[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.

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 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.

High-flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose.

OBJECTIVE: To report a case of valproic acid overdose treated successfully with high-flux hemodialysis without the addition of charcoal hemoperfusion. CASE SUMMARY: A 25-year-old white woman with a history of multiple suicide attempts and schizophrenia presented after ingesting an unknown amount of valproic acid. She became comatose and developed hypotension and lactic acidosis as valproic acid concentrations increased to > 1200 micrograms/mL (therapeutic concentration 50-100). High-flux hemodialysis was performed for four hours; the calculated elimination rate constant (kel) during the procedure was 0.2522 h-1 with a half-life (t1/2) of 2.74 hours compared with posthemodialysis kel of 0.0296 h-1 and t1/2 of 23.41 hours, suggesting that high-flux hemodialysis effectively eliminates valproic acid. The patient's hemodynamic status and mental function improved in conjunction with the acute reduction in valproic acid concentrations. Her subsequent hospital course was complicated only by transient thrombocytopenia. DISCUSSION: Most literature reports of valproic acid overdose have described the use of charcoal hemoperfusion alone or in combination with hemodialysis to accelerate valproic acid clearance at toxic concentrations. However, the pharmacokinetic properties of valproic acid indicate that hemodialysis alone would be effective therapy for an acute valproic acid overdose. CONCLUSIONS: We suggest that toxic concentrations of valproic acid can be effectively reduced with high-flux hemodialysis without the addition of charcoal hemoperfusion and its attendant risks.

[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.

[The prognostic relevance of preoperative pulmonary function tests]. / Die prognostische Relevanz präoperativer Lungenfunktionsdiagnostik.

At Leipzig University, preoperative pulmonary function testing has been performed for about 3 years in order to detect and classify patients at high pulmonary risk. During the postoperative period, the risk of developing pulmonary complications is particularly high due to factors influencing respiratory mechanics such as the supine position, pain, residual effects of narcotic drugs, etc. It has often been emphasised that an underlying ventilatory disturbance such as obstructive lung disease or smoking may enhance the postoperative pulmonary risk, although the extent of the influence of preoperative pulmonary diseases on the postoperative complication rate is still controversial. The prediction of postoperative lung function from preoperative spirometric values is complicated by factors such as patient cooperation, pulmonary complications secondary to aspiration, infection, peritonitis, etc., and by differing and therefore non-comparable postoperative care. For this reason, the criteria for assessing pulmonary risk vary widely. METHODS. We examined 339 patients (mean age 59.3 years) preoperatively by quiet and forced spirometry; in most cases we also measured airway resistance and functional residual capacity. We estimated the postoperative lung function using the quadrant scheme of Miller and compared this risk class with our spirometric diagnosis and the postoperative clinical course. RESULTS. According to our results, Miller's classification seems inadequately differentiated for patients with mild to moderate ventilatory disturbances. A relatively high percentage of these patients were considered to have normal postoperative lung function. Some patients with severely diminished pulmonary function were classified as having sufficient postoperative lung function. The number and severity of pulmonary complications also corresponded better with the spirometric diagnosis, which was made using all spirometric parameters and not only vital capacity (VC) and 1-s forced expiratory volume (FEV1). We found that the percentage of primary respiratory complications increased with deterioration of the preoperative spirometric values. To provide a prognostic model combining both the advantages of using only a few parameters (FEV1, VC) and appropriate risk assessment, we propose a modification of the Miller scheme consisting of five risk classes. The analysis of the respiratory therapy regimen was unsatisfactory because of discrepancies between the predicted pulmonary risk, the use of respiratory therapy, and the occurrence of pulmonary complications. CONCLUSIONS. For minimising perioperative pulmonary complications, respiratory care (prophylaxis and therapy) adequate for the functional risk of the patient is necessary. We assume that intensive pre- and postoperative respiratory care and therapy in patients with underlying reductions in ventilatory function can help to avoid or reduce respiratory complications. The modification of Miller's scheme proposed after evaluating the postoperative course of our patients provides a differentiated prognostic model that allows the establishment of an appropriate and economical therapeutic regimen of perioperative pulmonary care.

[A new emphasis on the diagnosis of malignant hyperthermia using the in vitro contracture test?]. / Neue Akzente bei der Maligne-Hyperthermie-Diagnostik mittels in-vitro-Kontrakturtest?

In accordance with the protocol of the European Malignant Hyperpyrexia Group, an account is given of the experience regarding establishment of the "in vitro contracture test" for diagnosis and exclusion of malignant hyperpyrexia disposition at the University Clinic of Leipzig. Since its commencement in 1986 these diagnostic possibilities are being increasingly utilized, and--basing on 76 MH manifestations and suspected cases--324 persons have been examined until now. Besides the representation of the methodical features (e.g. performance of biopsy in tranquanalgesia in children), emphasis was on the safety of executing this test (attaining higher specificity, total absence of MH manifestations). The epidemiological study of the results shows the varying knowledge of physicians and the interference by insufficient investigation alternatives in individual areas. On the basis of the results, the use of the in vitro contracture test is recommended in all MH suspected cases by the authorized and qualified regional centres.