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Biomedical subjects

A Urwyler

Publications and source records attributed to A Urwyler.

At least 19 recordsLinked to original sources
PubMed1998

Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect Of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors.

Malignant hyperthermia (MH) is a hypermetabolic disease triggered by volatile anesthetics and succinylcholine in genetically predisposed individuals. Nine point mutations in the skeletal muscle ryanodine receptor (RYR) gene have so far been identified and shown to correlate with the MH-susceptible phenotype, yet direct evidence linking abnormal Ca2+ homeostasis to mutations in the RYR1 cDNA has been obtained for few mutations. In this report, we show for the first time that cultured human skeletal muscle cells derived from MH-susceptible individuals exhibit a half-maximal halothane concentration causing an increase in intracellular Ca2+ concentration which is twofold lower than that of cells derived from MH-negative individuals. We also present evidence demonstrating that overexpression of wild-type RYR1 in cells obtained from MH-susceptible individuals does not restore the MH-negative phenotype, as far as Ca2+ transients elicited by halothane are concerned; on the other hand, overexpression of a mutated RYR1 Arg163Cys Ca2+ channel in muscle cells obtained from MH-negative individuals conveys hypersensitivity to halothane. Finally, our results show that the resting Ca2+ concentration of cultured skeletal muscle cells from MH-negative and MH-susceptible individuals is not significantly different.

Arginine↗
PubMed1998

Propofol reduces succinylcholine induced increase of masseter muscle tone.

PURPOSE: Succinylcholine is known to increase the tone of the masseter muscles. As excessive jaw tension may complicate rapid sequence induction, we investigated three induction techniques, all including the use of succinylcholine, with respect to masseter muscle tone, neuromuscular blockade, intubation conditions, and time course of intubation. METHODS: Sixty adult patients were allocated to one of three induction groups: Group THIO received 5 mg.kg-1 thiopentone, Group THIO/ATR received 5 mg.kg-1 thiopentone plus 0.05 mg.kg-1 atracurium for precurarization, and Group PROP received 2.5 mg.kg-1 propofol. All patients received 3 micrograms.kg-1 fentanyl and 1.5 mg.kg-1 succinylcholine. Time for induction of anaesthesia was recorded, and, after inserting a Grass Force Transducer between upper and lower incisors, jaw tone and the time course of jaw tension was recorded before and after the administration of succinylcholine. RESULTS: No differences in the onset of sleep were observed among the three groups (Group THIO 33 +/- 2 sec: THIO/ATR 30 +/- 2 sec: PROP 35 +/- 2 sec, mean +/- SE). Masseter preloads following induction of anaesthesia were similar in all three groups (THIO 16.4 +/- 2.1 N: THIO/ATR 15.1 +/- 2.0 N: PROP 12.7 +/- 1.6 N). However, after administration of succinylcholine, the increase in masseter tone was less in Groups PROP (5.0 +/- 1.1 N) and THIO/ATR (6.4 +/- 2.1 N) than in Group THIO (12.4 +/- 3.0 N; P < 0.05). CONCLUSION: Jaw tension after administration of succinylcholine is influenced by the choice of induction agent. The increase of masseter muscle tone is lower following propofol or thiopentone/atracurium induction than with thiopentone alone.

Adolescent↗
PubMed1998

Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered in genetically predisposed individuals by common anesthetics and muscle relaxants. The ryanodine receptor (RYR1) is mutated in a number of MH pedigrees, some members of which also have central core disease (CCD), an inherited myopathy closely associated with MH. Mutation screening of 6 kb of the RYR1 gene has identified four adjacent novel mutations, C6487T, G6488A, G6502A, and C6617T, which result in the amino acid alterations Arg2163Cys, Arg2163His, Val2168Met, and Thr2206Met, respectively. Collectively, these mutations account for 11% of MH cases and identify the gene segment 6400-6700 as a mutation hot spot. Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. This finding has important ramifications for assignment of the MH-susceptible phenotype, in genotyping studies, and indicates that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic. Interestingly, the data suggest a link between the caffeine threshold and tension values and the MH/CCD phenotype.

Female↗
PubMed1997

Muscle biopsy for malignant hyperthermia screening in children.

Malignant Hyperthermia (MH) remains a life-threatening event in anaesthetic practice. In paediatric patients, triggering agents such as volatile anaesthetics and other succinylcholine are widely used. For children with a positive family history or previous clinical signs of MH, muscle biopsy for the halothane and caffeine in vitro muscle contracture tests is the only reliable procedure for diagnosis of MH susceptibility. Here we investigated outcome and compliance of patients and parents involved in the test. Twenty-four children between 6 and 14 yrs of age were admitted to hospital for biopsy. Muscle withdrawal was performed at the upper leg from lateral vastus muscle using regional or trigger-free general anaesthesia. Outcome and compliance were controlled by a telephone interview or direct physical re-evaluation. Seventeen patients out of 24 were diagnosed as clinically MH-susceptible according to the protocol of the European MH Group. Seven children were excluded as MH-negative by the test. Twenty-one children were evaluated postoperatively. Minor side effects of wound healing occurred, but none of the patients showed any abnormalities of muscle contracture or movement performance. Considering the high risk of fatal complications in the presence of MH-susceptibility, muscle biopsy of the upper leg for in-vitro diagnosis is a justified procedure that is acceptable to children and their parents.

Adolescent↗
PubMed1997

In vitro contracture test for diagnosis of malignant hyperthermia following the protocol of the European MH Group: results of testing patients surviving fulminant MH and unrelated low-risk subjects. The European Malignant Hyperthermia Group.

BACKGROUND: Determination of sensitivity and specificity of the in vitro contracture test (IVCT) for malignant hyperthermia (MH) susceptibility using the European MH Group (EMHG) protocol has been performed in some laboratories but only on a small sample from the combined EMHG. Thus, the purpose of the present study was to determine combined EMHG sensitivity and specificity of the test. METHODS: Results of IVCT of patients with previous fulminant MH and normal, low-risk subjects (controls) were collected from 22 centres of the EMHG. IVCT was performed according to the EMHG protocol. Patients were included in the study if the clinical crisis had a score of at least 50 points with the Clinical Grading Scale. Low-risk subjects were included provided they did not belong to a family with known MH susceptibility, they had not developed any signs of MH at previous anaesthetics, and they did not suffer from any neuromuscular disease. For inclusion of both MH patients and low-risk subjects, at least 1 muscle bundle in the IVCT should have twitches of 10 mN (1 g) or more. For evaluation of individual tests, only muscle bundles with twitch heights of 10 mN (1 g) or more were used. RESULTS: A total of 1502 probands had undergone IVCT because of a previous anaesthesia with symptoms and signs suggestive of MH. Of these, 119 had clinical scores of 50 and above. From these 119 MH-suspected patients and from 202 low-risk subjects, IVCT data were collected. Subsequently, 14 MH-suspected patients were excluded from further analysis for the following reasons: In 3 patients, the suspected MH episode could be fully explained by diseases other than MH; in 11 MHS patients, IVCT was incomplete (n = 1), data were lost (n = 3), or none of the muscle bundles fulfilled twitch criteria (n = 7). Of the remaining 105 MH-suspected patients, 89 were MHS, 10 MHEh, 5 MHEc, and one MHN. Thus, we observed a diagnostic sensitivity of the IVCT of 99.0% if the MHE group is considered susceptible (95% confidence interval 94.8-100.0%). Of the 202 low-risk subjects, 3 were MHS, 5 MHEh, 5 MHEc, and 189 MHN. This gives a specificity of the IVCT of 93.6% (95% confidence interval 89.2-96.5%). CONCLUSION: The IVCT for diagnosis of MH susceptibility in Europe has a high sensitivity and a satisfactory specificity.

Adolescent↗
PubMed1996

Effects of intravenous lidocaine and/or esmolol on hemodynamic responses to laryngoscopy and intubation: a double-blind, controlled clinical trial.

STUDY OBJECTIVES: To evaluate the efficacy of intravenous lidocaine and two doses of esmolol for attenuating the cardiovascular responses to laryngoscopy and intubation, and to assess whether a combination of both drugs is more effective than either drug alone. DESIGN: Randomized, prospective, double-blind, placebo-controlled study. SETTING: University hospital. PATIENTS: 90 ASA status I and II normotensive women scheduled for elective gynecologic procedures with general anesthesia. INTERVENTIONS: Induction of anesthesia was standardized for all patients. The first group received lidocaine 1.5 mg/kg (Group LID); the second and third groups received esmolol 1 mg/kg and 2 mg/kg, respectively (Groups E1 and E2, respectively); the fourth group received lidocaine 1.5 mg/kg and esmolol 1 mg/kg (Group LID-E1); the fifth group received lidocaine 1.5 mg/kg and esmolol 2 mg/kg (Group LID-E2); the sixth group received saline as a placebo (Group PLAC). MEASUREMENTS AND MAIN RESULTS: Systolic blood pressure and heart rate (HR) were recorded before induction, before injection of the first test drug, immediately before laryngoscopy, and 1, 2, and 5 minutes following intubation. Duration of laryngoscopy was recorded. Only patients receiving placebo had increased HR values after intubation compared with baseline values (p < 0.05). The proportion of patients with a maximum HR exceeding 90 beats/min was significantly higher in the placebo group (8 of 15 patients) than in both esmolol groups (E1 2 of 15; E2 2 of 15) (p < 0.05). Systolic blood pressure values after tracheal intubation did not differ among groups except for those receiving the combinations of lidocaine and esmolol, and they had significantly lower blood pressure (BP) values compared with placebo (p < 0.05). CONCLUSIONS: Esmolol 1 to 2 mg/kg is reliably effective in attenuating HR response to tracheal intubation. Neither of the two doses of esmolol tested nor that of lidocaine affected the BP response. Only the combination of lidocaine and esmolol attenuated both HR and BP responses to tracheal intubation.

Adolescent↗
PubMed1995

Bee venom immunotherapy results in decrease of IL-4 and IL-5 and increase of IFN-gamma secretion in specific allergen-stimulated T cell cultures.

The mechanisms of bee venom immunotherapy (VIT) are largely unknown. The aim of this study was to follow the changes of T cell cytokine secretion during the course of VIT. Ten bee venom-allergic patients with a history of severe systemic reactions, positive skin tests, and bee venom (BV)-specific serum IgE Abs were treated as follows: on the first day, a cumulative dose of 111 micrograms, starting with 0.1 microgram, was administered s.c. under intensive care conditions. Further injections of 100 micrograms BV were given on day 7, day 21, and thereafter at intervals of 4 wk. Blood samples were obtained just before the initiation of VIT, after the last injection on the same day, and before the subsequent BV injections on days 7, 21, and 50 of VIT. Peripheral blood mononuclear cells (PBMC) were stimulated with phospholipase A (PLA), the major BV allergen, or with a control Ag tetanus toxoid (TT). Cytokine secretion was measured 24 h after restimulation of the cultures with solid-phase bound OKT3 F(ab')2 mAbs after 7 days of culture. In PLA-stimulated cultures, VIT resulted in decreased IL-4 and IL-5 and increased IFN-gamma secretion. In TT-stimulated cultures, we observed similar levels of cytokines before and during VIT. We conclude that ultra-rush VIT changes allergen-specific T cell reactivity.

Allergens↗
PubMed1995

Paravascular lumbar plexus block: block extension after femoral nerve stimulation and injection of 20 vs. 40 ml mepivacaine 10 mg/ml.

The goal of this prospective randomized study was to assess the extension of the "three-in-one" paravascular lumbar plexus block after femoral nerve stimulation and injection of 20 vs. 40 ml mepivacaine 10 mg/ml. Three-in-one blocks were achieved in 12 of 39 (31%) patients given 20 ml of 1% mepivacine (group 1), and 17 of 41 (41%) patients given 40 ml (Group 2) of the same solution (n.s.). The level of successful blockade at each nerve did not differ between groups. The femoral nerve was blocked in 92% vs. 93% of patients in groups 1 and 2, respectively; the obturator nerve in 62% vs. 78%; and the lateral cutaneous femoral nerve in 41% vs. 44%. We conclude that femoral nerve stimulation is effective in faciliating blockade in the femoral nerve but not the obturator or lateral cutaneous femoral nerve with the tested solution and volumes, and therefore not particularly effective for achieving complete 3-in-1 blockade. Within the clinically relevant range of 20-40 ml, the volume of mepivacaine 10 mg/ml does not appear to influence the extent of blockade.

Adult↗
PubMed1994

Neuropeptides are potent modulators of human in vitro immunoglobulin E synthesis.

We determined the effect of adrenocorticotropin hormone (ACTH) on the regulation of IgE synthesis. Depending on the concentration, ACTH enhanced or inhibited IgE synthesis in a culture system where IgE synthesis was induced with interleukin-4 (IL-4) and anti-CD40 monoclonal antibody in peripheral blood mononuclear cells. Similar effects on IgE synthesis were observed by adding ACTH-related peptides, e.g. corticotropin-releasing factor (CRF), the inducer of ACTH, or alpha-melanocyte stimulating hormone (alpha-MSH), a cleavage product of ACTH. However, ACTH had no effect on IgG or IgM synthesis in this culture system. ACTH did not act directly on either B or T cells as there was no influence on IgE synthesis in a system using purified B cells alone or co-cultured with T cells. The effect of ACTH on IgE synthesis was mediated by accessory cells. This was shown by priming purified CD14-positive monocytes with ACTH and reconstitution experiments. Therefore, these findings suggest that ACTH and the related peptides CRF and alpha-MSH can influence the microenvironment modulating an IL-4 and anti-CD40 monoclonal antibody driven class switching to IgE via accessory cells.

Adrenocorticotropic Hormone↗
PubMed1994

[Malignant hyperthermia].

Malignant hyperthermia (MH) is a rare, life-threatening pharmacogenetic disease. The genetic incidence is estimated to be 1:10,000. In predisposed individuals, MH is triggered by volatile anaesthetics and/or depolarizing muscle relaxants by an abnormal increase of intracellular calcium concentration in skeletal muscle cells. The clinical presentation may vary from abortive MH to the fulminant MH crisis. Early diagnosis, the use of electrocardiography and capnography for anaesthetic monitoring, immediate cessation of trigger agents and dantrolene treatment are essential components of an effective MH therapy. In some MH families, a genetic alteration of the ryanodine receptor gene (a calcium channel of the sarcoplasmic reticulum) on chromosome 19 has been identified as the potential cause of MH susceptibility. Recent molecular biological findings support the view of MH being a heterogenetic disease. At present, the diagnosis in potentially MH-susceptible individuals is still made using the in vitro halothane and caffeine muscle contracture test.

Anesthesia↗
PubMed1994

Are laboratory values in bone marrow aspirate predictable for venous blood in paediatric patients?

In an emergency situation, early laboratory results are important, but often difficult to obtain. If venous access cannot be established, the intraosseous route may be used as an alternative. This study investigated the predictive value of bone marrow aspirate in performing laboratory studies. Thirty children underwent general anaesthesia for bone marrow aspiration (iliac crest) for oncologic or haematologic reasons. The aspirate and a peripheral venous blood sample, which was obtained simultaneously, were subjected to different laboratory tests and the results were compared by means of confidence interval analyses of the individual ratios of venous/bone marrow values. Based on these analyses, a high predictability of bone marrow values were found for haemoglobin, sodium, chloride, glucose, bilirubin, urea, creatinine, pH, and standard bicarbonate. Moderate, but clinically useful predictability was found for haematocrit, potassium, and total protein, while bone marrow values of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, PCO2, PO2, thrombocytes and leukocytes were systematically different from values in venous blood. Our data suggest that the intraosseous route is not only an important emergency alternative to intravenous access for administering fluids and drugs but may also serve as a reliable alternative for obtaining initial diagnostic laboratory studies when intravascular access is not obtainable.

Analysis of Variance↗
PubMed1994

Detection of a novel RYR1 mutation in four malignant hyperthermia pedigrees.

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalational anaesthetics and depolarizing muscle relaxants. To date, six mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. Using SSCP analysis, we have screened the RYR1 gene in affected individuals for novel MHS mutations and have identified a G to A transition mutation which results in the replacement of a conserved Gly at position 2433 with an Arg. The Gly2433Arg mutation was present in four of 104 unrelated MHS individuals investigated and was not detected in a normal population sample. This mutation is adjacent to the previously identified Arg2434His mutation reported in a CCD/MH family and indicates that there may be a second region in the RYR1 gene where MHS/CCD mutations cluster.

Amino Acid Sequence↗
PubMed1994

Genetic effects on the variability of the halothane and caffeine muscle contracture tests.

BACKGROUND: The spectrum of the clinical presentation of malignant hyperthermia (MH) and the results of recent linkage studies suggest that there is a degree of heterogeneity in MH susceptibility. In the current study, we analyzed in vitro muscle contracture tests from members of large families with MH to evaluate if the results of these tests could be related to genetic influences. METHODS: Forty-seven subjects from four families with an MH-related death and with at least five clinically MH-susceptible individuals per family, as diagnosed by an in vitro muscle contracture test according to the protocol of the European MH Group, were included in the current analysis. We compared the strength of muscle contractures to challenges of halothane, caffeine, or both and the effect of these two drugs on twitch potentiation in response to supramaximal electrical stimulation among the families. RESULTS: Clinical MH susceptibility was confirmed in 36 individuals, and 11 individuals were diagnosed as MH-negative. In MH-susceptible individuals, muscle contractures to the 2% halothane challenge were significantly higher in family 1 (n = 15; 16.2 +/- 2.9 mN, mean +/- standard error of the mean) and in family 4 (n = 5; 16.4 +/- 5 mN) than in family 2 (n = 9; 5.8 +/- 1.5 mN) or family 3 (n = 7; 6.0 +/- 1.1 mN). Muscle contractures to the caffeine challenge (2 mM) were significantly increased in family 1 (7.3 +/- 1.4 mN) compared with those in family 3 (1.3 +/- 1.0 mN). In addition, we found a dose-dependent twitch potentiation to the halothane challenge in family 2 (P < 0.01) and to the caffeine challenge in families 2 (P < 0.001) and 3 (P < 0.01), whereas there was no twitch potentiation in families 1 and 4. CONCLUSIONS: The differences of in vitro muscle contracture tests among several families with MH provide evidence for genetic influences on the variability of this test procedure. However, it is not known if the observed differences are caused by heterogeneity of the MH gene mutation(s) or by other genetic factors that might modify muscle contractures in vitro.

Adult↗
PubMed1994

Effects of ondansetron in the prevention of postoperative nausea and vomiting in children.

BACKGROUND: Postoperative nausea and vomiting (PONV) is a commonly observed adverse effect of general anesthesia. Recently, ondansetron, a new serotonin3 (5-hydroxytryptamine3) receptor antagonist was shown to be effective in the prophylaxis and prevention of chemotherapy-induced nausea and vomiting in children and adults as well as of PONV in adults. The aim of the current study was to evaluate the capacity of ondansetron to prevent PONV in pediatric patients. METHODS: Two hundred children (132 boys and 68 girls) 2-10 yr of age received general inhalational anesthesia for surgical procedures (the extremities; ear, nose, and throat; inguinal hernia and phimosis; and dentistry) of an expected duration of less than 90 min. This study was divided into two phases: prophylaxis and rescue treatment. For prophylaxis, patients were randomly assigned to two groups: one group received an intravenous injection of 0.1 mg/kg ondansetron, and the other group received a placebo before surgical incision under double-blind conditions. For rescue treatment, only placebo patients were included; as a rescue medication they received an intravenous injection of 0.1 mg/kg ondansetron or 0.02 mg/kg droperidol according to a prestudy randomization under double-blind conditions. Incidence and severity of PONV (PONV score 0 = no nausea and no retching; 1 = complaining of sickness and retching; 2 = vomiting one or two time in 30 min; 3 = vomiting more than two times in 30 min) was recorded over a 4-h period in the postanesthesia care unit. Within 72 h of the procedure, a follow-up nurse interviewed the parents for late-onset nausea in the children. RESULTS: With regard to prophylaxis, 10% of patients receiving ondansetron had PONV during the 4-h observation period versus 40% of those receiving placebo (P < 0.001). The incidence of vomiting alone (PONV score > or = 2) was 5% and 25%, respectively (P < 0.001). There were no significant differences between ondansetron and droperidol in the treatment of PONV. However, at the end of the 4-h period, ondansetron patients were less sedated than were patients who had received droperidol (P < 0.01). Interviews with parents could be performed for 143 of 200 children (76 ondansetron and 67 placebo). Twenty-four children (15 ondansetron and 9 placebo) showed late-onset PONV after the 4-h observation period but within 24 h of the procedure (19.7% vs. 13.4%; P not significant). CONCLUSIONS: Ondansetron is effective in the prevention of PONV in pediatric patients for the first 4 h after general anesthesia. Lower sedation scores with ondansetron compared with droperidol may be an advantage, especially in ambulatory surgery. However, the incidence of late-onset PONV (> 4-24 h) was not influenced by prophylactic treatment with one dose of ondansetron preoperatively.

Anesthesia, General↗
PubMed1993

In vitro effect of ephedrine, adrenaline, noradrenaline and isoprenaline on halothane-induced contractures in skeletal muscle from patients potentially susceptible to malignant hyperthermia.

We have measured the effects of ephedrine, adrenaline, noradrenaline and isoprenaline on halothane-induced contractures in muscle biopsies from patients potentially susceptible to malignant hyperthermia (MH). At concentrations of 4-24 mmol litre-1, ephedrine induced in vitro contractures in halothane 0.44 mmol litre-1-prechallenged muscle, whilst adrenaline, noradrenaline and isoprenaline had no effect. There was a shift of the ephedrine concentration-response curve to the left and an increased maximum muscle contracture in the MH susceptible group compared with the MH negative group (P < 0.001). We conclude that ephedrine increased halothane-induced muscle contractures in vitro either by an unknown pharmacological mechanism or by an adrenergic stimulation which was different from those of the other investigated adrenoceptor agonists.

Dose-Response Relationship, Drug↗
PubMed1993

Effects of three different types of management on the elimination kinetics of volatile anaesthetics. Implications for malignant hyperthermia treatment.

The effectiveness of three types of management on the elimination kinetics of volatile anaesthetics was studied prospectively in 45 patients randomised to one of three groups. Patients were anaesthetised using isoflurane. Inspiratory and expiratory isoflurane concentrations were measured. After reaching a steady-state isoflurane concentration, the vaporizer was turned off. In group 1, only the fresh gas flow was increased from 40 to 120 ml.kg-1 x min-1. Patients in group 2, in addition to the increase in the fresh gas flow, had a charcoal filter connected in the inspiratory limb of the circuit. Patients in group 3 had the fresh gas flow increased and the anaesthetic machine and breathing system changed. There was a statistically significant difference in the isoflurane washout from the anaesthetic machines between group 1 (90% elimination time 39 [10] s) and group 2 (90% elimination time 25 [5] s) (p < 0.01). However, there was no significant difference in the isoflurane washout from the patients in any of the groups. Thus the use of a charcoal filter or a change of the anaesthetic machine and breathing system proved to be of no clinical advantage.

Adult↗