[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.

[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.

Mutation screening in the ryanodine receptor 1 gene (RYR1) in patients susceptible to malignant hyperthermia who show definite IVCT results: identification of three novel mutations.

BACKGROUND: The ryanodine receptor of the skeletal muscle (RYR1) seems to be of outstanding importance in the pathogenesis of malignant hyperthermia (MH). It has been shown that point mutations in the RYR1 gene are strongly associated with the MH phenotype. A correctly determined phenotype is the basic prerequisite for adequate genetic MH screening. In this study we examined only those MH susceptible patients for the presence of potential RYR1 mutations who showed strong pathological muscle responses in the in vitro contracture test (IVCT). METHODS: A total of 56 MHS index patients who complied with the following IVCT criteria were included in the molecular genetic investigation: Contracture forces > or =4 mN at a caffeine concentration of 2.0 mmol/l and > or =8 mN at a halothane concentration of 0.44 mmol/l. DNA sequences of exons 2, 6, 9, 11, 12, 14, 15, 17, 39, 40, 45, 46, 102 of the RYR1 gene were analysed by the direct sequencing technique. Furthermore, if an MH mutation was identified in an index patient, all relatives were screened for their family specific RYR1 defect. RESULTS: In 39 index patients an RYR1 mutation was detected: Arg163Cys (n = 2), Asp166Asn (n = 1), Gly341Arg (n = 2), Arg401His (n = 2), Arg614Cys (n = 12), Asp2129Glu (n = 1),Vol2168Met (n = 1), Thr2206Met (n = 9), Ala2428Thr (n = 1), Gly2434Arg (n = 2), Arg2435His (n = 1), Arg2452Trp (n = 1), Arg2454His (n = 4). Three new RYR1 mutations were identified. We found a potential MH mutation in a further 130 relatives of the 39 index patients. Thirty-seven individuals were classified as MHS exclusively by molecular genetic techniques and did not have to undergo the IVCT. CONCLUSIONS: The ascertained high rate of successful MH mutation screening (69.64%) is obviously associated with the more clearly defined MHS diagnosis in the IVCT. According to the EMHG guidelines for the molecular genetic detection of MH susceptibility, a positive MH disposition could be determined in numerous persons by a less invasive technique.

Determination of a positive malignant hyperthermia (MH) disposition without the in vitro contracture test in families carrying the RYR1 Arg614Cys mutation.

Molecular genetic methods are used with caution for determining positive malignant hyperthermia (MH) disposition in clinical MH diagnosis because of the genetic variability of this disease. But under defined conditions, genotyping can have an advantage over the standardized in vitro contracture test (IVCT) in respect of invasive approach, specificity, patient compliance, and the work and expense involved in the method. We aim to demonstrate this using 10 families with the Arg614Cys mutation in the ryanodine receptor as an example. Fifty-one index patients who had been classified as MH-susceptible (MHS) in the IVCT (European MH protocol) after a clinical MH incident or suspected MH were screened for the Arg614Cys (C1840-->T) mutation in the RYR1 gene because this mutation is more common in German MH families (9%). The family members of those index patients, in whom a Arg614Cys mutation was detectable, were also screened for the presence of this mutation (n=136), and the results were subjected to a more detailed analysis including existing IVCT findings (n=71). The Arg614Cys mutation was identified in a total of 64 members of the 10 independent families. In 35 individuals in this group, there was a definite concordance between the MHS diagnosis in the IVCT and the presence of the Arg614Cys mutation. No individual phenotyped as MH-negative carried the mutation. On the basis of the guidelines of the EMHG for molecular genetic detection of MH susceptibility, 29 individuals who bore the Arg614Cys mutation were classified as MHS without the IVCT. If a causal mutation is detected in an MH family, the MHS diagnosis can be deduced without the invasive IVCT in all other mutation carriers. Despite inclusion of only one (Arg614Cys) of all known MH mutations, the study emphasizes the practical use of a genetic approach for determination of a positive MH diagnosis.

Homozygous and heterozygous Arg614Cys mutations (1840C-->T) in the ryanodine receptor gene co-segregate with malignant hyperthermia susceptibility in a German family.

The determination of susceptibility to malignant hyperthermia (MH) by genetic investigation is a controversial issue because of the genetic heterogeneity of this disorder. The requirement for such an approach in MH diagnosis is a strong correlation between MH-associated genetic abnormalities and phenotypic findings in the in vitro contracture test (IVCT). After a severe clinical MH crisis during general anaesthesia a patient was diagnosed by the IVCT in which susceptibility to MH was confirmed. Genetic screening for MH-related mutations in the RYR1 gene revealed the presence of a homozygous 1840C-->T base exchange (Arg614Cys substitution) in this patient. A specific search for this defect in 20 relatives led to the identification of a total of 11 Arg614Cys mutations. Of these, 10 were heterozygous (including both parents) and one was homozygous (sister). Further IVCTs were subsequently performed on the parents of the index patient, the homozygous sister and all relatives who did not carry the Arg614Cys in order to determine the genotype/phenotype correlation. After analysing these data, and because of the strong correlation between clinical, phenotypic, and genetic results in the index patient, we assigned the diagnosis 'MHS' to all the remaining Arg614Cys mutation carriers of that family without performing the IVCT.

[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.

[Regional distribution of predisposition to maligant hyperthermia in Germany: tate in 1997]. / Die regionale Verbreitung der Veranlagung zur Malignen Hyperthermie in Deutschland: Stand 1997.

Malignant hyperthermia (MH) is a rare autosomally dominantly hereditary and potentially life-threatening disease. The prevalence of the genetic MH predisposition is estimated as 1:10,000 to 1:20,000. In Germany no data on the regional distribution are available. Therefore, the purpose of this investigation is to summarise and present the epidemiological data of all German MH laboratories. Nine German hospitals offer the specific in vitro contracture test to diagnose the MH predisposition. All German MH laboratories carry out the examination in accordance with the standardised protocol of the European Malignant Hyperthermia Group. The laboratories were asked to provide the number of all patients investigated, excluding those suffering from other neuromuscular diseases, separated according to diagnostic groups and their places of residence, the number of the identified MH-families as well as the number of the clinically suspected and investigated MH cases with their places of residence. Eight MH laboratories provided the requested data. Until September 1997 a total of 2620 patients were investigated. In 865 patients (34%) MH suspicion was confirmed (diagnosis: MHS). 1494 patients (56%) were released by investigation from MH-suspicion (diagnosis: MHN). In 261 patients (10%) the MH-predisposition remained unsolved (diagnosis: MHE). 580 MH families were identified. Among 2620 patients 757 were clinically suspected MH cases. 35% of these suspected MH cases were classified as MHS, 10% as MHE and 55% as MHN. The documentation of the patients places of residence classified as MHS and MHE into a map of Germany demonstrates an exhaustive distribution with an increased regional prevalence in the areas of the MH laboratories. This concentration in the area of the MH laboratories becomes even more evident, when the places of residence of the MH suspected cases are demonstrated. In conclusion, the distribution of the MH predisposition is uniform and exhaustive in Germany. The presented regional concentration of clinically suspected MH cases among the MH laboratories is mainly interpreted as an expression of effective regional education and information. Considering the overall incidence of the MH predisposition as described above only 15-20% of the MH patients have so far been identified. The MH laboratories have already released about 10,000 patients from the suspicion of MH predisposition. A preliminary prevalence of at least 1:60,000 to 1:80,000 in Germany can be estimated according to the presented data.

[Diagnosis of disposition for malignant hyperthermia--an updated review based on 1,001 studies]. / Diagnostik der Disposition zur Malignen Hyperthermie--eine aktualisierte Ubersicht auf der Basis von 1001 Untersuchungen.

The in vitro contracture test (IVCT) based on European Malignant Hyperpyrexia Group criteria including the linked quality guarantee is carried out in 6 centres in Germany. Due to the genetic heterogeneity of malignant hyperthermia. This test remains the existing standard, despite intensive search for less invasive diagnostic methods. The test is necessary for clarification of narcosis incidents and diagnosis of individual disposition of MH-afflicted families. The analysis of 11 years of experience with 1.001 investigations in the Leipzig centre focuses on characteristic problems. It indicates, that severe courses with resulting fatality (37 cases in the whole observation period in the centre district had a decreasing tendency. Independently thereof the rate of demands for diagnostics remains constant at 125 per year. Apparently MH related incidents are under better control now. Of the requested diagnostics 85% are related to anaesthesia incidents, 15% to other MH related problems [myopathies, unexplained fever attacks]. Of the patients tested 59.7% were MH-negative (MHN), 33.7% MH-positive (MHS) and 6.3% were equivocally positive (MHE). A parallel part of the study regarding IVCT and histology/morphometry in 230 consecutive examinations did not show any correlation. Ultrastructural investigations accordingly are carried out only if there is suspicion of myopathy. Differentiation of the in vitro threshold values shows a relation to the patients' risks. Low threshold values were detected in persons diagnosed as MHS from families with MH related deaths: one man diagnosed MHS died from an anaesthesia-unrelated MH crisis. In a parallel test of MH-positive muscles with new inhalational narcotics (sevoflurane, desflurane), a strong correlation to triggering of contracture by halothane was detected. In contrast, no information about a false negative result exists at this time. MH manifestation was observed postoperatively only in one patient 1337 patients MHS, 63 MHE). However, in 3 cases cardio-circulatory arrests occurred under local anaesthesia without further consequences. The analysis documents the safety of IVCT and the clarity of its results. IVCT is the base for an improved communication with patients and colleagues.

[Therapeutic possibilities of sympathoadrenergic reactions during general anesthesia using sublingual application of glycerol trinitrate]. / Untersuchungen zur Therapiemöglichkeit sympathoadrenerger Reaktionen unter Allgemeinanästhesie mittels sublingual applizierten Glyzeroltrinitrats.

Strong surgical stimulation (for e. g. sternotomy, mediastinal preparation and aortic dissection in heart surgery) leads to an adrenergic reaction with the so-called haemodynamic break-through phenomenon. The inhibition of this reaction by means of narcotics is always connected with a dangerous decrease of cardiac index. Therefore, the sublingual application of nitroglycerin (GTN: 7 micrograms/kg), well established in the therapy of angina pectoris, was used as a rapidly applicable alternative. Patients with coronary heart disease under neuroleptanaesthesia (n = 10) were investigated in comparison to volunteers (n = 5). Beside the registration of haemodynamic parameters by invasive monitoring, the determination of arterial plasma concentrations of GTN and its metabolites 1.2- and 1.3-glyceryl dinitrate (GDN) were performed using gas-chromatographic technique. Using the same doses the haemodynamic changes are more marked and of longer duration in the anaesthetised patients than in the awake volunteers. The cause seems to be the higher and longer detectable active concentrations of GTN and GDN (the average maximum GTN concentrations greater than 0.5 ng/ml still after 12 minutes in contrast to 7 minutes). After discussing various different pharmacokinetic possibilities this effect is probably related to the simple fact of an improved resorption of the drug in the anaesthetised patient (no salivation, no swallow movements). On the basis of this investigation the sublingual application of GTN is a very useful therapy for the blockade of sympathoadrenergic reactions under anaesthesia, but the commonly used doses of GTN has to be reduced by half (3-4 micrograms/kg).

[Determination of the basic data on fentanyl dosage in neuroleptanalgesia for heart surgery]. / Ermittlung von Basisdaten zur Fentanyl-Dosierung in der Neuroleptanalgesie für kardiochirurgische Eingriffe.

The use of high-dose fentanyl (50-150 micrograms/kg) in anaesthesia for cardiac surgery includes the need of prolonged ventilatory support in the postoperative period. Therefore, the possibility of choosing a useful dosage regimen of smaller doses of fentanyl (up to 20 micrograms/kg) leading to analgesic serum levels of greater than 3 ng/ml is investigated in this study. Fentanyl was determined by radioimmunoassay in 20 patients during and after typical cardiosurgical operations. Three bolus injections of 7 micrograms/kg were applied in the first group (n = 8). Analgesic fentanyl concentrations were reached 12-24 minutes after the first injections. The characteristic pharmacokinetic influences - especially the enlarged volume of distribution and the prolonged elimination time - were visible following repetitive doses during extracorporeal circulation. Based on these results the injection mode was changed in the second investigation group (n = 6) - 2/3 of the total dose before the start of extracorporeal circulation - resulting in analgesic fentanyl concentrations for the whole course of the operation. More stable serum levels were obtained with the combination of primary bolus injection followed by continuous infusion (3rd group, n = 6), but a higher fentanyl amount and prolonged postoperative ventilation times were registered in this group. Bolus injections adapted to the special pharmacokinetic situation seem to be the best variant for the desired effect of producing sufficient analgesic levels without long-lasting ventilatory depression with a limited total dose of fentanyl.

[New arguments in favor of early extubation following surgical interventions on the heart]. / Neue Argumente für die frühe Extubation nach kardiochirurgischen Eingriffen.

An algorithm was introduced for simplification of postoperative treatment after cardiac operations which safely enables an early weaning from the ventilator and extubation. Using this algorithm consequently, the postoperative time of respirator treatment was reduced to an average 132 minutes in adults. The extubation could be performed an average 36 minutes later. In 121 patients with aortocoronary bypass grafts and 57 patients with valve replacements, extensive haemodynamic investigations based on the SWAN-GANZ-monitoring system showed that after weaning from the ventilator and extubation stabilisation occurred after a short period of instability. The data including arterial and mixed venous blood gases confirm that under the conditions of modern cardiac surgery a short postoperative respirator treatment is not only possible but necessary for avoiding cardiocirculatory and respiratory side-effects.

[Anesthesia-induced changes in the preload-dependent circulatory reactions in patients with coronary heart disease]. / Anästhesiebedingte Veränderungen der vorlastabhängigen Kreislaufreaktionen bei Patienten mit koronarer Herzkrankheit.

The influence of preload changes (table tilt) on the hemodynamic regulation before and after induction of neuroleptanalgesia was studied in 31 patients with coronary heart disease. The induced preload changes are balanced in the awake patient for the maintenance of normal arterial pressure by regulation of stroke volume and peripheral vascular resistance. This regulation does not exist after induction of anaesthesia. Splitting the patients into sub-groups with good or poor left ventricular function, different ventricular function curves were obtained before and after the induction of anaesthesia. The pharmacologic and ventilatory reasons for the changed regulation of circulation are discussed. For investigations into hemodynamic changes produced by intervention in anaesthesia and intensive therapy, it is recommended to define more exactly the cardiovascular status of patients and the study conditions.

[Pharmacokinetic studies on the causes of increased neurotoxicity of lidocaine during heart surgery]. / Pharmakokinetische Untersuchungen zu den Ursachen der erhöhten Neurotoxizität des Lidokains während kardiochirurgischer Operationen.

A high incidence of pathological EEG changes were registered following the treatment of arrhythmias using intravenous bolus injections of lidocaine during heart surgery with cardiopulmonary bypass. Lidocaine plasma concentrations were analysed by gas chromatography in order to detect reasons for this phenomenon. No dangerously high plasma levels of lidocaine were observed. The pharmacokinetic data show initially a larger volume of distribution and a shortening of distribution halflife. As causes for the increased neurotoxicity, a decrease of plasma binding and changed conditions for faster uptake by the brain are discussed. A reduction of lidocaine doses is recommended for this special clinical setting.

[Effects of atropine in coronary heart disease]. / Untersuchungen zu den Atropin-Wirkungen bei koronarer Herzkrankheit.

For the detection of atropine effects the hemodynamic changes of 50 patients with coronary heart disease being premedicated intramuscularly with pethidine/diazepam have been registered 3 and 6 minutes after intravenous atropine application (0.01 mg/kg). All patients showed an increase of the heart rate, but only 80% demonstrated an increase of cardiac index at the same time. 20% of these patients exhibited a decrease of the stroke volume, whereas in 5 cases out of this group the patients complained ischemic pain. In a second part of this investigation the results of an induction of neuroleptanalgesia have been compared with another group of 50 patients with the same disease. The function of the right and left ventricle was significantly depressed in the patients with atropine application before the induction of anaesthesia. The results are discussed as an important argument against the routine use of atropine for premedication purposes.