Management of malignant hyperthermia susceptible parturients

The management of eleven women susceptible to malignant hyperthermia during twenty deliveries is presented. These women were managed over a six-year period following guidelines that were established in 1990. Initial problems identified were the management of labour and caesarean section, the use of sympathomimetics and potential problems for the newborn, viz placental transfer of drugs and the possibility of a stress-induced malignant hyperthermia reaction in the newborn. There was little evidence that the stress of labour produced hypermetabolic responses in either mother or neonates and the use of sympathomimetics increased throughout the six-year period with no evidence of adverse effects. A caesarean section using general anaesthesia was not required but the management of this situation is described in both the protocol and discussion sections of this paper.     

Muscle biopsy studies in malignant hyperthermia

Muscle biopsies were carried out in 41 patients with malignant hyperthermia, or supposed at-risk, as well as in some of their relatives. In 20 patients no changes were detected, and in 2 patients only acute rhabdomyolysis was seen (53.7%); in 19 patients (that is 46.3%) myopathic aspects were found in form of minimal changes, but also of syndrome-like tissue alterations (e.g. core disease, muscle dystrophy). These results confirm the existence of a morphologically detectable "subclinical myopathy" in about half of our patients. Four cases apt to demonstrate the variability, and the large morphological spectrum of these "myopathies" within the same family are described. In children, morphological changes are often missing. Carriers of such "subclinical myopathies" are occurring probably more frequently than supposed. Their identification in time is difficult, the only reliable methods being pharmacological fiber contraction-tests which can be performed in special laboratories only. A raw screening of patients-at-risk may be, however, achieved by exact anamnestic investigations and preoperative CPK-controls. Individuals suffering from paroxysmal myoglobinuria at any rate have to be considered patients at-risk.     

Effects of the 5-HT2 receptor antagonist ritanserin on halothane-induced increase of inositol phosphates in porcine malignant hyperthermia

Recent studies have shown a significant increase of inositol phosphates (IPs) in skeletal muscle during episodes of halothane-induced malignant hyperthermia (MH) in pigs. After treatment with dantrolene and disappearance of MH crisis the IP concentrations returned to basal levels. In order to examine if the increase of IPs during halothane-induced MH may be related to an enhanced IP synthesis in response to activation of 5-HT2 (5-hydroxytryptamine) receptors, the effects of ritanserin, a selective 5-HT2 receptor antagonist, on IP levels were investigated. Biopsies of skeletal muscle of the hindlimbs were obtained in random order and IPs were determined in homozygous MH-susceptible (MHS) and MH-non-susceptible (MHN) swine in the following order: (1) basal, (2) after treatment with ritanserin (2.0 mg/kg), (3) after halothane challenge (3 vol% for 20 min). Basal concentrations of all IPs were higher in MHS than in MHN swine. Ritanserin did not cause any significant changes of IP levels compared to the basal concentrations in MHS and MHN pigs. In MHS pigs, ritanserin did not prevent a halothane-induced MH-crisis. After halothane challenge, 1,3,4-IP3, 1,3,4,6-IP4 and 1,3,4,5-IP4 levels were increased in MHS (during MH crisis) vs. basal concentrations, whereas no changes were found in MHN pigs. Since the increases of IP levels in MHS pigs during MH crisis found in the present study were comparable to those without pretreatment with ritanserin, shown by recent studies, it may be concluded that ritanserin does not prevent the increase of IPs during a halothane-induced MH. Thus, the present data indicate that increases of IP levels during halothane-induced MH in swine are due to other mechanisms than 5-HT mediated enhancement of IP synthesis.     

Ten cases of malignant hyperthermia in Norway

Data are presented on ten cases of anaesthesia-induced malignant hyperthermia in Norway. Seven of the patients died, three recovered. The fatal cases were all boys in the age group 11-20 years. This age and sex distribution suggests that puberty with the increase in androgens is a precipitating factor in malignant hyperthermia. One of the victims who survived was a 4 1/2-year-old pseudohermaphrodite girl with the adrenogenital syndrome. The coincidence of malignant hyperthermia in a patient with such a rare syndrome points to the excessive formation of androgens in patients with this syndrome as a predisposing factor. The indications for surgery were traumatic injuries in five cases, congenital abnormalities in three and appendicitis in two cases. These conditions in themselves may cause an increased sensitivity to suxamethonium. One patient received only hexobarbitone, halothane and suxamethonium. After the last drug jaw rigidity and temperature rise to 41.3 degrees C prompted the anaesthetist to end the anaesthetic. The fact that the patient survived proves that suxamethonium induced jaw rigidity is valuable as a warning. The absence of cardiovascular depression after procaine 3.5 g in one patient is ascribed to the correction of acidosis at the time of infusion of this drug. It is suggested that procaine should be withheld until other measures such as cooling, correction of acidosis and steroid therapy have been tried.     

Myoglobinuria, malignant hyperthermia, neuroleptic malignant syndrome and serotonin syndrome

This article presents an overview of the causes and manifestations of myoglobinuria and provides criteria for its diagnosis and management. The article also reviews neuroleptic malignant syndrome, malignant hyperthermia, and serotonin syndrome, all of which could cause rhabdomyolysis and myoglobinuria.     

Perioperative severe rhabdomyolysis revealing susceptibility to malignant hyperthermia

Resection of extensive lung cancers invading thoracic vascular structures (T4 lesions) can yield long-term survival provided the margins and nodes are free of tumor. We report the resection of the suprahepatic inferior vena cava for direct tumor involvement by a pulmonary malignancy. The resection was performed without bypass, and the cava was subsequently reconstructed with a 22-mm-diameter Dacron graft. Patency was documented on postoperative magnetic resonance angiograms. The patient was discharged home on postoperative day 10 without complications and remains well 8 months after the operation. Potentially curative resections and reconstructions of suprahepatic inferior vena cava involved with pulmonary malignancies are possible and can be done without cardiopulmonary bypass.     

Prior hypothermia attenuates malignant hyperthermia in susceptible swine

This study was designed to determine the extent by which mild or moderate hyperthermia attenuates the triggering of malignant hypothermia (MH) induced by the combined administration of halothane and succinylcholine. Sixteen susceptible swine were initially anesthetized with nontriggering drugs and then either kept normothermic (approximately equal to 38 degrees C, n = 6) or cooled to induce mild (approximately equal to 35 degrees C, n = 6), or moderate (approximately equal to 33 degrees C, n = 4) hypothermia. Next, after a 30-min control period, the normothermic and mildly hypothermic animals were administered 1 minimum alveolar anesthetic concentration (MAC) halothane followed by a bolus dose of succinylcholine (2 mg/kg). Within 10 min all normothermic animals developed fulminant MH, whereas the onset of MH was slowed or was absent in the mildly hypothermic group. To test whether moderate hypothermia could more effectively minimize the signs of a MH episode, this group of animals was exposed to 1.5 MAC halothane followed 10 min later by a 3-mg/kg bolus of succinylcholine. MH was not induced and anesthesia was then changed to nontriggering drugs (ketamine and pancuronium). The animals were then aggressively rewarmed to 38 degrees C: a slight increase in the ETCO2 was detected, but MH episodes did not spontaneously occur. Subsequently, the readministration of halothane and succinylcholine rapidly provoked fulminant MH. We concluded that the induction of mild hypothermia impairs triggering and reduces the progression of MH induced by the combined administration of halothane and succinylcholine, whereas moderate hypothermia was completely protective and thus could be considered for prophylaxis.     

Physiologic, biochemical and genetic aspects of malignant hyperthermia

The value of the TAG-72 (CA 72-4) serum marker in primary diagnosis was investigated in 110 patients with histologically diagnosed ovarian cancer. A reference group consisted of 103 patients with benign pelvic masses. Compared to the well-established CA-125, TAG-72 showed a low sensitivity of 42% in the detection of ovarian cancer. By contrast, when the cut-off level for TAG-72 was set at 6 U/ml, it showed a very high specificity of 99%. When the measurement of TAG-72 was combined to that of CA-125, improvements in both the specificity (as compared to a single CA-125 determination) and the sensitivity (as compared to a single TAG-72 assay) were observed. In such a combined assay, our results suggest that the best predictive value (positive and negative) was obtained if CA-125 is assigned a relatively high cut-off value (65 U/ml) in conjunction with a low cut-off level (3.2 U/ml or 4 U/ml) for TAG-72. In the present study, at threshold values of 65 U/ml respectively, a sensitivity of 86%, a specificity of 83% and a positive and negative predictive value of 85% were obtained. In mucinous carcinomas of the ovary, however, the additional TAG-72 determination did not lead to a better predictive power than did CA-125 measurement alone.     

Voltage-dependent calcium release in human malignant hyperthermia muscle fibers

Malignant hyperthermia (MH) results from a defect of calcium release control in skeletal muscle that is often caused by point mutations in the ryanodine receptor gene (RYR1). In malignant hyperthermia-susceptible (MHS) muscle, calcium release responds more sensitively to drugs such as halothane and caffeine. In addition, experiments on the porcine homolog of malignant hyperthermia (mutation Arg615Cys in RYR1) indicated a higher sensitivity to membrane depolarization. Here, we investigated depolarization-dependent calcium release under voltage clamp conditions in human MHS muscle. Segments of muscle fibers dissected from biopsies of the vastus lateralis muscle of MHN (malignant hyperthermia negative) and MHS subjects were voltage-clamped in a double vaseline gap system. Free calcium was determined with the fluorescent indicator fura-2 and converted to an estimate of the rate of SR calcium release. Both MHN and MHS fibers showed an initial peak of the release rate, a subsequent decline, and rapid turn-off after repolarization. Neither the kinetics nor the voltage dependence of calcium release showed significant deviations from controls, but the average maximal peak rate of release was about threefold larger in MHS fibers.     

Molecular pathology of malignant hyperthermia and central core disease

Recent advances of research on malignant hyperthermia(MH) were reviewed. The rate of Ca-induced Ca release(CICR) from the sarcoplasmic reticulum(SR) was measured on the skinned muscle fiber preparation of porcine and human MH. The rate of CICR was significantly increased both in porcine and human MH. These observations supported conclusion obtained by genetical studies that the ryanodine receptor (RYR1) was site of abnormality in most of porcine and part of human MH. The RYR1 is Ca release channel of skeletal muscle SR and CICR is one of main function of the channel. Subsequently, point mutation of RYR1 gene was found in the foot domain of the molecule. Heretofore, 9 kind of mutations were described in association of MH-susceptible(MHS) trait. 4 of them were accompanied by a form of congenital myopathy, central core disease(CCD). CCD is considered as an allelic disease of MH. But pathogenesis of peculiar morphological abnormality of CCD is mostly unknown. Mutations are identified only in half of familial MH cases, suggesting MH is heterogeneous. Recently, it was reported that mutation of the dihydropyridine receptor gene was associated with MHS in a french family. The dihydropyridine receptor is distributed on the transverse tubule membrane and constitutes the triad structure with RYR1.     

Circulatory and metabolic responses of malignant tumors during localized hyperthermia

The effect of localized hyperthermia on the circulatory responses and on the oxygen and glucose supply has been evaluated in tissue-isolated rat tumors utilizing an in situ perfusion system. On the average, localized hyperthermia caused a significant increase in total tumor blood flow after raising of the mean tumor temperature from 37 degrees C to 39.5 degrees C. At higher temperatures (42 degrees C) total tumor blood flow decreased to a level somewhat below the flow during normothermia. However, there were great interindividual differences in the response of blood flow to temperature. The changes in blood flow were paralleled by variations of the O2-consumption and of the glucose uptake of the tumor tissue. The alteration of the oxygen and glucose supply seem to be predominantly mediated through changes of tumor blood flow with temperature. Tumor microcirculation appears to be improved at moderate hyperthermic temperatures (39 degrees C -40 degrees C) and deteriorated at higher temperatures. Whereas a vasodilation of tumor vessels seems to be a paramount factor for flow improvements, a reduction of red blood cell flexibility due to severe tissue acidosis, multiple microthromboses as well as occlusions of microvessels should be taken into consideration as factors for flow impairments at higher tumor temperatures.     

Feasibility of ultrasound hyperthermia in the treatment of malignant brain tumors

In order to test the biological feasibility of using ultrasound-generated hyperthermia for the treatment of brain tumors, damage threshold studied and thermal dosimetry studies as a function of temperature were performed in 44 acute experiments in cats. Bilateral craniotomies were performed to expose the dural surface. Ultrasonic radiation was applied for 50 minutes at different intensities to generate temperatures up to 48 degrees C. Thermal fields were mapped using an electrode array of three triple-junction thermocouple probes. Each probe left a track easily identified histologically. Serial sections of each brain were cut and stained, allowing for precise correlation of histology and thermocouple location and temperature. At temperatures of less than 42 degrees C for 50 minutes, no evidence of damage could be detected in either gray or white matter. At 43 degrees C partial loss of neurons was seen in the brain adjacent to the probe, but at the same temperature in white matter, only edema was seen. At temperatures of 44-45 degrees C there was definite loss of both neurons in the gray matter and myelin tracts in the white matter. The lesions created by using ultrasound-generated hyperthermia were sharply marginated. This sharp demarcation histologically correlated well with the abrupt fall off in temperature as a function of distance from the lesion edge. The results of this study are important in two respects. First, it demonstrates that ultrasound can effectively heat the brain in an extremely controlled and precise manner. Second, the brain can withstand temperatures to 42 degrees C without showing histological evidence of damage, which is the temperature range at which neoplastic cells begin to show cytotoxic effects.     

Free radicals and calcium homeostasis: relevance to malignant hyperthermia?

The regulation of intracellular free calcium ions (Ca2+) in skeletal muscle at rest and during contraction depends on mechanisms such as Na(+)-Ca2+ exchangers, Ca(2+)-ATPases, and the voltage-sensitive ryanodine receptor. The susceptibility of these regulatory mechanisms to free-radical-mediated damage may be increased because of their location within the lipid membranes of sarcolemma, sarcoplasmic reticulum, and mitochondrion with resultant uncontrolled increases in myoplasmic Ca2+ concentration and cell death. The potentially fatal pharmacogenetic disorder, malignant hyperthermia (MH), is characterised by muscle rigidity, arrhythmias, lactic acidosis, and a rapid rise in body temperature. The sequence of events responsible for the MH syndrome remains uncertain, but it has been variously ascribed to faults in many of the Ca2+ regulatory mechanisms. In swine the condition is associated with a specific mutation in the ryanodine receptor, whereas in humans the syndrome is genetically heterogenous. Free-radical-mediated peroxidation of membrane lipids and proteins also results in the rapid efflux of Ca2+ from organelles, and the detection of products of free radical reactions in tissue from MH-susceptible individuals using electron spin resonance spectroscopy provides evidence for the involvement of free radicals in the MH syndrome.     

局部热疗联合腔内化疗对恶性胸腔积液的疗效观察

Objective: The aim of our study was to assess the efficacy of regional hyperthermia combined with intrapleural chemotherapy and to evaluate the effect on the immunologic cells and vascular endothelial growth factor (VEGF) in patients with malignant pleural effusion. Methods: The 102 patients with malignant pleural effusion were included in this study: 52patients undergoing regional hyperthermia with intrapleural chemotherapy (HICT), and 50 patients treated with intrapleural chemotherapy (ICT). Chemotherapy was administered into the thoracic cavity weekly through a tube with CDDP (dose = 40mg/m2), and hyperthermia was performed twice a week for 60 minutes following the ICT. We evaluated the response rates and side-effects after 4 weeks. Before and after the treatment, T cell subsets and NK cells were detected by flow cytometry and VEGF was measured with ELISA kits. Results: Compared HICT to ICT, the overall response rates of the whole group,breast cancers and lung cancers were 80.8% vs 54% (P ＜ 0.01), 86.7% vs 56.3% (P ＞ 0.05) and 78.4% vs 52.9% (P ＜ 0.05)respectively. The ratios of CD4+, CD4+/CD8+ and NK cells increased and the concentration of VEGF decreased more significantly after HICT. Conclusion: We concluded that combined regional hyperthermia with intrapleural chemotherapy could control the malignant pleural effusion effectively with mild toxicity. The levels of the T cell subset, NK cells and VEGF in both blood and effusion changed obviously.     

Effect of chlorocresol vs caffeine on muscle contracture in malignant hyperthermia susceptible patients

The phenotype of susceptibility to malignant hyperthermia (MHS); can only be detected reliably by the in vitro caffeine-halothane contracture test (CHCT). Enhanced sensitivity of the calcium-induced calcium release mechanism is responsible for the exaggerated contracture response of skeletal muscle fibers from MHS patients to halothane and caffeine. Chlorocresol was demonstrated to be a potent activator of Ca++ release from skeletal muscle sarcoplasmic reticulum. This effect is probably mediated through action on a ryanodine sensitive Ca++ release channel known to be more sensitive in MH. We studied the effect of chlorocresol on the mechanical contracture response of skeletal muscle from patients presenting for the in vitro CHCT. Chlorocresol induces contracture response in a concentration 1/200 of that of caffeine in muscle strips from MH patients. By adding chlorocresol to the protocol of the CHCT, there is clearer discrimination between the responses of MH patients and normal subjects can be achieved.