Hans F. Ginz

Genotyping the butyrylcholinesterase in patients with prolonged neuromuscular block after succinylcholine.

Background:Succinylcholine remains the standard neuromuscular blocking drug for tracheal intubation in emergency situations. The short duration of action is due to its rapid hydrolytic degradation by butyrylcholinesterase (plasmacholinesterase). Multiple variants of this enzyme are known (A, F, S, H, J, K variants) with different effects on enzyme activity. This study was undertaken to evaluate the use of molecular genetic methods in patients with clinically prolonged neuromuscular block. Methods:Nine patients with a neuromuscular block of 14 min to 5 h were selected. All four exons of the butyrylcholinesterase were amplified by polymerase chain reaction and analyzed by automated sequencing. Molecular genetic results were compared with clinical relaxation time and with biochemical test results (total butyrylcholinesterase activity, dibucaine and fluoride inhibition). Results:Seven of nine patients were mutation carriers. Five of these had more than one mutation. The A and K variants were the most frequent variations. Three of four patients who were homozygous for the A variant were also carriers of the K allele. The authors identified one novel mutation (G1294T) introducing a stop codon at amino acid position 432. The duration of neuromuscular block was substantially different between patients with identical butyrylcholinesterase genotypes. Conclusions:Variations in the genetic sequence of butyrylcholinesterase are frequent in patients with prolonged duration of action of succinylcholine. Direct sequencing of the whole butyrylcholinesterase gene is an appropriate method for genotyping and, accordingly, should be used in future clinical studies with drugs metabolized by this enzyme (e.g., succinylcholine, mivacurium).

Use of non‐invasive‐stimulated muscle force assessment in long‐term critically ill patients: a future standard in the intensive care unit?

Background:  This study’s main purpose was to test the feasibility of employing a non‐invasive‐stimulated muscle force assessment approach in long‐term critically ill patients.

Similar susceptibility to halothane, caffeine and ryanodine in vitro reflects pharmacogenetic variability of malignant hyperthermia.

Background and objective: To analyse the use of standardized application of ryanodine for in vitro muscle contracture testing to define cut-off values separating malignant hyperthermia susceptible from malignant hyper-thermia negative subjects. Furthermore, we compared the results of in vitro muscle-contracture tests following the halothane, caffeine and ryanodine challenges. Methods: In 113 subjects, halothane, caffeine and ryanodine muscle-contracture tests were performed according to the protocol of the European Malignant Hyperthermia Group. Results: Malignant hyperthermia susceptible subjects (n = 77) had significantly shorter onset times in the ryanodine in vitro muscle-contracture test (1 μmol ryanodine) compared with malignant hyperthermia negative subjects (n = 36), median 4.8 vs. 20.1 min, respectively, without any influence of age or gender. The best cut-off value was 10 min (sensitivity 0.78 and specificity 0.94, respectively). Shorter cut-off values had greater specificity, but lower sensitivity. Groups could not be separated without an overlap. In susceptible subjects, we found a correlation between onset time and threshold concentrations for halothane and caffeine (ρ = 0.47 and 0.52, respectively). In addition, muscle bundles with high susceptibility to halothane and caffeine also showed high susceptibility to ryanodine. Conclusions: The ryanodine in vitro muscle-contracture test confirmed the malignant hyperthermia status that was determined using the halothane and caffeine in vitro muscle-contracture tests. Due to an overlap between the two groups, discrimination ability was not always perfect and short cut-off values with higher specificity had reduced sensitivity and vice versa. The correlation of contractures following the halothane, caffeine and ryanodine challenges points towards a similar individual pharmacogenetic effect rather than a specific, different pharmacological action between the three agents.

Dantrolene for severe rhabdomyolysis in Staphylococcus aureus toxic shock syndrome

rs12985668 c.594A>G p.Leu198 rs10406027 c.1077T>C p.Ala359 rs2288888 c.1668G>A p.Ser556 rs3745847 c.2286C>T p.Pro762 rs2228070 c.2979C>T p.Asn993 rs11083462 c.3456C>T p.Ile1152 rs2228071 c.7089C>T p.Cys2363 rs2229142 c.7863C>T p.His2621 Novel c.7864C>T p.Leu2622 rs2229144 c.7977G>A p.Thr2659 rs2960340 c.8118T>C p.Ile2706 rs2915951 c.8190T>C p.Asp2730 rs2915952 c.8337G>A p.Glu2779 rs2229146 c.8589T>C p.Ser2863 rs2071089 c.9186A>G p.Pro3062 rs2229145 c.10188C>T p.Asp3396 rs35959206 c.13671C>G p.Ser4557

Tissue oedema is not associated with skeletal muscle weakness in septic patients

1. Ala-Kokko TI, Ohtonen P, Koskenkari J, Laurila J. Improved outcome after trauma care in university-level intensive care units. Acta Anaesthesiol Scand 2009; 53: 1251–6. 2. Reinikainen M, Karlsson S, Varpula T, Parviainen I, Ruokonen E, Varpula M, Ala-Kokko T, Pettilä V. Are small hospitals with small intensive care units able to treat patient with severe sepsis? Intensive Care Med 2010; 36: 673–9. 3. Uusaro A, Parviainen I, Takala J, Ruokonen E. Safe longdistance interhospital ground transfer of critically ill patients with acute severe unstable respiratory and circulatory failure. Intensive Care Med 2002; 28: 1122–5.

Die hereditäre motorisch-sensible Neuropathie: Charcot-Marie-Tooth-Erkrankung : Anästhesiologisches Management : ein Fallbericht und eine Literaturübersicht

ZusammenfassungDie hereditäre motorisch-sensible Neuropathie (HMSN) oder das Charcot-Marie-Tooth-Syndrom (CMT) ist eine seltene, periphere Nerven und Muskulatur befallende Erkrankung. Eine Disposition zu einer malignen Hyperthermie (MH) weisen diese Patienten nach der gängigen Literatur nicht auf. Es liegen jedoch bisher nur wenige Fallberichte über die Narkoseführung bei dieser Erkrankung vor, wobei zumindest eine Kasuistik mit MH unter Desflurananästhesie beschrieben ist. Eine sichere Möglichkeit, um potentielle Triggersubstanzen einer MH zu vermeiden (triggerfreie Narkose), besteht in der total intravenösen Anästhesie (TIVA). Wir berichten von einer Patientin mit CMT-Erkrankung, die aufgrund einer unerwartet schwierigen Intubationsanatomie fiberoptisch intubiert werden musste. Eine TIVA mit Propofol und Alfentanil ohne Anwendung von Muskelrelaxanzien (MR) konnte problemlos durchgeführt werden. Die aktuelle Literatur hierzu wird diskutiert.AbstractA 53-year-old woman diagnosed as having hereditary motor-sensory neuropathy Charcot-Marie-Tooth (CMT) disease Type 2, underwent inguinal hernia surgery. In this patient CMT disease was manifested as distal muscle weakness and wasting. Anaesthetic experience with patients who have CMT disease is limited. Association to malignant hyperthermia is very unlikely although there is one case report that shows that there could be a relationship. We describe a total intravenous anaesthesia (TIVA) protocol with propofol and alfentanil without any muscle relaxants after fiberoptic intubation. The patient made an uneventful recovery and was discharged from the hospital on the fourth postoperative day. TIVA was a safe technique in this patient and should be considered as an alternative for patients presenting with CMT disease.

A mathematical model to improve on phenotyping for molecular genetic research in malignant hyperthermia

BackgroundThe in-vitro contracture test is the standard test to diagnose malignant hyperthermia (MH) susceptibility. Maximum sensitivity is important for patient safety. For scientific purposes, the reduced specificity of contracture testing is a major drawback, and precise phenotyping is of utmost importance. Our study aimed to improve phenotyping for MH susceptibility to more accurately select patients for molecular genetic research in MH, thus, improving the probability to detect novel MH associated variants. MethodsPatients who underwent contracture and molecular genetic testing were selected from the database of two MH investigation centres (Basel and Leipzig). The area under the curve of halothane and caffeine contracture tests was calculated and a logistic regression model was applied to determine the odds of carrying a MH associated genetic variant. This model was subsequently applied to patients without familial MH related genetic variant. ResultsValidation of the logistic regression model showed 98% concordance with molecular genetic results. Among patients with unclear in-vitro contracture test diagnosis (MH equivocal), half of the mutation carriers were classified as positive by the model, whereas 86% of those without familial mutation were classified as negative. Excluding the MH equivocal group, the model showed sensitivity of 0.99 (95% confidence interval: 0.95–0.99) and specificity 0.98 (95% confidence interval: 0.94–0.99), respectively, to identify genetically positive MH individuals. ConclusionOur model is a valuable tool to select patients from MH families for further molecular genetic research. This preselection increases the probability of successful molecular genetic research and is important when available resources are limited.

Isometric skeletal muscle force measurement in primary myopathies

Introduction: In myopathy patients, it is useful to measure skeletal muscle forces. Conventional methods require voluntary muscle activation, which can be unreliable. We evaluated a device for nonvoluntary force assessment. Methods: We tested 8 patients (unknown myopathy n = 2, inflammatory myopathy, facioscapulohumeral muscular dystrophy, mitochondrial myopathy, dysferlinopathy, multi‐minicore disease, Becker‐Kiener muscular dystrophy, n = 1 each). Isometric twitch torques of ankle dorsiflexors were measured after fibular nerve stimulation. Results: Six patients had decreased torques vs. 8 controls (men: median Newton‐meter 1.6 vs. 5.7, women: 0.2 vs. 3.9, both P < 0.0001). Values correlated with Manual Muscle Test results (r = 0.73; r2 = 0.53; P < 0.0001). In weak dorsiflexors, torque could be measured despite lower signal‐to‐noise ratios. In 2 patients with hypertrophy, we measured increased torques. Conclusions: Nonvoluntary muscle force assessment can be used in patients with myopathies, and values correlate with voluntary forces determined by traditional methods. Muscle Nerve 53: 913–917, 2016

Inter-electrode tissue resistance is not affected by tissue oedema when electrically stimulating the lower limb of sepsis patients.

Abstract ICU patients typically are given large amounts of fluid and often develop oedema. The purpose of this study was to evaluate whether the oedema would change inter-electrode resistance and, thus, require a different approach to using non-invasive electrical stimulation of nerves to assess muscle force. Inter-electrode tissue resistance in the lower leg was measured by applying a 300 µs constant current pulse and measuring the current through and voltage across the stimulating electrodes. The protocol was administered to nine ICU patients with oedema, eight surgical patients without oedema and eight healthy controls. No significant difference in inter-electrode resistance was found between the three groups. For all groups, resistance decreased as stimulation current increased. In conclusion, inter-electrode resistance in ICU patients with severe oedema is the same as the resistance in regular surgical patients and healthy controls. This means that non-invasive nerve stimulation devices do not need to be designed to accommodate different resistances when used with oedema patients; however, surface stimulation does require higher current levels with oedema patients because of the increased distance between the skin surface and the targeted nerve or muscle.