[Delayed Takotsubo syndrome - A critical perioperative incident]. / Das verspätete Tako-Tsubo-Syndrom ­ Ein kritischer perioperativer Zwischenfall.

INTRODUCTION: The term Takotsubo syndrome (TTS) describes a transient ventricular dysfunction. Symptoms and complication rate are similar to those of a myocardial infarction. MEDICAL HISTORY: An 81-year-old female patient was admitted for thrombendarterectomy of the left femoral artery. Prior to a recent biological aortic valve replacement, coronary heart disease had been ruled out. ANESTHETIC INDUCTION AND CLINICAL FINDINGS: After induction of anesthesia, relevant arterial hypotension and sinus bradycardia occurred. After catecholamine administration, transient ST segment elevations were observed, which postoperatively developed a myocardial infarction-like dynamic. Echocardiography and values of cardiac enzymes initially revealed no abnormalities. THERAPY, COURSE AND DIAGNOSIS: After a symptom-free interval the patient developed severe cardiac decompensation on the third postoperative day. At this point, the clinical picture of TTS was visible. Stabilisation of the clinical condition was achieved with levosimendan therapy. CONCLUSION: Dynamic ECG changes in the perioperative situation always require differentiated diagnosis and possibly longer monitoring. TTS is a relevant differential diagnosis because it is subject to severe complications.

Effects of theophylline on anesthetized malignant hyperthermia-susceptible pigs.

BACKGROUND: Theophylline was shown to induce contracture development in porcine malignant hyperthermia (MH) susceptible (MHS) skeletal muscles in vitro. The purpose of the current study was to investigate the in vivo effects of theophylline in MHS and MH normal (MHN) swine. METHODS: MH-trigger-free general anesthesia was performed in MHS and MHN swine. Theophylline was administered intravenously in cumulative doses up to 93.5 mg·kg⁻¹. The clinical occurrence of MH was defined by changes of central-venous pCO2, central-venous pH, and body core temperature. RESULTS: Theophylline induced comparable clinical alterations in the anesthetized MHS and MHN swine, especially in regard to hemodynamic data. No pig developed hypermetabolism and/or MH according to defined criteria. All animals died with tachycardia followed by ventricular fibrillation. CONCLUSIONS: The cumulative theophylline doses used in this study were much higher than doses used therapeutically in humans, as demonstrated by measured blood concentrations. Theophylline is thus not a trigger of MH in genetically determined swine.

Duration of mission time in prehospital emergency medicine: effects of emergency severity and physicians level of education.

BACKGROUND: Prehospital emergency care is provided in many European countries by specialised emergency physicians. However, little is known about the impact of experience and educational level of emergency physicians on providing prehospital care. METHODS: During a 6-month period all deployments of an emergency physician-staffed ambulance in a metropolitan area were studied according to possible predictors of prehospital mission times. RESULTS: In the univariate comparison the junior emergency physicians had 6.3-minute longer prehospital mission times than senior emergency physicians. This difference was evident in several National Advisory Committee for Aeronautics (NACA) score subgroups. However, in multivariate analysis, patient conditions, like NACA score, Glasgow coma scale or prehospital diagnosis had by far the more significant impact on mission times. CONCLUSION: The effect of education on treatment process and outcome in prehospital emergency care should merit further research, especially to ensure that junior emergency physicians are properly trained before they work in prehospital emergency medicine.

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 micromol/L) or bolus (75 and 100 micromol/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 micromol/L. There was no overlap between the diagnostic groups at 75 micromol/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.

Ryanodine contracture threshold times for diagnosis of malignant hyperthermia susceptibility: an experimental approach from a single laboratory.

STUDY OBJECTIVES: To define threshold times for ryanodine contracture testing (RCT) using skeletal muscle specimens from malignant hyperthermia-susceptible (MHS) and control individuals. DESIGN: Prospective study. SETTING: Malignant hyperthermia (MH) laboratory at a university hospital. PATIENTS: 8 patients with previous fulminant MH and 53 control patients undergoing in vitro contracture test (IVCT) for diagnosis of MH susceptibility. INTERVENTIONS: Biopsies of the quadriceps femoris muscle were performed with a 3-in-1 nerve block, with spinal anesthesia, or with trigger-free general anesthesia. MEASUREMENTS AND MAIN RESULTS: Patients were classified as MHS, MH normal (MHN), or MH equivocal (MHE) by the IVCT according to the protocol of the European MH Group (EMHG). Ryanodine 1 microM was added as a bolus to the organ bath to extra vital muscle specimens. Contracture levels were defined as: 1 = start of contracture (OT; min); 2 = time (min) to reach a contracture of 2 mN, and 3 = time (min) to reach a contracture of 10 mN. The effects of ryanodine on contracture responses were measured. Ryanodine induced contractures in all specimens. MHS specimens reached all defined contracture levels significantly sooner than did the controls. Ryanodine contracture test enables a clear discrimination of MHS specimens from controls at contracture levels of OT and 2 mN, whereas at 10 mN a small overlap was observed. CONCLUSIONS: Using this test, which is an experimental approach from a single laboratory, an assignment to MHS or MHN is possible. To define contracture levels for RCT more precisely and to agree on commonly used thresholds, multicenter studies with larger numbers of patients are required.

Histomorphologic examination of skeletal muscle preparations does not differentiate between malignant hyperthermia-susceptible and -normal patients.

BACKGROUND: It has been suggested that malignant hyperthermia (MH) can be diagnosed by specific myopathologic alterations. The purpose of this study was to investigate whether there are characteristic myopathologic changes in skeletal muscles of MH-susceptible (MHS) compared with MH-normal (MHN) patients. METHODS: Four hundred forty patients with clinical suspicion of MH were classified as MHN, MH equivocal (MHE), or MHS by the in vitro contracture test with halothane and caffeine. In addition, a small muscle sample excised from each patient was analyzed by histologic, histochemical, immunohistochemical, and computer-aided morphometric methods. RESULTS: MHN was diagnosed in 243 patients, MHE was diagnosed in 65, and MHS was diagnosed in 132. No myopathologic abnormalities were found in 53.5% of the MHN, 53.9% of the MHE, and 56.1% of the MHS patients. Thirty-five percent of all patients showed one, 9.8% showed two, and only 0.9% showed three different pathologic findings within skeletal muscle preparations. The frequency of pathologic findings did not differ between the MHN and the MHS patients; only fiber type I predominance was observed more often in MHN. MHE patients could not be assigned to a diagnostic group by detection of myopathologic alterations. In six clinically unaffected patients, a former unrecognized myopathy, such as central core disease, was diagnosed. This disease is characterized by a specific alteration (cores). CONCLUSIONS: Histologic differences between MHS and MHN statuses could not be demonstrated in this study. Histopathologic examinations can neither improve the diagnosis of MH nor contribute to a better definition of the MH status. However, histopathologic examinations might be useful to detect formerly unrecognized specific myopathies.

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 /= 2.0 degrees 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.

In vitro and in vivo effects of the phosphodiesterase-III inhibitor enoximone on malignant hyperthermia-susceptible swine.

BACKGROUND: In human skeletal muscles, the phosphodiesterase-III inhibitor enoximone induces in vitro contracture development, and it has been suggested that enoximone could trigger malignant hyperthermia (MH). In this study, the in vitro and in vivo effects of enoximone in MH-normal (MHN) and MH-susceptible (MHS) swine were investigated. METHODS: Malignant hyperthermia trigger-free general anesthesia was performed in MHS and MHN swine. Skeletal muscle specimens were excised for an in vitro contracture test with 0.6 mm enoximone. Thereafter, MHS and MHN swine were exposed to cumulative administration of 0.5, 1, 2, 4, 8, 16, and 32 mg/kg enoximone intravenously. Clinical occurrence of MH was defined by a Pco(2) greater than 70 mmHg, a pH less than 7.20, and an increase in body temperature of more than 2.0 degrees C. RESULTS: Enoximone induced marked contractures in all MHS muscle specimens in vitro. In contrast, only small or no contracture development was observed in MHN muscle specimens, without an overlap in contractures between MHS and MHN muscles. However, in vivo, no clinical differences were found between MHS and MHN swine following cumulative enoximone doses. According to the defined criteria, none of the swine developed MH during the experiment. Furthermore, high enoximone doses induced progressive circulatory insufficiency, and after receiving 32 mg/kg enoximone, all animals died of cardiovascular failure. CONCLUSIONS: The cumulative enoximone doses used in this study were 30- to 50-fold higher than therapeutic doses in humans. Enoximone does not trigger MH in genetically determined swine. However, enoximone might be useful for in vitro diagnosis of MH.

Evidence for a spontaneous C1840-T mutation in the RYR1 gene after DNA fingerprinting in a malignant hyperthermia susceptible family.

Malignant hyperthermia (MH) is a potentially lethal inherited pharmacogenetic syndrome due to a dysfunction of the intracellular calcium regulation of skeletal muscle following administration of volatile anaesthetics and depolarizing muscle relaxants. The ryanodine receptor of skeletal muscle (RYR1), which is an intracellular calcium release channel, has been proposed to be a candidate structure for the MH defect. In some families with a history of MH a C1840-T nucleotide exchange has been found in the RYR1 gene which cosegregates with the MH susceptible phenotype. Sixteen individuals (5 males and 11 females; age 8-68 years, 7 MH susceptible, 9 MH non-susceptible) of a family with a history of MH were screened for the C1840-T mutation in the RYR1 gene using standard methods. DNA fingerprinting was performed in order to verify the kinship. MH susceptibility was determined using the standard in vitro contracture test with halothane and caffeine. The present article describes a German MH pedigree carrying a spontaneous C1840-T mutation. The mutation was detected in one individual of the third generation. This person was classified as MH susceptible according to the in vitro contracture test protocol. None of the other family members (6 MH susceptible and 9 MH non-susceptible persons), including the parents of the child carrying the mutation, presented the C to T nucleotide exchange at position 1840.This novel observation clearly demonstrates that only the detection of the C1840-T mutation may lead to the diagnosis of MH susceptibility, but missing the mutation does not justify diagnosing a patient as non-susceptible within a single pedigree.

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 microm 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.