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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.

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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.

Background Sevoflurane is a known triggering agent of malignant hyperthermia (MH). The present study analyzed different effects of sevoflurane on skeletal muscle of MH susceptible and nonsusceptible individuals in vitro and compared the results to the standardized test protocol with halothane and caffeine. A potential influence of a present ryanodine receptor type 1 (RyR1) mutation was investigated. Methods Muscle bundles of 24 MH-susceptible patients with or without an RyR1 mutation, 35 MH-nonsusceptible and 10 MH-equivocal patients were exposed either to sevoflurane 8 vol% bolus or increasing doses of 2, 4, 6, and 8 vol%. In MH-positive patients, a screening for mutations in the RyR1 gene was performed. Results The in vitro parameters initial length, weight, predrug resting tension, and predrug twitch height did not differ between the groups. Sevoflurane caused significant contractures in MH-susceptible but not in MH-nonsusceptible muscle after increasing doses [1.4 (0.3–6.0) vs. 0 (0-0) mN] and after bolus application [6.9 (2.4–21.4) vs. 0 (0-0) mN]. However, only 50% of the susceptible patients developed contractures ≥ 2 mN after increasing concentrations while 83% did so after rapid bolus administration. Presence of an RyR1 mutation was detected in 36% of the examined MH-positive patients but had no influence on developing contractures. Conclusion Sevoflurane-induced contractures do not reliably detect MH susceptibility on an individual level. Therefore, sevoflurane is no suitable alternative for diagnostic use. Mutation-specific effects regarding contracture sizes after incubation with sevoflurane, halothane, or caffeine were not found.

Introduction: Persistently elevated serum creatine kinase (CK) is frequently associated with predisposition to malignant hyperthermia (MH). We investigated whether a minimally invasive metabolic test is suitable to diagnose MH susceptibility among patients with hyperCKemia. Methods: Thirty-nine participants were included: 10 were MH susceptible (MHS); 21 MH were non-susceptible (MHN); and 8 had MHN with persistent hyperCKemia >500 U/L. Microdialysis probes were inserted into the vastus lateralis muscle, and halothane or caffeine was injected via an attached microtubing catheter. Lactate concentrations in dialysis samples were measured spectrophotometrically. Results: Baseline lactate did not differ between the groups. After local application of halothane or caffeine, a significant lactate increase was detected only in the MHS group. Conclusions: Test results were not influenced by hyperCKemia. To avoid risks and complications of a surgical muscle biopsy this microdialysis test might be a useful screening tool for MH susceptibility among patients with persistent CK elevation. Muscle Nerve 47: 677–681, 2013

Patients with neuromuscular disorders undergoing anaesthesia are at risk of various complications due to muscular weakness and the involvement of other organ systems. This article reviews the anaesthetic approach with regard to preoperative considerations and perioperative management in this heterogeneous group of patients.

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.

Die maligne Hyperthermie ist eine seltene, aber lebensbedrohliche Komplikation der Allgemeinanasthesie. Eine sehr variable Symptomatik erschwert die Diagnose. Fur eine erfolgreiche Behandlung mussen zeitnah Masnahmen eingeleitet werden; abhangig vom klinischen Erscheinungsbild kann eine differenzierte Therapie notwendig werden. Fur den vorliegenden Beitrag wurden die aktuellen Therapieempfehlungen begutachtet und in einer konkreten SOP zusammengefasst, die Ihnen als Grundlage fur die Erarbeitung eigener Handlungsempfehlungen fur Ihre Klinik dienen kann.

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.

Background Malignant hyperthermia (MH), a metabolic myopathy triggered by volatile anesthetics and depolarizing muscle relaxants, is a potentially lethal complication of general anesthesia in susceptible patients. The implementation of modern inhalation anesthetics that research indicates as less potent trigger substances and the recommended limitations of succinylcholine use, suggests there may be considerable decline of fulminant MH cases. In the presented study, the authors analyzed suspected MH episodes during general anesthesia of patients that were referred to the Wuerzburg MH unit between 2007 and 2011, assuming that MH is still a relevant anesthetic problem in our days. Methods With approval of the local ethics committee data of patients that underwent muscle biopsy and in vitro contracture test (IVCT) between 2007 and 2011 were analyzed. Only patients with a history of suspected MH crisis were included in the study. The incidents were evaluated retrospectively using anesthetic documentation and medical records. Results Between 2007 and 2011 a total of 124 patients were tested. 19 of them were referred because of suspected MH events; 7 patients were diagnosed MH-susceptible, 4 MH-equivocal and 8 MH-non-susceptible by IVCT. In a majority of cases masseter spasm after succinylcholine had been the primary symptom. Cardiac arrhythmias and hypercapnia frequently occurred early in the course of events. Interestingly, dantrolene treatment was initiated in a few cases only. Conclusions MH is still an important anesthetic complication. Every anesthetist must be aware of this life-threatening syndrome at any time. The rapid onset of adequate therapy is crucial to avoid major harm and possibly lethal outcome. Dantrolene must be readily available wherever MH triggering agents are used for anesthesia.

Beggs et al.[1][1] presented two interesting case reports postulating an association between rocuronium and malignant hyperthermia (MH). Although the observed fever in these patients declined after discontinuation of rocuronium, several points need further discussion. First, the definition of MH

Persistently elevated serum creatine kinase (CK) is frequently associated with predisposition to malignant hyperthermia (MH). We investigated whether a minimally invasive metabolic test is suitable to diagnose MH susceptibility among patients with hyperCKemia.Thirty-nine participants were included: 10 were MH susceptible (MHS); 21 MH were non-susceptible (MHN); and 8 had MHN with persistent hyperCKemia500 U/L. Microdialysis probes were inserted into the vastus lateralis muscle, and halothane or caffeine was injected via an attached microtubing catheter. Lactate concentrations in dialysis samples were measured spectrophotometrically.Baseline lactate did not differ between the groups. After local application of halothane or caffeine, a significant lactate increase was detected only in the MHS group.Test results were not influenced by hyperCKemia. To avoid risks and complications of a surgical muscle biopsy this microdialysis test might be a useful screening tool for MH susceptibility among patients with persistent CK elevation.

Objectives We hypothesized that the phosphodiesterase-III-inhibitor milrinone and the non-specific G-protein activator sodium fluoride increase the skeletal muscular lactate levels as a sign of a hypermetabolic response. Methods With approval of the local animal care committee Sprague–Dawley rats were killed and artificially perfused either with Ringer's solution or sodium fluoride 110 mm, while milrinone 1.32 mm or Ringer's solution at 1 μl/min was applied via microdialysis probes in both hind limbs. Lactate was measured spectrophotometrically in the dialysate. Key findings Baseline lactate levels before drug application did not differ between hind limbs. Local infusion of milrinone via microdialysis did not significantly increase intramuscular lactate concentrations compared with the Ringer control group. Muscular perfusion with sodium fluoride resulted in a significant increase of lactate and was potentiated by combination with local milrinone. Conclusions Phosphodiesterase-III-inhibition alone does not significantly influence the lactate levels in skeletal muscle of sacrificed rats. Sodium fluoride infusion leads to an intramuscular lactate increase, which was further potentiated by local inhibition of phosphodiesterase-III. The fluoride-mediated hypermetabolic response following sodium fluoride could be a possible explanation for the observed myotoxic adverse effects in individuals treated by fluoride-containing agents.

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.

Patients with neuromuscular disorders undergoing anaesthesia are at risk of various complications due to muscular weakness and the involvement of other organ systems. This article reviews the anaesthetic approach with regard to preoperative considerations and perioperative management in this heterogeneous group of patients.

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).

Malignant hyperthermia (MH) is a life-threatening, inherited disorder of skeletal muscle calcium homeostasis. In susceptible individuals, exposure to trigger agents such as volatile anesthetics and depolarizing muscle relaxants, typically administered to induce or maintain general anesthesia, may lead to a hypermetabolic muscular syndrome [1]. Recently, an anesthetic conserving device (AnaConDa®; Sedana Medical AB, Geretsried, Germany) was introduced for sedation of intensive care patients using volatile anesthetics, associated with shorter wake-up and extubation time, reduced duration of mechanical ventilation and earlier hospital discharge [2]. After obtaining oral and written consent, we report the case of a 59-year-old male patient, who was hospitalized due to persistent lumbalgia. On the second day of the patient’s hospital stay, increasing dyspnea and tachypnea required admission to the ICU and tracheal intubation. Sedation was maintained by propofol and sufentanil infusion. A chest radiography revealed bilateral pulmonary infiltration, suggestive of influenza pneumonia. Moxifloxacin, piperacillin/tazobactam and oseltamivir were started immediately. After 4 days on mechanical ventilation, sedation needed to be escalated and an anesthetic conserving device for additional sevoflurane sedation was installed. Suddenly, after 5 hours of sevoflurane administration, hemodynamic instability occurred. The arterial blood pressure rapidly decreased to 78/44 mmHg, while the heart rate remained constant around 110 beats/minute. Arterial blood gas analysis revealed severe acidosis (pH, 7.17; carbon dioxide partial pressure, 70.4 mmHg; oxygen partial pressure, 104 mmHg (fraction of inspired oxygen, 50%); base excess, 9.8; lactate, 0.6 mmol/l), and a rapid increase of body temperature from 39.6 to 40.7 °C within 30 minutes was noticed. Creatine kinase and myoglobin levels were significantly increased to maximum levels of 3,455 U/l and 4,197 μg/l, respectively, due to acute rhabdomyolysis. Since MH was suspected, sevoflurane application was discontinued, and dantrolene (225 mg) was administered intravenously, resulting in gradual improvement of the hemodynamic and metabolic situation. The further course was unremarkable. The subsequent ICU stay remained uneventful and the patient was extubated on day 17 without neurological deficits. Nine months after the suspected MH event, the patient underwent muscle biopsy and in vitro contracture testing according to the guidelines of the European MH group. The patient’s MH susceptibility was thus confirmed, by significant contractures at the defined thresholds after halothane and caffeine exposure [3]. The presented case underlines that MH is an important differential diagnosis in intensive care patients with hemodynamic and metabolic breakdown if volatile anesthetics are used for sedation. Hence, every ICU physician must be aware of the symptoms of MH to rapidly initiate sufficient treatment.

Background: Malignant hyperthermia (MH) is a rare pharmacogenetic disorder which is characterized by life-threatening metabolic crises during general anesthesia. Classical triggering substances are volatile anesthetics and succinylcholine (SCh). The molecular basis of MH is excessive release of Ca2+ in skeletal muscle principally by a mutated ryanodine receptor type 1 (RyR1). To identify factors explaining the variable phenotypic presentation and complex pathomechanism, we analyzed proven MH events in terms of clinical course, muscle contracture, genetic factors and pharmocological triggers. Methods: In a multi-centre study including seven European MH units, patients with a history of a clinical MH episode confirmed by susceptible (MHS) or equivocal (MHE) in vitro contracture tests (IVCT) were investigated. A test result is considered to be MHE if the muscle specimens develop pathological contractures in response to only one of the two test substances, halothane or caffeine. Crises were evaluated using a clinical grading scale (CGS), results of IVCT and genetic screening. The effects of SCh and volatile anesthetics on Ca2+ release from sarcoplasmic reticulum (SR) were studied in vitro. Results: A total of 200 patients met the inclusion criteria. Two MH crises (1%) were triggered by SCh (1 MHS, 1 MHE), 18% by volatile anesthetics and 81% by a combination of both. Patients were 70% male and 50% were younger than 12 years old. Overall, CGS was in accord with IVCT results. Crises triggered by enflurane had a significantly higher CGS compared to halothane, isoflurane and sevoflurane. Of the 200 patients, 103 carried RyR1 variants, of which 14 were novel. CGS varied depending on the location of the mutation within the RyR1 gene. In contrast to volatile anesthetics, SCh did not evoke Ca2+ release from isolated rat SR vesicles. Conclusions: An MH event could depend on patient-related risk factors such as male gender, young age and causative RyR1 mutations as well as on the use of drugs lowering the threshold of myoplasmic Ca2+ release. SCh might act as an accelerant by promoting unspecific Ca2+ influx via the sarcolemma and indirect RyR1 activation. Most MH crises develop in response to the combined administration of SCh and volatile anesthetics.

BACKGROUND The 5-HT(3)-receptor antagonist ondansetron, commonly used to treat nausea and vomiting, was suspected of triggering malignant hyperthermia (MH) when a 5-year-old boy died after receiving a therapeutic dose of ondansetron. To evaluate a possible influence of ondansetron on the onset of MH, we investigated its effect on muscle specimens of MH-susceptible (MHS) and MH-nonsusceptible (MHN) individuals in vitro. METHODS Muscle bundles of 6 MHS and 10 MHN patients were incubated in a tissue bath with ondansetron at increasing concentrations (0.1 to 300 μg/mL). Changes in resting tension and twitch height were monitored continuously. Data are reported as median and interquartile range; Mann-Whitney U test for differences between the groups (P < 0.05). RESULTS Weight, length, initial resting tension, and twitch height of the muscle bundles did not significantly differ between the investigated groups. An increasing twitch amplitude after ondansetron application was observed in both groups. However, contractures developed only in MHS but not in MHN muscle at ondansetron concentrations of 50 μg/mL (MHS 2.5 [2.1 to 4.0] vs. MHN 0 [0 to 0] mN) and 100 μg/mL (18.0 [11.8 to 22.8] vs 0 [0 to 0] mN). At 300 μg/mL ondansetron, a muscular response was also observed in MHN (23.3 [20.1 to 40.1] vs 1.8 [0.3 to 4.9] mN). CONCLUSIONS Ondansetron induced contractures in skeletal muscle bundles in vitro. The effect was significantly higher in MHS than in MHN muscle. Because the necessary concentration of ondansetron exceeded the therapeutic plasma levels by a minimum of 500 times, a trigger potency in vivo seems unlikely.