MH-susceptible Patients Research Articles

A remote access system for inquiry of centrally stored data on patients suspected of malignant hyperthermia . A prototypical development for the Internet

Malignant hyperthermia (MH) is an inherited, potentially life-threatening syndrome of the skeletal muscles. It is a life-threatening complication of anaesthesia with a high mortality (8-10%). The risk of the patient during anaesthesia due to an overlooked predisposition for MH can be reduced by organisational measures, such as, all data of MH-susceptible patients and their families known in Germany must be brought together in a central register, MH-relevant data of patients must be readily retrievable, optional oral advice for those making an inquiry must be available. To achieve this goal, a client-server system has been implemented: Standard Multimedia personal computers installed at the user's (anaesthetist's) site, linked to the Internet, will act as clients. On a server, relevant data of patients concerning MH-susceptibility are integrated in a central database. The newly developed software of this project ensures the legally prescribed data security on the server and the data routes. At the client's site, standard software together with automatically installed programmes from the server using Java applets ensure easy use and maintenance. The total system was implemented and tested. Its functionality and high availability was demonstrated during this test period. Relevant aspects of data security were successfully examined by the data security officer of the University Hospitals of Baden-Württemberg. The user can optionally call a multifunctional teleconference which secures on-line advice if needed. This system demonstrates a safe and quick retrieval of MH relevant data of patients via Internet while at the same time guaranteeing all aspects of data protection and security. A prototypical database access system is described. It ensures safe access to patient data via Internet, while guaranteeing all aspects of data security.

31Phosphorus magnetic resonance spectroscopy characterization of muscular metabolic anomalies in patients with malignant hyperthermia: application to diagnosis.

Metabolic anomalies are known in skeletal muscles of patients with malignant hyperthermia (MH). The authors used 31-phosphorus (31P) magnetic resonance spectroscopy (MRS) to compare metabolic changes of the finger flexor muscles recorded throughout two rest-exercise-recovery protocols (each including aerobic or ischemic exercise) in 26 healthy persons and in 13 MH-susceptible (MHS) persons who were unequivocally diagnosed by in vitro halothane-caffeine contracture tests on muscle biopsies. No abnormality was observed at rest and during recovery periods. A larger phosphocreatine decrease associated with an early drop of pH was noted during the first minute of both exercise periods for MHS patients compared with controls. The early pH decrease indicated a disorder affecting glycolytic activation, probably reflecting defects of Ca2+ cycling, and provided a sensitivity of 77% for MHS diagnosis. A diagnostic strategy based on the retrospective analysis of 19 selected MR parameters was developed. An MRS score, corresponding to the number of abnormal values among the 19 parameters, was calculated and provided sensitivity and specificity rates of 100%; that is, no false-positive or false-negative results were found. A prospective analysis of 10 new participants further confirmed these findings. These results (1) further confirm that MH is associated with the preexistence of latent muscular disorders; (2) enhance the potential diagnostic capacity of MRS, although it should be tested prospectively on a larger group of participants; and (3) allows the characterization of several abnormal metabolic profiles, in persons with MHS, reflecting the recently described polymorphism of MH.

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

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. 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. 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. 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.

Slower recovery of muscle phosphocreatine in malignant hyperthermia-susceptible individuals assessed by 31P-MR spectroscopy.

Our aim was to develop an exercise protocol using 31P-magnetic resonance spectroscopy (31P-MRS), which can discriminate between malignant hyperthermia-susceptible (MHS) individuals and controls. MRS spectra of the forearm muscles were recorded at rest, during and after a standardized exercise protocol in 10 MHS patients and compared with spectra obtained in 10 controls. There was no difference in resting intracellular pH (pHi) or PCr/(Pi+PCr) ratio between the groups (PCr = phosphocreatine, Pi = inorganic phosphorus). At the end of the exercise and during the initial recovery phase, the pHi and PCr/(Pi+PCr) ratio were significantly lower in the MHS group ([pHi: 6.37 (0.07) for MHS vs 6.70 (0.05) for controls, P < 0.005; PCr/(Pi+PCr): 0.784 (0.017) for MHS vs 0.954 (0.020) for controls, P < 0.0005]). For PCr/(Pi+PCr), complete separation between the two groups was observed during the initial recovery phase. The mean recovery time of PCr/(Pi+PCr) was 0.57 min for the control group and 1.28 min for the MHS group. The slower recovery of PCr/(Pi+PCr) is likely to be caused by a combination of several factors, including the lower pHi in MHS subjects at the start of recovery (inhibiting ATP production) and excessive sarcoplasmic calcium overload (causing continued enzyme activation and ATP consumption). Our exercise protocol can be a valuable adjunct to discriminate between MHS and non susceptible subjects.

4-chloro-m-cresol-induced contractures of skeletal muscle specimen from patients at risk for malignant hyperthermia

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. 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. 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. 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.

A196 Delayed Recovery of pH After Exercise in Malignant Hyperthermia Susceptible Patients

A196 Delayed Recovery of pH After Exercise in Malignant Hyperthermia Susceptible Patients

Histological support for the difference between malignant hyperthermia susceptible (MHS), equivocal (MHE) and negative (MHN) muscle biopsies

The aim of this study was to find, using modern techniques, any histological differences in muscle biopsies between malignant hyperthermia (MH) susceptible (MHS), MH equivocal (MHE) and MH negative (MHN) patients. On the basis of the European MH contracture test carried out in 83 patients, 23 were shown to be MHS, nine MHE and 51 MHN. Four lesions were found with a significantly high frequency in MHS and MHE biopsies: muscle fibre hypertrophy and atrophy, internal nuclei and myofibrillar necrosis. These four lesions were observed together in 35% of MHS but in none of the MHE or MHN biopsies. Three of these lesions occurred together in 57% of MHS, 33% of MHE and 4% of MHN biopsies. Our results support a histological difference between MHE, MHS and MHN biopsies and attempt to contribute towards a better definition of MHE status.

4-Chloro-m-cresol test--a possible supplementary test for diagnosis of malignant hyperthermia susceptibility.

In vitro contracture test (IVCT) for diagnosis of MH in our laboratory has a sensitivity of 100% and a specificity of 93%. The results are equivocal in 10-15%, and supplementary tests may thus be required. We have tested the hypothesis that 4-chloro-m-cresol (4-cmc) may be useful for a supplementary test. Muscle from 41 consecutive patients from 7 families undergoing diagnostic muscle biopsy with IVCT was exposed in vitro to increasing concentrations of 4-cmc (25, 50, 75, 100, 150, and 200 mumol l-1), and the force development recorded. Diagnosis of MH susceptibility was made with standard halothane and caffeine tests and included as results MHS (MH susceptible), MHN (MH negative), and MHE (equivoval result). At all concentrations of 4-cmc, the increase in baseline force was significantly greater in the MHS group compared to the MHN group (P < 0.05). Muscle from 15 MH-susceptible (MHS) patients responded to 4-cmc with increasing force at a threshold concentration of 75 mumol l-1 or less, whereas muscle from 23 MH-non-susceptible (MHN) patients had thresholds of 100 mumol l-1 or more. The accuracy of the chlorocresol test was thus 100% (95% confidence limits 90.75-100%) at a threshold of 75 mumol l-1. Amplitude of contractures at 2 mmol l-1 caffeine was not different from contractures at 75 mumol l-1 of 4-cmc in either the MHS or the MHN group (P > 0.05). In vivo concentrations of chlorocresol from clinical use of insulin and somatropin are estimated to be 20 times less than the threshold concentration and thus these drugs seem safe in MH patients. 4-chloro-m-cresol may be a suitable aid to clarify puzzling results of standard testing of MH susceptibility.

Malignant Hyperthermia

Malignant hyperthermia (MH) is a medical emergency that all perioperative nurses should be prepared to handle. Patients with the inherited MH trait have a rare skeletal muscle disease that causes them to develop life-threatening hyperthermia (ie, body temperatures of 43.3 degrees C [110.0 degrees F] or higher) at the time MH-triggering agents are administered to induce general anesthesia or shortly thereafter. The incidence of MH episodes is reported to be 1 in every 12,000 pediatric anesthetic procedures and 1 in every 40,000 adult anesthetic procedures. The MH syndrome also is characterized by continuous skeletal muscle rigidity, hypermetabolism, hypercapnia, tachypnea, and tachycardia that result in cardiac arrest and death if left untreated. Perioperative staff members' knowledge of MH, the care of MH-susceptible patients, and adequate preparation for MH crises are the cornerstones of successful patient outcomes to this life-threatening syndrome.

In vitro effects of the serotonin receptor agonist DOI on skeletal muscles from malignant hyperthermia susceptible patients are attenuated by dantrolene

In vitro effects of the serotonin receptor agonist DOI on skeletal muscles from malignant hyperthermia susceptible patients are attenuated by dantrolene

Malignant hyperthermia susceptibility: anaesthetic implications and risk stratification.

Malignant hyperthermia (MH) is a rare autosomal dominant trait that predisposes individuals to great danger when exposed to certain anaesthetic triggering agents, such as potent volatile anaesthetics and succinylcholine. Sudden hypermetabolic reaction occurs in skeletal muscle, leading to hyperthermia and massive rhabdomyolysis. Precautions must be taken before the anaesthesia of MH-susceptible patients. No triggering agents should be administered, central body temperature and ETCO2 should be carefully monitored, and dantrolene must be immediately available. In addition, the anaesthesia machine should be carefully washed to remove traces of halogenated agents, and the use of fresh disposable anaesthetic circuits is recommended. Early diagnosis of the syndrome by alert, informed anaesthesiologists, and the immediate administration of dantrolene and other supportive measures, has reduced mortality. Patients with MH susceptibility should be instructed to alert the anaesthesiologist about their condition whenever anaesthesia is needed. Although people diagnosed with MH susceptibility should not change their lifestyle in general, military service is limited.

Effects of the serotonin2 receptor agonist DOI on skeletal muscle specimens from malignant hyperthermia-susceptible patients.

Administration of serotonin2 (5-HT2) receptor agonists in pigs triggers malignant hyperthermia (MH) and psychotic-like behavior. Both can be reduced by 5-HT2 receptor antagonists. Furthermore, an increase in the plasma concentration of 5-HT has been found during onset of halothane-induced MH in pigs. Therefore, in this study, the in vitro effects of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were investigated in muscle specimens from MH-susceptible (MHS) and -negative (MHN) patients. After MH classification using the caffeine-halothane contracture test (CHCT), surplus muscle specimens from 23 MHS and 17 MHN patients were used to examine the effects of DOI. In the first study, DOI was added to the bath in a concentration of 0.02 mM. In a second experiment, muscles were preincubated for 60 min with 0.02 mM DOI, and subsequently, halothane was added incrementally to the organ bath (0.11-0.22-0.44 mM) for 15 min according to the CHCT protocol. The in vitro effects of DOI on contracture development and muscle twitch were measured for 120 min in both investigations. Muscle specimens form all patients developed contractures after administration of DOI, characterized by a significantly earlier development of contracture in MHS (16.8 +/- 1.7 min) than in MHN (66.3 +/- 5.8 min) muscles (P < 0.05). There was no overlap between the groups in the range of times. The onset of contracture development after DOI was prolonged by halothane in specimens from MHN patients (89.7 +/- 5.6 min) but not MHS patients. Preincubation with DOI increased the halothane-induced contractures in specimens from MHS patients compared to the results of the CHCT. The contracture development in specimens from MHS patients was larger than from MHN patients. At the end of the experiment, contractures had reached a maximum of 12.9 +/- 1.1 mN in specimens from MHS and 5.3 +/- 0.6 mN in MHN patients (P < 0.05). The additional administration of halothane led to significantly increased contractures in specimens from MHS individuals (15.9 +/- 0.9 mN) at 120 min. However, the contracture development decreased significantly to 3.1 +/- 0.4 mN in MHN muscles. Muscle twitch after DOI administration was reduced significantly in specimens from MHS and MHN patients. A functional or structural altered serotonin system might be involved in the development of MH in humans.

In vitro 31P-magnetic resonance spectroscopy of muscle extracts in malignant hyperthermia-susceptible patients.

It was recently suggested that malignant hyperthermia-susceptible (MHS) patients could have an elevated peak of phosphodiesters in leg muscles using in vivo phosphorus magnetic resonance spectroscopy. In the current study, analysis of the phosphodiesters of muscle extracts of MHS and malignant hyperthermia-negative patients was performed using in vitro phosphorus magnetic resonance spectroscopy to chemically identify and to compare the muscle concentrations of water-soluble compounds between the two groups with respect to the muscle fiber type composition. Perchloric acid extracts of the vastus medialis muscle of seven MHS patients and ten malignant hyperthermia-negative patients on the basis of the European malignant hyperthermia contracture test were subjected to in vitro phosphorus magnetic resonance spectroscopy carried out at 9.4 T. In addition, chemical identification of the phosphodiester region and histologic examination of the muscle specimens were performed. The peak in the phosphodiester region was assigned to glycerophosphorylcholine. Muscle perchloric acid extracts of MHS patients had a significantly (P < 0.05) higher glycerophosphorylcholine to the sum of phosphocreatine and inorganic phosphate (glycerophosphorylcholine/ [phosphocreatine +inorganic phosphate]) value than those of malignant hyperthermia-negative patients. Neither a difference in the fiber type composition between the two groups nor any specific myopathy were found. In the absence of histologic differences between muscle specimens of MHS and malignant hyperthermia-negative patients, these results could suggest that glycerophosphorylcholine could be a marker of an impairment in the phospholipid metabolism in the skeletal muscle of MHS patients.

Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia.

The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in...

Effect of Cocaine on the Contracture Response to 1% Halothane in Patients Undergoing Diagnostic Muscle Biopsy for Malignant Hyperthermia

Comment: This study demonstrates that cocaine does not have a direct effect on muscle contracture in the presence of halothane in MH-susceptible patients. Symptoms of cocaine overdose include excessive sympathetic stimulation and hyperthermia that mimic MH. Two previous case reports suggested that overdoses of cocaine may cause such malignant hyperthermia-like responses. Awake triggers for MH can be elicited in swine models, but the significance in humans is controversial. In general, in anesthesia only the traditional anesthetic triggering agents, such as volatile anesthetic agents and succinylcholine, need to be avoided in MH-susceptible patients.

Mutation screening of dihydropyridine receptor γ subunit cDNA from malignant hyperthermia susceptible patients

Mutation screening of dihydropyridine receptor γ subunit cDNA from malignant hyperthermia susceptible patients

Incidence of malignant hyperthermia reactions in 2,214 patients undergoing muscle biopsy.

To determine the incidence of malignant hyperthermia (MH) reactions after trigger-free anaesthesia in a large population of MH-susceptible (MHS) patients, the charts of 2,214 patients who underwent elective muscle biopsy for malignant hyperthermia were reviewed. Either general or regional anaesthesia with non-triggering drugs was used. For general anaesthesia, the trachea was intubated in the absence of muscle relaxants. The halothane/caffeine contracture test was performed on the biopsied muscle. Suspected MH reactions were identified according to their site of occurrence (in the operating room, recovery room or ward). Ninety-seven percent of patients received a general anaesthetic; 3% received a regional anaesthetic or field block. Of the 2214 patients whose muscles were biopsied, 1082 patients were biopsy-positive for MH. Five patients in whom MH reactions were diagnosed in the recovery room were all subsequently proved to be biopsy-positive for MH. Four of the five received intravenous dantrolene as part of their therapy; the fifth received only symptomatic therapy as parenteral dantrolene was not commercially available. All patients recovered completely from their reactions. We conclude that the incidence of MH reactions in biopsy-positive patients who receive a trigger-free anaesthetic for minor surgery is small (0.46%, (0.15-1.07%, 95% CI)). These reactions occur in the immediate postoperative period.

Malignant Hyperthermia During Sevoflurane Administration

Malignant Hyperthermia During Sevoflurane Administration

Effect of cocaine on the contracture response to 1% halothane in patients undergoing diagnostic muscle biopsy for malignant hyperthermia.

Two case reports have cited the recreational use of cocaine as possible trigger of a malignant hyperthermia (MH) crisis. We evaluated whether toxic concentrations of cocaine altered the in vitro muscle response to halothane during contracture tests for MH. Twenty-two patients were studied. Muscle biopsies were obtained and first tested for MH susceptibility with 3% halothane and caffeine contracture testing. Ten patients were diagnosed as MH-susceptible and 12 as MH non-susceptible, in accordance with the North American Malignant Hyperthermia Group protocol. Then, muscle strips were exposed to 1% halothane in the presence and absence of 0.1 mmol.L-1 cocaine. Cocaine alone did not affect baseline muscle tension in either group. With 1% halothane, MH non-susceptible muscle showed no contracture with or without cocaine. In contrast, in the presence of 1% halothane, MH-susceptible muscle showed either no change in contracture (six patients), an increase (two patients), or a decrease (two patients) when exposed to cocaine. However, the overall effect of cocaine on muscle contracture in the presence of 1% halothane was insignificant in both groups. We conclude that cocaine, even at toxic levels, does not have a direct effect on skeletal muscle contractility and thus is safe for MH-susceptible patients.

C1840-T mutation in the human skeletal muscle ryanodine receptor gene: frequency in northern German families susceptible to malignant hyperthermia and the relationship to in vitro contracture response

In swine, a point mutation in the ryanodine receptor gene can account for all cases of malignant hyperthermia (MH). The frequency of a corresponding mutation in humans (C1840-T) and its relationship to the in vitro contracture profile is unknown. We screened 192 patients from 28 unrelated northern German families for the C1840-T mutation in the human ryanodine receptor gene and tested for MH susceptibility using the in vitro contracture test (IVCT) according to the European MH Protocol. In our patients 106 revealed MH susceptible (MHS), 56 MH nonsusceptible and 30 MH equivocal status following IVCT. In each family one or two individuals had developed clinical signs of MH or a MH crisis. All of these patients were classified MHS. The C1840-T mutation was found in 2 of 28 families (7.1%). All eight individuals of the two families characterized by this mutation revealed MHS status following IVCT. The thresholds for halothane- and caffeine-induced contractures as well as the contracture profiles following cumulative (0.4-10.0 mumol/l every 3 min) and bolus (10 mumol/l) administration of ryanodine were found to be similar in MHS patients with and without the C1840-T mutation. In conclusion, the C1840-T mutation in the human ryanodine receptor gene is a rare abnormality in MHS families. Similar contracture profiles in the presence and absence of this mutation might imply no major functional role with respect to the contracture response. At present, molecular genetic analysis cannot replace IVCT to discover MH susceptibility in humans.