[Further education in anesthesiology. Implementation at the University Hospital Hamburg-Eppendorf]. / Weiterbildung in der Anästhesiologie. Umsetzung am Universitätsklinikum Hamburg-Eppendorf.

Due to the lack of physicians and the changing demands of junior staff more attractive curricula are needed in anesthesiology in Germany. In the German Society of Anesthesiology and Intensive Care Medicine as well as the Association of German Anesthesiologists discussions on the optimization of training have a long tradition. The following article gives a description of the concept and the practical approach to the training curricular at the University Hospital Hamburg-Eppendorf and is designed to stimulate discussion on possible concepts for training in anesthesiology.

Influence of resident training on anaesthesia induction times.

BACKGROUND: The effect of resident training in anaesthesiology on operating room (OR) economics is an issue of debate. Comparisons of anaesthesia process times between residents and consultants might be systematically skewed by interactions of anaesthesia technique and patient factors. METHODS: In this prospective, observational study, we analysed anaesthesia process times in 599 cases performed for four different surgical services in a University hospital. The following factors were recorded for each case and used in multivariate analyses of process times: age, American Society of Anesthesiologist (ASA) status, BMI, emergency status, the educational level of the anaesthetist, and the anaesthesia technique. RESULTS: In the non-adjusted comparison, only for two of seven anaesthetic techniques did resident cases have statistically significant longer induction times than consultant cases: general anaesthesia with placement of a central venous catheter [mean (sd) anaesthesia time for resident cases 38.2 (17.0) vs 22.3 (10.0) min for consultant cases, P=0.001] and general anaesthesia with a laryngeal mask airway [resident cases 11.3 (5.5) vs consultant cases 7.3 (5.0) min, P=0.003]. Anaesthetic technique had the greatest effect on anaesthesia induction time. Educational level of the anaesthetist and age of the patients had small, but significant effects. CONCLUSIONS: Anaesthesia cases performed by residents have in some, but not in all, anaesthesia techniques increased process times compared with cases performed by consultants. This limits a possible negative impact on OR economics by resident education. Patient-based factors including ASA status, BMI, and emergency status have minimal or no effect on anaesthesia process times.

5-HT2 receptor antagonist-mediated inhibition of halothane-induced contractures in skeletal muscle specimens from malignant hyperthermia susceptible patients.

Administration of 5-HT2 receptor agonists induced malignant hyperthermia (MH) in susceptible pigs. Furthermore, the 5-HT2 receptor antagonist ritanserin prevented 5-HT-induced porcine MH. It has been shown that 5-HT2 receptor agonists induce marked contractures in skeletal muscle specimens from MH susceptible (MHS) but not in specimens from normal patients. The purpose of this study was to investigate the effects of ritanserin on halothane-induced contractures in muscle specimens from MHS patients. Twenty-five patients aged 8-56 years (29.5+/-13.6) classified as MHS by the in vitro contracture test (IVCT) with halothane and caffeine according to the protocol of the European MH Group participated in this study. Muscle specimens were pretreated with ritanserin 10 micromol/l (n= 14), 20 micromol/l (n=14) and 100 micromol/l (n=12) for 10 min and subsequently halothane was added incrementally (0.11-0.22-0.44 mmol/l) to the tissue bath as described in the European MH protocol. The results of the halothane contracture test were used as control. Following administration of halothane, muscle contractures reached a maximum of 16.9+/-4.2 mN. Ritanserin led to a significant inhibition of halothane-induced contractures in MHS muscles. Following pretreatment with ritanserin, halothane-induced contracture maximum was significantly smaller with 7.5+/-3.1 mN after 10 micromol/l ritanserin, 4.9+/-1.5 mN after 20 micromol/l ritanserin and 0.5+/- 0.2 mN after 100 micromol/l ritanserin than without pretreatment. Administration of ritanserin induced at all concentrations a decrease in muscle twitch height. Increase in muscle twitch following halothane was reduced in a concentration-dependent manner by ritanserin. The presented findings indicate that 5-HT might be involved in the mechanisms of halothane-induced MH in humans. Further studies have to determine the pathophysiological role of the 5-HT system in MH, and whether ritanserin could be an alternative for treatment or prevention of halothane-induced MH.

Effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible patients.

STUDY OBJECTIVES: To study the in vitro effects of the phosphodiesterase-III inhibitor enoximone on skeletal muscle specimens from malignant hyperthermia susceptible (MHS) and normal (MHN) patients. DESIGN: Prospective study. SETTING: Malignant hyperthermia (MH) laboratory at a university hospital. PATIENTS: 47 patients with clinical suspicion for MH undergoing in vitro contracture test (IVCT) for diagnosis of MH susceptibility. INTERVENTIONS: Biopsies of M. quadriceps femoris were performed in adult patients with a 3-in-1 nerve block and in children with trigger-free general anesthesia. MEASUREMENTS AND MAIN RESULT: Patients were first classified as MHS or MHN by the IVCT according to the protocol of the European MH Group (EMHG). Patients with equivocal results (MHE) or with neuromuscular diseases were excluded from the study. Enoximone was added to the organ bath to surplus vital muscle specimens in single bolus concentrations of 0.4, 0.6, 0. 8, or 1.6 mmol/L. The in vitro effects of enoximone on muscle contractures and twitch were measured. Seventeen patients were classified as MHS and 30 as MHN by the EMHG criteria. Enoximone induced contractures in skeletal muscles in a dose-dependent manner. Contractures of MHS compared to MHN muscle specimens were significantly larger at all concentrations used in this study. No overlap in maximum contractures was seen between MHS and MHN muscles at a bath concentration of 0.6 mmol/L enoximone only. CONCLUSIONS: Diagnosis of MH by an IVCT test with a single bolus administration of enoximone seems to be possible using a concentration of 0.6 mmol/L. The findings of this study may indicate an involvement of the phosphodiesterase-III and cAMP system in pathogenesis of MH. Further in vivo investigation should determine the trigger potency of enoximone in MH susceptible individuals.

[Key performance indicators of OR efficiency. Myths and evidence of key performance indicators in OR management]. / Kennzahlen der OP-Effizienz. Mythos und Evidenz der Steuerungskennzahlen im OP-Management.

A variety of different key performance indicators, both for process and financial performance, are used to evaluate OR efficiency. Certain indicators like OR utilization and turnover times seem to become common standard in many hospitals to evaluate OR process performance. Despite the general use and availability of these indicators in OR management, the scientific evidence behind these data is relatively low. These process indicators are strongly influenced by artefacts and depend on planning process, resource allocation and documentation. Direct financial indicators become more important with increasing autonomy of OR management. Besides budgetary compliance the focus is set on the net results of internal transfer pricing systems. By taking part in an internal transfer pricing system, OR management develops from a mere passive cost center to an active shaper of perioperative processes. However, detailed knowledge of the origin of costs and pitfalls of internal transfer pricing systems is crucial. The increased transparency due to the free accessibility of diagnosis-related-groups (DRG) cost breakdown data can help to develop tools for economic analysis of OR efficiency.

[Utilization rates and turnover times as indicators of OR workflow efficiency]. / Auslastung und Wechselzeit als Kennzahlen der OP-Effizienz.

BACKGROUND: In many hospitals operating room (OR) utilization rates and turnover times (the time from the end of the previous surgical procedure to the beginning of the next) are used as indicators of OR workflow inefficiency. However, there have been no detailed studies to determine whether these indicators really provide an adequate picture of avoidable wasting of time in the OR. METHODS: All relevant OR processes in a busy surgical suite with nine ORs were studied in detail over an 8-week period. Productive OR processes, and also reasons for unused times, were recorded by independent observers at 5-minute intervals; they were able to code for 10 different productive activities and 20 different reasons for unused time. Unused time in the OR, the OR utilization rate and the average perioperative turnover times were calculated for each day and a correlation analysis was performed. RESULTS: In all, 3,501 OR hours and 790 surgical cases were studied. Productive processes accounted for 85.7% of the total OR time; the unused times were times with no scheduled cases (7.7%) and waiting times that arose for many different reasons (6.6%). Correlation analysis showed that there was no close correlation between waiting time and OR utilization (Spearman's r(s) 0.104 and r(s) 0.233). The correlations between total unused time (r(s) 0.718 and r(s) 0.745) and time with no scheduled cases (r(s) 0.706 and r(s) 0.620) and utilization were more robust, but for any given OR utilization rate the range of corresponding unused time or time without scheduled cases per day was considerable. The correlation between waiting time and perioperative turnover times was negligible (r(s) 0.185 and r(s) 0.175). When different definitions of utilization rate or perioperative turnover were used the results obtained were virtually identical. CONCLUSIONS: Utilization rate and perioperative turnover time cannot be used as indicators of OR workflow efficiency, since they cannot identify the days during which avoidable waiting times occur. If the aim is to identify underused OR time and factors that hamper workflow efficiency, waiting times and times without scheduled cases need to be recorded directly and separately.

[The new regulations for the licence to practice medicine. Implementation for the faculty of anesthesiology at the University Clinic Hamburg-Eppendorf]. / Die neue Approbationsordnung für Arzte. Umsetzung für das Fach Anästhesiologie am Universitätsklinikum Hamburg-Eppendorf.

After the amendments to the regulations for the licence to practice medicine, the rating of the faculty of anesthesiology has clearly increased. In the following article a concept will be described whereby these standards were implemented at the University of Hamburg. The basic principle, especially the training in the practical proficiencies, is to achieve a continuous learning process from students through to specialists for anesthesiology.

Phosphodiesterase-III-inhibition with amrinone leads to contracture development in skeletal muscle preparations of malignant hyperthermia susceptible swine.

BACKGROUND AND OBJECTIVE: The phosphodiesterase-III (PDE-III) inhibitor enoximone-induced marked contractures in skeletal muscle specimens of malignant hyperthermia (MH) susceptible (MHS) human beings and swine. Whether this is a substance specific effect of enoximone or caused by inhibition of PDE-III remained unclear. Therefore, the effects of the PDE-III inhibitor amrinone in porcine MH normal (MHN) and MHS skeletal muscles were investigated. METHODS: MH-trigger-free general anaesthesia was performed in eight MHS and eight MHN swine. The MH status of the swine was determined by detection of the Arg615-Cys point mutation on chromosome 6 indicating MH susceptibility. Skeletal muscle specimens were excised for the in vitro contracture tests with amrinone. Amrinone was added cumulatively every 5 min to muscle specimens in order to obtain organ bath concentrations between 20 and 400 micromol L(-1). The in vitro effects of amrinone on muscle contractures and twitches were measured. RESULTS: Amrinone-induced contractures in all skeletal muscle preparations. MHS muscles developed contractures at significantly lower bath concentrations of amrinone than MHN muscles. Contractures of MHS compared to MHN muscles were significantly larger at bath concentrations of 80, 100, 150, 200 and 400 micromol L(-1) amrinone. Muscle twitches remained unchanged up to and including 200 micromol L(-1) amrinone. CONCLUSIONS: Inhibition of PDE-III in general elicited higher contractures in MHS than in MHN muscles. Therefore, a contribution of PDE-III and the cyclic adenosine monophosphate (cAMP) system in the pathophysiology of MH must be suspected.

Dantrolene--a review of its pharmacology, therapeutic use and new developments.

Human malignant hyperthermia is a life-threatening genetic sensitivity of skeletal muscles to volatile anaesthetics and depolarizing neuromuscular blocking drugs occurring during or after anaesthesia. The skeletal muscle relaxant dantrolene is the only currently available drug for specific and effective therapy of this syndrome in man. After its introduction, the mortality of malignant hyperthermia decreased from 80% in the 1960s to < 10% today. It was soon discovered that dantrolene depresses the intrinsic mechanisms of excitation-contraction coupling in skeletal muscle. However, its precise mechanism of action and its molecular targets are still incompletely known. Recent studies have identified the ryanodine receptor as a dantrolene-binding site. A direct or indirect inhibition of the ryanodine receptor, the major calcium release channel of the skeletal muscle sarcoplasmic reticulum, is thought to be fundamental in the molecular action of dantrolene in decreasing intracellular calcium concentration. Dantrolene is not only used for the treatment of malignant hyperthermia, but also in the management of neuroleptic malignant syndrome, spasticity and Ecstasy intoxication. The main disadvantage of dantrolene is its poor water solubility, and hence difficulties are experienced in rapidly preparing intravenous solutions in emergency situations. Due to economic considerations, no other similar drugs have been introduced into routine clinical practice.

[Theophylline induces contractures in porcine skeletal muscle preparations with the disposition to malignant hyperthermia]. / Theophyllin induziert Kontrakturen an Skelettmuskelpräparaten des Schweines mit Disposition zu Maligner Hyperthermie.

OBJECTIVE: Theophylline, a methylxanthine, leads to an increase of the cytoplasmic Ca(2+)-concentration in the muscle cell. Since the in-vitro contracture test (IVCT) with halothane and caffeine does not distinguish a 100% between malignant hyperthermia susceptible (MHS) and non-susceptible (MHN), we examined the in-vitro effects of theophylline in porcine skeletal muscle preparations. METHODS: After approval by the local animal care committee ten MHS- and nine MHN-swine were anaesthetized and muscle biopsies taken. For IVCT, muscle specimens were exposed to bolus administrations of theophylline in concentrations of 3.0 respectively 5.0 mmol/l. Muscle contracture development and twitch amplitudes were recorded over a period of 30 minutes. Data are expressed as medians and ranges. RESULTS: After both theophylline bolus administrations MHS-muscles developed significantly higher contractures compared to the MHN-specimens. The MHS-muscles reached a maximum contracture of 17.0 mN (7.2-59.6 mN) after administration of 3.0 mmol/l theophylline. In comparison, two MHN-specimens showed weak contractures with a maximum of 1.4 mN. The 5.0 mmol/l theophylline IVCT resulted in maximum contractures of 19.1 mN (2.1-39.2 mN) for the MHS-preparations. Just in three MHN-muscles weak contractures of 0.0 mN (0.0-0.8 mN) were recorded. Thus, a significant difference without overlap was revealed for the maximum contracture. CONCLUSION: Theophylline in concentrations of 3.0 and 5.0 mmol/l revealed a clear difference between MHS- and MHN-porcine muscle preparations. Further examinations on human skeletal muscles are needed to demonstrate the value of theophylline in the IVCT MH-diagnosis.

[Dantrolene. Pharmacological and therapeutic aspects]. / Dantrolen. Pharmakologische und therapeutische Aspekte.

Malignant hyperthermia (MH) is a genetic, potentially life-threatening disorder of the skeletal muscle presenting during or following general anaesthesia. Trigger agents are volatile anaesthetics and depolarising muscle relaxants. Dantrolene is the only available drug for effective and specific MH therapy, which reduces significantly the mortality rate. Dantrolene is a skeletal muscle relaxant that depresses the excitation-contraction coupling,however, the specificity of action remains unknown. Recent studies identified the ryanodine receptor, the calcium release channel of the sarcoplasmic reticulum, as the direct molecular target of dantrolene. In addition to its use for MH, dantrolene is used in other disorders such as neuroleptic malignant syndrome and spasticity. Since dantrolene is weakly water soluble, the clinical preparation is time and manpower consuming. New agents have been synthesized, but because of economic considerations no registration for clinical usage has been realised.

[Malignant neuroleptic syndrome after haloperidol administration]. / Malignes neuroleptisches Syndrom nach Haloperidolapplikation.

The neuroleptic malignant syndrome (NMS) is a rare complication of antipsychotic therapy. We report on a 65-year-old patient who was treated with haloperidol, diazepam and mirtazapin because of a severe depressive episode with psychotic symptoms. He exhibited most of the signs and symptoms characteristic of NMS, e.g.: hyperthermia, rigidity, elevated creatine phosphokinase, leukocytosis, elevated liver enzymes, reduced consciousness and autonomic nervous system disturbances. A secondary pneumonia was diagnosed 2 days after the onset of the NMS, which might have been due to chest wall rigidity. Intensive care treatment consisted of immediate discontinuation of the offending agent, supportive therapy with rehydratation and catecholamines as well as application of dantrolen. After 23 days of intensive therapy all pathological parameters were normalised and the patient was transferred to an internal ward. Three main theories on the pathogenesis of NMS exist: 1. blockade of central receptors, 2. a skeletal muscle target model and 3. sympathoadrenal hyperactivity. The differential diagnosis includes among others malignant hyperthermia and serotonin syndrome.

[Evaluation of malignant hyperthermia episodes with the Clinical Grading Scale]. / Evaluierung von Maligne-Hyperthermie-Episoden mit der Clinical Grading Scale.

PURPOSE: The Clinical Grading Scale (CGS) was introduced to predict malignant hyperthermia (MH) susceptibility in adverse anaesthetic events. Because many of the clinical symptoms that occur during MH episodes are nonspecific, the CGS was designed as a tool to estimate the qualitative likelihood of MH. The purpose of this study was to compare the results of the CGS with the established in vitro contracture test (IVCT). METHODS: 92 patients with a personal history for MH were tested for MH susceptibility with the IVCT according to the protocol of the European MH Group. All patients were also evaluated with the CGS. Clinical indicators for the CGS are rigidity, muscle breakdown, respiratory acidosis, temperature increase and cardiac involvement. There are additional indicators in case of a family history for MH. For each indicator 3-15 points are added to build a raw score; this raw score corresponds to a MH rank in the CGS that describes the likelihood of MH in the suspected event. The higher the raw score rank, the higher the likelihood of MH and vice versa. RESULTS: From 92 patients, 32 (35%) were diagnosed as MH-susceptible (MHS) with the IVCT, 47 (51%) were MH-normal (MHN), and 13 (14%) were MH-equivocal (MHE). One patient with MH-rank 1 (MH almost never) in the CGS was diagnosed as MHS; on the other hand no patient with MH-rank 6 (MH almost certain) in the CGS was diagnosed as MHN. However, the majority of patients (72%) were assigned to ranks 3 and 4 (MH somewhat less than likely/MH somewhat greater than likely). The qualitative likelihood of MH could therefore not be clearly estimated. CONCLUSION: Our study shows that the MH-rank of the CGS corresponds poorly with the results of the IVCT. In any case the evaluation of an MH suspicious event depends on the availability of data of that event. It is often difficult to obtain sufficient data, especially if the event occurred a long while ago. In these cases the MH rank may underestimate the likelihood of MH susceptibility. On the other hand, overestimation is also possible because some of the scoring indicators depend on the anaesthesiologist's judgement only. At present, the use of the CGS is neither validated nor clinically feasible. The CGS cannot replace IVCT.

[In-vitro-effects of cocaine in skeletal muscle specimens of patients susceptible to malignant hyperthermia]. / In-vitro-Effekte von Kokain an Skelettmuskelpräparaten von Patienten mit Veranlagung zuMaligner Hyperthermie.

OBJECTIVE: The abuse of cocaine can cause serious medical complications like tachycardia, rhabdomyolysis, and hyperthermia. Because of the clinical similarities, it has been suggested that cocaine might be a trigger of malignant hyperthermia (MH). Therefore, aim of this study was to investigate the in-vitro effects of cocaine in skeletal muscle specimens of MH susceptible (MHS) and normal (MHN) patients. METHODS: 62 patients undergoing the in-vitro contracture test (IVCT) according to the protocol of the European MH Group (EMHG) for diagnosis of MH susceptibility were included in this study. In muscle specimens surplus to diagnostic requirements cocaine was added in order to achieve tissue bath concentrations of 0.01, 0.1 and 1.0 mM. The contracture development and twitch response have been registered. RESULTS: 21 patients were diagnosed as MHS and 36 patients as MHN. 5 patients tested as MH-equivocal (MHE) were excluded from the study. Following bolus administration of cocaine, no contracture development was observed in MHS, as well as MHN specimens. The muscle twitch decreased after cocaine administration significantly in both diagnostic groups. CONCLUSION: In contrast to the established MH trigger substances like volatile anaesthetics, cocaine produced no contracture development in MHS muscle specimens. Furthermore, cocaine produced a negative inotropic effect in all skeletal muscle preparations, which might be explained by local anaesthetic effects. Regarding these results, cocaine seems not to be a MH trigger agent.

Spin-directed stereoselectivity of carbonyl-alkene photocycloadditions

The concentration dependence of the Paterno-Buchi photocycloaddition of the two cyclic enolethers 2,3-dihydrofuran and 2,3-dihydropyran, respectively, with aromatic as well as aliphatic aldehydes was studied. For aliphatic aldehydes, a sharp transition from low to high diastereostereoselectivity was observed, indicating a switch from singlet to triplet photocycloaddition with different selectivity controlling mechanisms.

[Is a presymptomatic malignant hyperthermia in-vitro diagnosis with 4-chloro-3-ethyl phenol possible? A study using porcine skeletal preparations]. / Ist eine präsymptomatische Maligne Hyperthermie in-vitro Diagnostik mit 4-Chlor-3-Ethylphenol möglich? Eine Studie an Skelettmuskelpräparaten des Schweins.

OBJECTIVE: The diagnosis of malignant hyperthermia is currently performed with the in-vitro contracture test (IVCT) with halothane and caffeine. This test has a sensitivity of 99.0 % but only a specificity of 93.6 %. A cumulative IVCT with 4-chloro-3-ethyl-phenole (CEP) has recently been shown to differentiate between MH susceptible (MHS) and MH normal (MHN) swine. The pur-pose of this study was to investigate the ability of bolus CEP-applications to distinguish between porcine MHS- and MHN-muscle specimens using the IVCT. METHODS: After approval by the local animal care committee 8 MHS- and 8 MHN-swine were anaesthetized and muscle biopsies taken. For IVCT, muscle specimens were exposed to bolus administration of CEP in concentrations of 75 resp. 100 micro mol l (-1). Predefined parameters were: (1) onset time of the contracture development, (2) time to the achievement of the 2, 5 and 10 mN contracture level and (3) maximum contracture level. Data are expressed as medians and ranges. RESULTS: After 75 micro mol l (-1) CEP administration all MHS-muscles showed contractures after 0.5 min (0.2 min/0.9 min). The 2 mN contracture level was reached by all MHS-, the 5 mN level by four MHS- and the 10 mN level by one MHS-specimen. The maximum contracture was 5.3 mN (2.4 mN/12.9 mN). The onset time after 100 micro mol l (-1) CEP was registered as 0.3 min (0.1 min/0.7 min) in the MHS-preparations. Again, the 2 mN level was achieved by all MHS-specimens, the 5 mN level by 5 and the 10 mN level by one MHS-bundle. The maximum contracture was measured as 5.9 mN (2.8 mN/13.9 mN). In 7 MHN-specimens no contracture development was measured. After 75 micro mol l (-1) CEP one MHN-muscle showed a maximum contracture of 1.0 mN, after 100 micro mol l (-1) CEP one MHN-bundle demonstrated a maximum contracture of 1.1 mN. Hence, a significant difference between MHS and MHN without overlap was revealed with both CEP-concentrations in the onset time of contracture, in the 2 mN contracture level and the maximum contracture. CONCLUSION: Since a clear differentiation between MHS and MHN porcine specimens was achieved after bolus application of 75 and 100 micro mol l (-1) CEP, MH-diagnosis might be possible with a CEP-IVCT. It seems worthwhile to examine this hypothesis in men.

Attenuation of serotonin-induced contractures in skeletal muscle from malignant hyperthermia-susceptible patients with dantrolene.

BACKGROUND: Porcine malignant hyperthermia (MH) can be triggered by administration of certain serotonin2 receptor agonists. Pretreatment with dantrolene completely abolished serotonin-induced MH. The purpose of this study was to investigate the effects of the serotonin2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in skeletal muscle specimens from MH-susceptible (MHS) and MH-nonsusceptible (MHN) patients following pretreatment with dantrolene. METHOD: We used muscle specimens surplus to diagnostic requirements from 12 MHS and 13 MHN patients in this study. In the first experiment, DOI 0.02 mM was added to the organ bath. In the second experiment, muscle specimens were preincubated with dantrolene 0.5 microM or 1.0 microM, respectively, for 10 min before DOI 0.02 mM was administered. RESULTS: Administration of DOI 0.02 mM induced contractures in muscle specimens from MHS and MHN patients. Contracture development started significantly earlier in MHS than in MHN specimens. In MHS muscle the maximum contracture was significantly greater than in MHN. Pretreatment with dantrolene significantly delayed the start of contracture development in MHS muscles, whereas in MHN muscles no contractures were observed after dantrolene. The contracture maximum was significantly reduced in MHS. CONCLUSION: The acceleration of DOI-induced contracture development in skeletal muscle specimens from MHS patients indicates that an altered serotonin system might be involved in human MH. Dantrolene effectively delayed serotonin-induced contractures. Further investigations are needed to determine whether serotonin2 receptors of skeletal muscle from MHS subjects are altered in function or structure, or whether this response is a secondary phenomenon.

[4-chloro-m-cresol-induced contractures of skeletal muscle specimen from patients at risk for malignant hyperthermia]. / 4-Chloro-m-Cresol induziert Kontrakturen an Skelettmuskelpräparaten von Patienten mit Disposition zu maligner Hyperthermie.

PURPOSE: 4-chloro-m-cresol (4-CmC), commonly used as preservative, has been shown to induce contractures in skeletal muscle specimens from individuals susceptible to malignant hyperthermia (MH). It has been suggested that a defect of the calcium release channel of the skeletal muscle sarcoplasmic reticulum (ryanodine receptor) in MH susceptible (MHS) patients could be responsible for this phenomenon. 4-CmC was found to be a potent activator of ryanodine receptor-mediated Ca2+ release. The aim of this study was to determine the in vitro effects of 4-CmC on muscle specimens from MHS and normal (MHN) patients, and whether contracture testing with different concentrations of 4-CmC could result in a more precise discrimination between MHS and MHN. METHODS: In this prospective study muscle biopsies were obtained from 40 patients with clinical suspicion of MH. The patients were first classified by the in vitro contracture test (IVCT) according to the European MH protocol. After MH classification, surplus muscle specimens were subjected to the 4-CmC study. RESULTS: Cumulative administration of 4-CmC (25, 50, 75, 100, 150, and 200 mumol/l) produced contractures in a concentration-dependent manner. However, contractures developed significantly earlier and were greater in MHS (n = 17) than in MHN specimens (n = 23). After bolus administration of 50, 75, and 100 mumol/l 14-CmC MHS specimens developed distinct muscle contractures. In contrast, in MHN specimens only 100 mumol/l 4-CmC produced contractures. All contracture levels following bolus administration of 100 mumol/l 4-CmC were attained significantly earlier in MHS than in MHN. There was no overlapping in the range of times between both groups. CONCLUSION: In vitro contracture testing with 4-CmC seems to be a specific method to distinguish between MHS and MHN patients. However, the question whether 4-CmC is an MH-triggering agent is not completely solved. 4-CmC is a preservative within a large number of commercially available preparations (e.g. insulin, hormones, etc.). Regarding the results of contracture testing with 4-CmC it has been suggested that 4-CmC possibly represents a high-risk agent for MHS individuals. To reduce the risk of MH in susceptible patients due to administration of chlorocresols, we recommend avoiding preparations containing the preservative 4-CmC.

4-chloro-m-cresol is a trigger of malignant hyperthermia in susceptible swine.

BACKGROUND: 4-Chloro-m-cresol (4-CmC) induces marked contractures in skeletal muscle specimens from individuals susceptible to malignant hyperthermia (MHS). In contrast, 4-CmC induces only small contractures in specimens from normal (MHN) patients. 4-CmC is a preservative within a large number of commercially available drug-preparations (e.g., insulin, heparin, succinylcholine), and it has been suggested that 4-CmC might trigger malignant hyperthermia. This study was designed to investigate the effects of 4-CmC in vivo and in vitro in the same animals. METHODS: After approval of the animal care committee, six Pietrain MHS and six control (MHN) swine were anesthetized with azaperone 4 mg/kg intramuscularly and metomidate 10 mg/kg intraperitoneally. After endotracheal intubation, lungs were mechanically ventilated (inspired oxygen fraction 0.3) and anesthesia was maintained with etomidate 2.5 mg x kg(-1) x h(-1) and fentanyl 50 microg x kg(-1) x h(-1). Animals were surgically prepared with arterial and central venous catheters for measurement of hemodynamic parameters and to obtain blood samples. Before exposure to 4-CmC in vivo, muscle specimens were excised for in vitro contracture tests with 4-CmC in concentrations of 75 and 200 microM. Subsequently, pigs were exposed to cumulative administration of 3, 6, 12, 24, and 48 mg/kg 4-CmC intravenously. If an unequivocal episode of malignant hyperthermia occurred, as indicated by venous carbon dioxide concentration > or = 70 mmHg, pH < or = 7.25, and an increase of temperature > or = 2 degrees C, the animals were treated with dantrolene, 3.5 mg/kg. RESULTS: All MHS swine developed malignant hyperthermia after administration of 4-CmC in doses of 12 or 24 mg/kg. Venous carbon dioxide concentration significantly increased and pH significantly decreased. Temperature increased in all MHS animals more than 2 degrees C. Blood lactate concentrations and creatine kinase levels were significantly elevated. All MHS swine were treated successfully with dantrolene. In contrast, no MHN swine developed signs of malignant hyperthermia. After receiving 4-CmC in a concentration of 48 mg/kg, however, all MHN animals died by ventricular fibrillation. The in vitro experiments showed that both concentrations of 4-CmC produced significantly greater contractures in MHS than in MHN specimens. CONCLUSIONS: 4-CmC is in vivo a trigger of malignant hyperthermia in swine. However, the 4-CmC doses required for induction of malignant hyperthermia were between 12 and 24 mg/kg, which is about 150-fold higher than the 4-CmC concentrations within clinically used preparations.

[Diagnosis of susceptibility to malignant hyperthermia with an in vitro contracture test with the phosphodiesterase iii inhibitor enoximone]. / Diagnostik der Disposition zur malignen Hyperthermie durch einen in vitro Kontrakturtest mit dem Phosphodiesterase-III-Hemmstoff Enoximon.

PURPOSE: Inhibition of phosphodiesterase III (PDE-III) by enoximone elevates cyclic AMP (cAMP) content and intracellular calcium in human cardiac muscle. An involvement of cAMP in the pathogenesis of malignant hyperthermia (MH) has been suggested, because a higher basal content of cAMP was found in skeletal muscles from MH susceptible (MHS) than in normal (MHN) individuals and swine. In this study the in vitro effects of enoximone on skeletal muscles and the possibility to distinguish MHS from MHN patients were investigated. METHODS: Muscle biopsies from 37 patients with clinical suspicion for MH were obtained. The patients were first classified as MHS, MHE (equivocal result) or MHN by the caffeine halothane contracture tests according to the procedure of the European MH Group (EMHG). MHE-patients and patients with neuromuscular diseases were excluded from the study. Enoximone was added cumulatively every five minutes to surplus muscle specimens to obtain organ bath concentrations of 0.2, 0.4, 0.6, 0.8, 1.2 and 1.6 mmol/l. The in vitro effects of enoximone on muscle contractures and twitch were measured. RESULTS: Twelve patients were classified as MHS and 21 as MHN by the EMHG criteria. Enoximone induced contractures in skeletal muscles from all patients. MHS muscles developed contractures at significantly lower bath concentrations of enoximone than MHN muscles. Contractures of MHS compared to MHN muscles were significantly larger at bath concentrations of 0.4, 0.6, 0.8 and 1.2 mmol/l enoximone. No overlap in maximum contractures was seen between MHS and MHN muscles at bath concentrations of 0.6 and 0.8 mmol/l enoximone. Muscle twitch increased in both groups after administration of enoximone. CONCLUSION: The PDE-III-inhibitor enoximone induces contracture development in skeletal muscles. These contractures were attained at lower concentrations and were larger in MHS compared to MHN muscles. In vitro diagnosis of MH by a contracture test with enoximone appears to be possible. Furthermore, regarding these results a trigger potency for MH by enoximone could not be proved, but the use of enoximone in MHS patients might be dangerous.