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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.

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.

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

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.

To the Editor, The introduction of a lightweight mini vaporizer (AnaConDa; Sedana Medical, Sweden) that can be used with an intensive care unit (ICU) ventilator has led to a resurgence of interest in the use of potent volatile agents as an alternative to intravenous agents for longterm sedation or for treatment of status asthmaticus in patients requiring tracheal intubation. In an editorial comment concerning the use of sevoflurane for treatment of status asthmaticus, Wasowicz and Jerath review the benefits of using volatile anesthetics for these reasons and mention several of the potential dangers of administration of potent volatile anesthetic agents outside the operating room environment. Unfortunately, what is omitted from their discussion is the mention of the risk of malignant hyperthermia (MH), although the danger of MH is stated clearly in the report by Ruszkai et al. To underline this possibility, at the European Malignant Hyperthermia Group meeting in May 2014, Johannsen et al. reported on the development of MH in an ICU patient sedated with sevoflurane. In their case, the AnaConDa device was used for management of pneumonia in a 59-yr-old man and MH developed after five hours of sevoflurane anesthetic sedation. The signs included acute hemodynamic deterioration, metabolic and respiratory acidosis, increase of body temperature from 39.6-40.7 C over 30 min, and elevation of creatine kinase to 3,450 U L. Fortunately, the clinicians recognized the signs of MH and treated with dantrolene, and the patient survived. A subsequent in vitro contracture test substantiated the clinical diagnosis of MH. Although only low concentrations of potent volatile agents are used to achieve sedation in the ICU, the risk of developing MH still exists, and appropriate therapy with dantrolene and supportive care must be immediately available. Because early symptoms of developing MH crisis are rather non-specific and can be misleading to other more frequent diagnoses, e.g., sepsis, the awareness of MH is crucial for ICU physicians of any medical specialty wherever volatile anesthetics are applied. It is recommended that, when MH occurs as a result of sedation with volatile anesthetics, the details should be reported to the appropriate MH registry or similar database. Certainly, the Malignant Hyperthermia Association of the United States (www.mhaus.org) as well as the European Malignant Hyperthermia Group (www.emhg.org) would be interested in learning of such cases.

Emery-Dreifuss muscular dystrophy (EDMD) is a hereditary neuromuscular disorder characterized by slowly progressive muscle weakness, early contractures, and dilated cardiomyopathy. We reported an uneventful general anaesthesia using total intravenous anaesthesia (TIVA) for cardiac transplantation in a 19-year-old woman suffering from EDMD. In vitro contracture test results of two pectoralis major muscle bundles of the patient suggest that exposition to triggering agents does not induce a pathological sarcoplasmic calcium release in the lamin A/C phenotype. However, due to the lack of evidence in the literature, we would recommend TIVA for patients with EDMD if general anaesthesia is required.

Background Fulminant malignant hyperthermia (MH) is a rare emergency that should be known to every medical professional although practical exposure is a rarity even for experienced anesthesiologists. The vast majority of documented MH cases occurred during general anesthesia in the operating room following application of volatile anesthetics and/or depolarizing muscle relaxants. With increasing utilization of the anesthetic conserving device AnaConDa for sedation of intensive care patients, who could benefit from reduced duration of mechanical ventilation and earlier hospital discharge, volatile anesthetics made their way into the intensive care unit (ICU).