracellular resting calcium was slightly but significantly elevated in mutation positive cells. Calcium release following stimulation with 4-chloro-m-cresol was significantly increased in B lymphocytes carrying the p.Arg4737Trp mutation compared to mutation negative controls. Hence, the functional properties of the RYR1 mutation p.Arg4737Trp are consistent with susceptibility to MH. Together with previously published data, the mutation has now been reported in three independent MH positive families.