[Telephone enquiries on the topic of malignant hyperthermia: Evaluation of the content and subsequent diagnostic results at the MH Center Leipzig]. / Telefonische Anfragen zum Thema maligne Hyperthermie: Auswertung der Inhalte und der resultierenden Diagnostikergebnisse am MH-Zentrum Leipzig.

BACKGROUND: Malignant hyperthermia (MH) is an autosomal dominant metabolic myopathy. The in vitro contracture test (IVCT) is still considered to be the gold standard for diagnosing a disposition for MH. However, advances in genetic testing for MH disposition have supplemented or even replaced the invasive procedure of the IVCT. Information about MH can be obtained by either contacting the hotline for MH as a nationwide 24 h/7 days a week service or one of the regional MH centers. METHODS: The protocols of telephone conversations concerning MH at the MH Center University Leipzig were retrospectively analyzed. Data were collected from January 2011 to March 2015. Additionally, the results of the IVCT and genetic testing evolving from the counseling interviews were examined. RESULTS: A total of 205 telephone calls were documented during the period in question and an IVCT was performed as a consequence of 112 of the telephone calls. The IVCT resulted in 27 individuals being identified as MH susceptible which was subsequently diagnosed in 15 individuals with known familial MH disposition and 12 individuals were identified as new index patients. In 24 individuals a total of 13 different mutations were detected and of these 4 mutations were causative concerning MH. Of the 205 telephone calls 131 were private and 74 of medical professional origin. Among the private enquiries MH disposition within the family was a frequent reason for contacting the MH Center (61.8%). Conversations relating to MH-like symptoms during general anesthesia were carried out with 35.1% of medical doctors and with 22.9% of private callers. Advice about neuromuscular symptoms of unknown genesis was given to 15.3% of private individuals and to 24.3% of medical doctors. Overall MH topics were discussed with 23% (N = 17) of the medical profession and approximately half of these were anesthesiologists (N = 8). Not a single call was documented for the treatment of a suspected MH crisis. CONCLUSION: Private individuals and families affected by a MH disposition often showed good compliance with respect to counseling and diagnostics for MH and contacted the MH center more often than medical doctors. A more comprehensive cooperation with the medical profession is preferable and necessary to obtain a systematic and broad synopsis of characteristic and uncharacteristic signs and symptoms of MH. The telephone conversations analyzed as well as the diagnostic results (IVCT and genetic testing) underline that MH disposition is still a current and relevant topic.

European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility.

It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory findings.

Pharmacokinetics and clinical toxicity of prilocaine and ropivacaine following combined drug administration in brachial plexus anesthesia.

OBJECTIVE: Local anesthetics (LA) are often administered in combination for regional anesthesia in order to obtain the specific advantages (onset and duration of effect) of each drug. However, few data on the safety of such combinations are available and consequently plasma concentrations possibly associated with toxicity and interactions between the specific anesthetics are not sufficiently established. We measured pharmacokinetics and toxicity parameters of prilocaine and ropivacaine after combined use as single doses in brachial plexus blockade. METHODS: In an open clinical study using a combined dose regime (300 mg prilocaine followed immediately by 75 mg ropivacaine) total plasma concentrations of prilocaine and ropivacaine were measured serially in 60 patients using a gas-chromatographic method. The data were analyzed regarding a relationship with central nervous and cardiovascular toxicity. RESULTS: Following the administration in combination prilocaine and ropivacaine were rapidly absorbed. Mean prilocaine peak plasma concentrations (mean Cmax = 1.51 microg/ml) were measured between 15 and 30 min after injection. Highest ropivacaine plasma concentrations (mean Cmax = 1.12 microg/ml) were seen between 30 min and 1 hour after injection (calculated mean tmax = 44 min). One of 59 patients showed signs of myoclonus which were suspected of being due to intravascular injection. There was no relevant cardiovascular toxicity observed in terms of changes in the QRS complex, PQ interval prolongation, AV dissociation, occurrence of extrasystoles or sinus arrest. The pharmacokinetics of combined administration did not differ from those of prilocaine and ropivacaine given alone. CONCLUSION: The use of a combined prilocaine/ ropivacaine (300 mg/75 mg) dose regimen in patients given single dose for brachial plexus blockade can generally be regarded as safe with regard to peak plasma concentrations and cardiovascular toxicity and this holds true for patients with a higher perioperative risk profile (ASA III grading, American Society of Anesthesiologists). The considerable inter-individual variation in LA peak plasma concentrations observed in our patients and the one case of suspected accidental intravascular injection, highlight the necessity of adequate monitoring of the patients undergoing LA injections.

Mutation screening of the RYR1-cDNA from peripheral B-lymphocytes in 15 Swedish malignant hyperthermia index cases.

BACKGROUND: Malignant hyperthermia (MH), linked to the ryanodine receptor 1 gene (RYR1) on chromosome 19, is a potentially lethal pharmacogenetic disorder which may lead to a disturbance of intracellular calcium homeostasis when susceptible individuals are exposed to halogenated anaesthetics, suxamethonium, or both. Central core disease (CCD) is a rare dominantly inherited congenital myopathy allelic to MH-susceptibility. METHODS: In this study, 14 unrelated MH-susceptible probands and one CCD patient from Sweden were screened for mutations in the RYR1. Since the RYR1 is also expressed in B-lymphocytes, RYR1-cDNA was transcribed from total RNA extracted from white blood cells. RESULTS: We detected two known RYR1 mutations and two previously described unclassified sequence variants. In addition, six novel sequence variants were detected. All mutations or sequence variants were verified on genomic DNA. Seven of the probands did not show any candidate mutation, although the total coding region of RYR1 was sequenced. Segregation data in in vitro contracture tested family members of three probands support a causative role of three of the novel sequence variants. CONCLUSIONS: Our study contributes to the genetic aetiology of MH in Sweden, but also raises questions about the involvement of genes other than RYR1 since nearly half of the probands did not show any sequence variants in the total coding region of the RYR1.

Anaesthesia and cardiac contractility modulation.

Chronic heart failure is known to be an important risk factor for adverse perioperative outcome in patients undergoing non-cardiac surgery. A promising new form of electric therapy is currently being used in a phase III trial in patients with severe chronic heart failure (cardiac contractility modulation). Cardiac contractility modulation is a non-pharmacological approach to improve Ca2+ effect on cardiac myofilaments using electric currents. The cardiac contractility modulation system used at present (OPTIMIZER III, Impulse Dynamics, Orangeburg, NY, USA) consists of a subcutaneously implanted pulse generator and three electrodes. As far as we know, cardiac contractility modulation therapy is a safe and feasible way of improving the systolic function of the heart in congestive heart failure patients. No pro-arrhythmic effects of this new therapy have been reported. The technique shows promise as an additive treatment for severe chronic heart failure. The perioperative and intraoperative management of patients should follow current cardiac pacemaker/implantable cardioverter defibrillator guidelines.

[Malignant hyperthermia. The ugly]. / Maligne Hyperthermie. The ugly.

The term "malignant hyperthermia" (MH), regarded as the typical anaesthetic disease, refers to a clinical syndrome of varying intensity (from abortive courses to fulminant crises) and develops only under exposure of certain triggering substances or mechanisms. MH is caused by a defect in the ryanodine receptor subtype 1, which can often be proved genetically. Furthermore, it may also be generated by other mechanisms which disturb the membranous integrity of skeletal muscle cells (e.g. some myotonias, muscular dystrophies, malformation syndromes). Hyperthermia is only one of a number of life-threatening symptoms that may occur during a fulminant crisis, which ultimately results from an excessive release of calcium into the cytoplasm of muscle cells. Due to a current good knowledge about classical triggers, symptoms and therapeutic interventions, a clinical MH presentation may successfully be treated in the perioperative period. However, it appears to be likely that there are unreported cases outside hospitals since atypical courses or alternative MH triggers (e.g. alcohol, drugs, physical stress) may impair the correct diagnosis. In contrast severe hyperthermia can also arise from other drug-induced diseases, e.g. the neuroleptic malignant syndrome or the serotonin syndrome.

[Tumescent anaesthesia for dermatological surgery. Plasma concentrations of lidocaine and prilocaine]. / Tumeszenzlokalanästhesie bei dermatologischen Eingriffen. Plasmakonzentrationen von Lidocain und Prilocain.

BACKGROUND: Tumescent anaesthesia is currently used for several dermatological procedures. The objective of this study was to determine the plasma concentrations of local anaesthetics under real operating conditions with this anaesthetic technique. METHODS: A total of 31 patients received 3 different anaesthetic solutions with prilocaine and lidocaine for several surgical procedures. The concentrations of local anaesthetics, methemoglobin, epinephrine as well as the occurrence of adverse reactions were determined 30 min, 1 h, 3 h, 6 h, 12 h and 24 h after administration RESULTS: Maximum plasma concentrations of prilocaine were measured predominantly after 3 and 6 h, for lidocaine after 6 h. In two patients maximum plasma levels occurred 24 h after infiltration. Although toxic concentrations were not exceeded, side-effects could be observed in four patients. CONCLUSIONS: Even if the measured concentrations of local anaesthetics appeared to be safe, slight and moderate side-effects could be observed in 12.9% of cases. Maximum plasma levels of local anaesthetics may still occur 24 h after administration.

[Streptococcal Toxic Shock-like Syndrome associated with detectable autoantibodies]. / Toxisches Streptokokken Schock Syndrom in Verbindung mit serologisch nachgewiesenen Autoantikörpern.

We report on the severe course of a Streptococcal Toxic Shocklike Syndrome (STSLS). The initial diagnosis as well as the causal therapeutic approaches were complicated and prolongated definitely by the serological detection of auto-antibodies. Besides the presentation of clinical and paraclinical findings the report responds to relevant differential diagnoses and the corresponding strategies of therapeutic intervention.

[Current aspects of the diagnosis of malignant hyperthermia]. / Aktuelle Aspekte der Diagnostik der malignen Hyperthermie.

OBJECTIVES: The aim of this work was to give a survey of experiences and results obtained over a period of 15 years of diagnosis of malignant hyperthermia in the MH centre in Leipzig. The new branch of MH diagnosis, the molecular genetics and its general diagnostic potential will be presented in more detail. METHODS: The in vitro contracture test (IVCT), which has been used in our department since 1986, represents the standard method for determining disposition to MH and in addition, suspected MH events were analysed by the clinical grading scale (CGS). In 1999, the diagnosis of MH in our centre was supplemented by molecular genetic examination of the skeletal ryanodine receptor gene (RYR1). RESULTS: A total of 1,456 muscle tests (IVCT) in patients with a potential MH disposition, provided 376 MH susceptible (MHS), 121 MH equivocal (MHE) and 921 MH negative (MHN) results. Out of these 309 persons had a previous clinical MH event, but for the majority of these persons a real MH disposition could be excluded by the IVCT (197 MHN). In 99 independent MH families, the RYR1 was genetically screened identifying a mutation in 46, whereby 18 different RYR1 point mutations were found of which 4 (Arg401Cys, Ile2182Phe, Gly2375Ala, Ile2453Thr) have not yet been published. CONCLUSIONS: The disposition to MH may be assessed by the IVCT, DNA analysis and with limitations by the clinical phenotype. The IVCT represents a highly specific method, the DNA analysis appears to be very specific. Under defined conditions an alternative use of the methods is possible. However, these methods should not be regarded as in competition but rather their potential should be complementary or used in specific situations in order to avoid non-detection of MH events in affected families.

[In vitro contracture test and gene typing in diagnosing malignant hyperthermia. Each as an appropriate complement to the other method]. / In-vitro-Kontrakturtest und Gentypisierung in der Maligne Hyperthermie-Diagnostik. Ein Beispiel für die sinnvolle Ergänzung beider Methoden.

BACKGROUND: Malignant hyperthermia (MH) is an autosomal dominantly inherited disorder, triggered in susceptible individuals by inhalation anesthetics and depolarizing muscle relaxants such as succinylcholine. Because of its high sensitivity (97-99%) and specificity (93.6%) as well as the genetic heterogeneity of MH disorder, the in vitro contracture test (IVCT) following the European-MH-Group is considered to be the "Gold Standard" for phenotypical determination of predisposed patients. On the other hand mutations in the skeletal muscle ryanodine receptor gene (RYR1) are tightly linked with MH susceptibility. After detecting a C1840T-mutation (Arg614Cys) in the RYR1 gene in one individual of a large MH family, we searched for this mutation in the remaining family members and determined the concordance with IVCT. METHODS: According to the European standard protocol for MH, 43 individuals of a large MH pedigree were assigned the status of MH susceptible (MHS),--negative (MHN) or--equivocal (MHE). The genetic investigation of 44 family members for the Arg614Cys-mutation was carried out by restriction fragment analysis: Genomic DNA was prepared from EDTA whole blood followed by amplification of a 918 bp RYR1 gene fragment by polymerase chain reaction. In presence of the Arg614Cys-mutation digestion with the restriction endonuclease Rsal would result in different DNA fragments of the amplified sequence than in absence of mutation. RESULTS: According to the response to IVCT, 25 individuals phenotypically revealed MHS, 7 MHE and 11 MHN status. Out of the 44 family members screened genetically for the Arg614Cys-mutation, the mutation was detected in 23 individuals. Out of them 19 were MHS and one was MHEc. The mutation was absent in 9 predisposed individuals, but six of them were MHE and three MHS. The mutation was also present in three individuals who had no MH screening (IVCT) before. For these last mentioned individuals the diagnosis MHS was deduced from genetic results. CONCLUSION: Based on results of IVCT the identification of a MH associated mutation in a MH-family can make and support a correct MH diagnosis and can resolve MHE findings.

[Effect of local anesthetics on hemodynamic effects during Mayfield skull clamp fixation in neurosurgery using total intravenous anesthesia]. / Der Einfluss von Lokalanästhetika auf hämodynamische Effekte beim Anlegen der Mayfield-Klammer in der Neurochirurgie unter totaler intravenöser Anästhesie.

For neurosurgical procedures, the association between insertion of the Mayfield skull clamp and haemodynamic changes is generally recognized. We investigated the protective effect of two local anaesthetic substances (lidocaine and bupivacaine) under the conditions of total intravenous anaesthesia (TIVA) with propofol and alfentanil. Forty-two patients undergoing an elective craniotomy (tumor resection) were included in the study and randomly divided into three groups. All patients were given a total intravenous anaesthesia with propofol and aflfentanil. After induction, the skin areas for the pin were infiltrated with 0.9% sodium chloride (n = 14, control group 1), 1% lidocain (n = 14, group 2) or 0.5% bupivacaine (n = 14, group 3). After an interval of 1 to 2 minutes the pins were inserted. The intra-arterial line was inserted before induction. The haemodynamic parameters heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and mean arterial pressure (MAP) were monitored continuously. The haemodynamic parameters were recorded at four set times: (1) after induction of anaesthesia, (2) at the onset of the local anaesthesia, (3) at the insertion of the pin-holder, (4) five minutes after insertion. Insertion of the pins led to a significant increase in HR, SAP, MAP and DAP in the control group. These haemodynamic changes can be reduced by local infiltration with lidocaine or bupivacaine. The effect of both substances was the same in our study. Our results suggest that a significant reduction of the haemodynamic effects caused by insertion of the Mayfield skull clamp can be achieved by the use of local anaesthesia. Total intravenous anaesthesia alone with propofol and alfentanil cannot protect against these haemodynamic stimuli.