Mark U. Gerbershagen

Induction of malignant hyperthermia in susceptible swine by 3,4-methylenedioxymethamphetamine ("ecstasy").

Background 3,4-Methylenedioxymethamphetamine (MDMA, “ecstasy”) can mediate acute toxic effects such as muscle rigidity, metabolic acidosis, and hyperthermia. Because of close clinical similarities, an association between MDMA intoxication and malignant hyperthermia (MH) was suggested. The aim of this study was to investigate whether MDMA is a trigger of MH in susceptible swine. Methods MH-nontriggering general anesthesia was performed in six MH-susceptible (MHS) and six MH-normal swine. The animals were exposed to MDMA in cumulative doses of 0.5, 1, 2, 4, 8, and 12 mg/kg. The clinical occurrence of MH was defined by achievement of two of three conditions: central venous Pco2 ≥75 mmHg, central venous pH ≤ 7.20, and increase of body core temperature ≥ 2.0°C. Once MH occurred, a standardized therapy with dantrolene, sodium bicarbonate, and hyperventilation with 100% oxygen was initialized. Results Administration of 8 mg/kg MDMA triggered MH in all MHS swine. The MH-normal swine also developed clinical signs of hypermetabolism, but even after administration of 12 mg/kg MDMA, changes were moderate compared with the MHS swine. Dantrolene therapy of MDMA-induced MH crisis in the MHS swine partially counteracted the clinical signs of MH immediately. Conclusions MDMA induces MH in genetically susceptible swine in relevant doses. Therefore, MHS patients should avoid use of MDMA or related drugs. Patients with a personal or family history of MDMA-induced hyperthermia should be tested for a diagnosis of MH susceptibility. Dantrolene is effective in therapy of MDMA-induced porcine MH.

Pain Prevalence and Risk Distribution Among Inpatients in a German Teaching Hospital

ObjectivesThis study was designed to provide a cross-sectional analysis of pain prevalence, chronicity, and severity as well as the impact of pain on psychological and social variables in inpatients in various departments of a German teaching hospital. MethodsPatients were asked to complete a questionnaire including sections on sociodemographic and socioeconomic data, pain variables, recent and past health care utilization, and screening questionnaires for depression, anxiety, and health-related quality of life. ResultsOf the 438 patients, 386 (88.1%) had experienced pain in the past 12 months; 367 (83.8%) reported having pain in the previous 3 months. Sixty-four percent of the pain patients stated that pain was the main reason for hospital admission; 48% reported having three or more pain sites. The most common location of pain was the back (26.9%). Pain patients showed significantly higher depression and anxiety scores and markedly reduced physical health when compared to non-pain patients. DiscussionThe results of this study indicate that in most medical disciplines pain is more than merely a symptom of disease. In many instances pain should be considered a serious comorbidity that can influence the outcome of medical and surgical treatment. Recent research has shown that prevention of the pain chronification process is the most promising strategy for avoiding the development of intractable pain. Acceptance, recognition, and assessment of pain as a risk factor at an early stage are essential factors. A first step might involve routine screening for pain on admission to any hospital facility, and subsequently evaluating the impact of pain on biopsychosocial functions.

Results of contracture tests with halothane, caffeine, and ryanodine depend on different malignant hyperthermia-associated ryanodine receptor gene mutations.

Background More than 20 mutations in the gene encoding for the ryanodine receptor (RYR1), a Ca2+ release channel of the skeletal muscle sarcoplasmic reticulum, have been found to be associated with malignant hyperthermia (MH). This study was designed to investigate the effects of different mutations in the RYR1 gene on contracture development in in vitro contracture tests (IVCT) with halothane, caffeine, and ryanodine. Methods Ninety-three MH-susceptible (MHS) patients, diagnosed by the standard IVCT with halothane and caffeine, were included in this prospective study. Surplus muscle specimens were used for an IVCT with 1 &mgr;m ryanodine. The contracture course during the ryanodine IVCT was described by the attainment of different time points: onset time of contracture and times when contracture reached 2 mN or 10 mN. In addition, all patients were screened for mutations of the RYR1 gene. Results In 36 patients, four different mutations of the RYR1 gene (C487-T, G1021-A, C1840-T, G7300-A) were found. The IVCT threshold concentrations of halothane and caffeine were lower in patients with the C487-T mutation compared with patients without a detected mutation in the RYR1 gene. In the IVCT with ryanodine, contracture levels of 2 mN and 10 mN were reached earlier in muscle specimens from patients with C487-T, C1840-T, and G7300-A mutations compared with specimens from patients with the G1021-A mutation and patients without detected mutation in the RYR1 gene. Conclusions The differences between the groups in the halothane and caffeine IVCT threshold concentrations and in the time course of contracture development in the ryanodine IVCT underline the hypothesis that certain mutations in the RYR1 gene could make the ryanodine receptor more sensitive to specific ligands. This may be an explanation for varying clinical symptoms of MH crisis in humans.

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 μmol 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 μmol L−1 amrinone. Muscle twitches remained unchanged up to and including 200 μmol 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.

Malignes neuroleptisches Syndrom nach Haloperidolapplikation

ZusammenfassungDas maligne neuroleptische Syndrom (MNS) stellt eine schwerwiegende Komplikation der Therapie mit antipsychotischen Pharmaka dar. Wir berichten über einen 65-jährigen Patienten, der zur Therapie einer schweren depressiven Episode mit psychotischen Symptomen mit Haloperidol, Diazepam und Mirtazapin eingestellt wurde. Er entwickelte viele der MNS definierenden bzw. assoziierten Zeichen und Symptome: Hyperthermie, Rigor, erhöhte Kreatinphosphatkinase, Leukozytose, erhöhte Leberenzyme, eingeschränktes Bewusstsein und vegetative Störungen. Zwei Tage nach Beginn des MNS war eine sekundäre Pneumonie festzustellen, die sich aufgrund einer Brustwandrigidität entwickelt haben könnte. Die intensivmedizinische Behandlung beinhaltete das sofortige Absetzen des auslösenden Agens, die supportive Therapie mit Rehydratation und Katecholaminen sowie die Applikation von Dantrolen. Nach 23-tägiger Intensivtherapie waren alle pathologischen Werte normalisiert und der Patient wurde auf eine internistische Station überwiesen. Drei bedeutende Theorien der Pathogenese wurden aufgestellt: 1. Blockade zentraler Rezeptoren; 2. Skelettmuskelzellen als primäres Zielsubstrat und 3. sympathoadrenerge Hyperaktivität. Die Differentialdiagnose beinhaltet u. a. maligne Hyperthermie und Serotoninsyndrom.AbstractThe 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.

Anaesthetic management of patients with myopathies

: The anaesthetic management of patients with myopathies is challenging. Considering the low incidence and heterogeneity of these disorders, most anaesthetists are unfamiliar with key symptoms, associated co-morbidities and implications for anaesthesia. The pre-anaesthetic assessment aims at the detection of potentially undiagnosed myopathic patients and, in case of known or suspected muscular disease, on the quantification of disease progression. Ancillary testing (e.g. echocardiography, ECG, lung function testing etc.) is frequently indicated, even at a young patient age. One must differentiate between myopathies associated with malignant hyperthermia (MH) and those that are not, as this has significant impact on preoperative preparation of the anaesthesia workstation and pharmacologic management. Only few myopathies are clearly associated with MH. If a regional anaesthetic technique is not possible, total intravenous anaesthesia is considered the safest approach for most patients with myopathies to avoid anaesthesia-associated rhabdomyolysis. However, the use of propofol in patients with mitochondrial myopathies may be problematic, considering the risk for propofol-infusion syndrome. Succinylcholine is contra-indicated in all patients with myopathies. Following an individual risk/benefit evaluation, the use of volatile anaesthetics in several non-MH-linked myopathies (e.g. myotonic syndromes, mitochondrial myopathies) is considered to be well tolerated. Perioperative monitoring should specifically focus on the cardiopulmonary system, the level of muscular paralysis and core temperature. Given the high risk of respiratory compromise and other postoperative complications, patients need to be closely monitored postoperatively.

3,4-Methylenedioxymethamphetamine induces a hyperthermic and hypermetabolic crisis in pigs with and without a genetic disposition for malignant hyperthermia.

Background Clinical symptoms of acute 3,4-methylenedioxymethamphetamine (MDMA) intoxication and malignant hyperthermia have many similarities. At present, however, there is contradictory evidence concerning the malignant hyperthermia trigger potency of MDMA. Objective This study was designed to investigate whether MDMA has malignant hyperthermia trigger potential and leads to malignant hyperthermia in pigs with or without a genetic predisposition to the condition. In addition, the therapeutic effectiveness of a new dantrolene sodium suspension was examined. Design Experimental study, using an animal model of Piétrain pigs. Settings Institute for Research in Operative Medicine, University of Witten/Herdecke, Hospital Cologne Merheim, Cologne, Germany, October 2006 to February 2007. Trigger-free anaesthesia was performed on seven malignant hyperthermia-susceptible and six malignant hyperthermia-normal Piétrain pigs, and cumulative doses of MDMA were administered to each animal. Interventions After achieving predefined malignant hyperthermia criteria, standardised therapy was initiated; dantrolene sodium suspension (5 mg kg−1) was administered and the injection was repeated after 24 min. Main outcome measures The malignant hyperthermia trigger potency of MDMA was analysed by monitoring pH, PaCO2 and temperature. In addition, concentrations of thyroid hormone, mitochondrial uncoupling protein 3, noradrenaline and free fatty acids during administration of MDMA and dantrolene sodium suspension were analysed. Results MDMA administration led to fulminant hypermetabolic and hyperthermic responses in malignant hyperthermia-susceptible and malignant hyperthermia-normal pigs, with significant decreases in pH (susceptible: pH 7.21 ± 0.11, normal: pH 7.21 ± 0.07), severe hypercapnia (susceptible: paCO2 10.3 ± 3.5 kPa, normal: paCO2 9.8 ± 1.7 kPa), and hyperthermia (susceptible: 40.6 ± 2.0°C, normal: 40.1 ± 0.4°C). There were no significant differences in changes in clinical and laboratory variables between groups. The dantrolene therapy regimen was effective in treating the MDMA-induced metabolic crises. Conclusion MDMA is not a classic trigger for the development of malignant hyperthermia reactions in pigs. MDMA intoxication leads to severe, long-lasting hyperthermia and hypermetabolism in both malignant hyperthermia-susceptible and hyperthermia-normal pigs, with life-threatening malignant hyperthermia-like symptoms which are responsive to supportive treatment and dantrolene sodium suspension.

Cumulative and bolus in vitro contracture testing with 4-chloro-3-ethylphenol in malignant hyperthermia positive and negative human skeletal muscles.

In this study we evaluated the in vitro effects of 4-chloro-3-ethylphenol (CEP) using cumulative (12.5–200 &mgr;mol/L) or bolus (75 and 100 &mgr;mol/L) administrations, on muscle specimens from malignant hyperthermia (MH) susceptible and MH nonsusceptible patients, respectively. In the cumulative CEP in vitro contracture test, contractures were significantly greater in the MH susceptible compared with the MH nonsusceptible muscles in all concentrations between 25 and 100 &mgr;mol/L. There was no overlap between the diagnostic groups at 75 &mgr;mol/L of CEP, so this test appears to be feasible for diagnosis of MH susceptibility. The two bolus tests are not diagnostically useful, as overlaps between the diagnostic groups were observed.

Inhibition of sarcoplasmic Ca2+ adenosine triphosphatase in porcine skeletal muscle samples with cyclopiazonic acid enables in vitro malignant hyperthermia discrimination.

IT is generally accepted that malignant hyperthermia (MH) susceptibility is caused by an abnormal Ca metabolism within the skeletal muscle cell. Ca homeostasis in skeletal muscles is regulated by two main receptors, the ryanodine receptor type I and the dihydropyridine receptor, and by a variety of intracellular second messenger systems. They have a direct or indirect Ca releasing potency from the sarcoplasmic reticulum in common. However, it is not known whether a passive accumulation of Ca might also be a relevant mechanism in MH. Hence, the aim of this study was to examine whether the blockade of the Ca reuptake in the sarcoplasmic reticulum is a potent method to induce in vitro contractures in MH susceptible (MHS) and MH normal (MHN) skeletal muscle specimens. To answer this question in porcine in vitro contracture tests we used cyclopiazonic acid (CPA). We examined the in vitro effects of CPA in a cumulative pattern in MHS and MHN porcine skeletal muscle specimens.

Anästhesie bei neuromuskulären Erkrankungen

ZusammenfassungUnter den neuromuskulären Erkrankungen (NME) werden über 800 eigenständige Entitäten subsumiert. Die meisten dieser Erkrankungen treten sehr selten auf, aber die Gesamtheit der NME hat eine Prävalenz von 1:1500. Entsprechend gilt die plakative Aussage: „Seltene Erkrankungen sind häufig“. Die Variationsbreite der NME, von dem Befall einzelner Muskelgruppen bis zur gesamten Muskulatur, von langsam progredienten bis zu fulminanten Verlaufsformen, vom perinatalen bis zum adulten Manifestationszeitpunkt, sowie Zahl, Art und Ausprägung der assoziierten Komorbiditäten sind sehr groß. Daher ist es für den Anästhesisten wichtig, anästhesierelevante Komorbiditäten und Indikationen bzw. Kontraindikationen der einzelnen Anästhetika bei NME zu kennen.AbstractAmong the neuromuscular diseases (NMDs) over 800 individual entities have been identified. The vast majority of these diseases occur very seldom but all NMDs together add up to a prevalence of 1:1,500. Accordingly the conclusion “seldom diseases are common” seems to be appropriate. The scope of NMDs is very wide varying from the affection of single muscle groups to the complete musculature, from slowly progressive to fulminant progressive forms, from perinatal to the adult manifestation as well as number, course and character of associated comorbidities. Due to the wide heterogeneity concerning NMDs it is of great importance for anesthesiologists to be knowledgeable on relevant comorbidities as well as indications and contraindications for the various anesthetics.