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D Bendixen

Publications and source records attributed to D Bendixen.

17 recordsLinked to original sources
PubMed2000

Between-center variability of results of the in vitro contracture test for malignant hyperthermia susceptibility.

UNLABELLED: The in vitro contracture test (IVCT) remains the standard test for the diagnosis of malignant hyperthermia (MH) susceptibility. The aim of this study was to investigate whether results of the IVCT varied between two diagnostic centers. The study took place at the national MH centers in Denmark and Sweden. Forty-three patients investigated for MH gave informed consent to have four extra muscle specimens excised. These were sent to the other center and immediately used for a parallel IVCT, according to the protocol of the European MH Group. Results of the IVCTs performed in the two centers on muscle samples from the same patients were compared. Each patient was assigned a diagnosis according to the result obtained in the "mother-center." Identical diagnostic results were obtained for 56% of the patients. The differing diagnostic outcomes were almost exclusively seen in cases with contractures of <5 mN (0.5 g) and abnormal results in only one or two muscle strips. We suggest different criteria for the interpretation of results for clinical and scientific purposes. The clinical criteria should remain unchanged. The scientific designation of susceptibility should be used in cases with contractures of > or =5 mN and abnormal results in at least 75% of the tested muscle strips. IMPLICATIONS: The diagnostic outcomes of tests for malignant hyperthermia susceptibility were compared between two laboratories by using muscle tissue from the same patients. Identical outcomes were found for 56% of the patients. Almost all diverging outcomes were seen in cases with a few small contractures near the cutoff limit. Different diagnostic criteria for clinical and scientific purposes are suggested.

Adolescent↗
PubMed1998

Identification of novel mutations in the ryanodine-receptor gene (RYR1) in malignant hyperthermia: genotype-phenotype correlation.

Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that is triggered in genetically predisposed individuals by common anesthetics and muscle relaxants. The ryanodine receptor (RYR1) is mutated in a number of MH pedigrees, some members of which also have central core disease (CCD), an inherited myopathy closely associated with MH. Mutation screening of 6 kb of the RYR1 gene has identified four adjacent novel mutations, C6487T, G6488A, G6502A, and C6617T, which result in the amino acid alterations Arg2163Cys, Arg2163His, Val2168Met, and Thr2206Met, respectively. Collectively, these mutations account for 11% of MH cases and identify the gene segment 6400-6700 as a mutation hot spot. Correlation analysis of the in vitro contracture-test data available for pedigrees bearing these and other RYR1 mutations showed an exceptionally good correlation between caffeine threshold and tension values, whereas no correlation was observed between halothane threshold and tension values. This finding has important ramifications for assignment of the MH-susceptible phenotype, in genotyping studies, and indicates that assessment of recombinant individuals on the basis of caffeine response is justified, whereas assessment on the basis of halothane response may be problematic. Interestingly, the data suggest a link between the caffeine threshold and tension values and the MH/CCD phenotype.

Female↗
PubMed1997

Detection of a novel mutation at amino acid position 614 in the ryanodine receptor in malignant hyperthermia.

Malignant hyperthermia (MH) is a potentially fatal autosomal dominant disorder of skeletal muscle and is triggered in susceptible people by all commonly used inhalation anaesthetics and depolarizing neuromuscular blocking agents. To date, eight mutations in the skeletal muscle ryanodine receptor gene (RYR1) have been identified in malignant hyperthermia susceptible (MHS) and central core disease (CCD) cases. We have screened the RYR1 gene in affected individuals for novel MHS mutations by single stranded conformational polymorphism (SSCP) analysis and have identified a G to T transition mutation which results in the replacement of a conserved arginine (Arg) at position 614 with a leucine (Leu). The Arg614Leu mutation was present in three unrelated MHS individuals of 151 investigated. The mutation was not detected in 148 normal chromosomes and segregated precisely with MHS in family members from one of the probands where DNA was available for analysis. This mutation occurs at the same position as the previously identified Arg to Cys mutation reported in all cases of porcine MH and in approximately 5% of human MH. A comparison of the phenotypes of the Arg614Leu and Arg614Cys probands is presented.

Amino Acid Sequence↗
PubMed1997

Discordance between malignant hyperthermia susceptibility and RYR1 mutation C1840T in two Scandinavian MH families exhibiting this mutation.

The ryanodine receptor 1 (RYR1) mutation C1840T has been reported to segregate with malignant hyperthermia (MH) susceptibility in several families. We have investigated several Scandinavian MH families with respect to five different RYR1 mutations reported to cause predisposition to MH, and we here report on two of the families in which the C1840T mutation was detected. In these two families there was recombination between MH susceptibility and this mutation in one and three individuals, respectively. These findings may suggest that it is necessary to reconsider the specificity of the IVCT and the role of C1840T as a cause of MH susceptibility in some families exhibiting this mutation.

Anesthesia↗
PubMed1997

Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test.

BACKGROUND: It is well known that patients susceptible to malignant hyperthermia (MH) do not always develop clinical signs of MH at their first anaesthetic. Large material concerning this epidemiological problem do not exist. Therefore, we undertook the present investigation at the Danish Malignant Hyperthermia Register. METHODS: Retrospective analysis of anaesthetics given to 371 patients before in vitro contracture test (IVCT) for susceptibility to MH or before death of MH. Patients (or relatives in the case of a dead patient) gave information about previous anaesthetics and anaesthetic charts were collected and reviewed. RESULTS: Fifteen patients died of clinical MH, 112 patients survived an episode of suspected MH, and 244 patients were relatives of the above. Of the 127 patients with clinical signs of MH, 37% had received anaesthesia before, and trigger agents (potent inhalational agents and/or suxamethonium) were used in 98% of patients with no statistical difference between MH-susceptible (MHS) and non-susceptible (MHN) patients. Emergency anaesthesia was more frequent in patients with fulminant MH compared to those with abortive forms of MH (P < 0.01). Of the 244 relatives, 48% had received anaesthesia before MH was suspected in the family and trigger agents were used in 44% of the anaesthetics without statistical difference between MHS and MHN relatives. In 17 cases, trigger agents were used for anaesthesia after MH was suspected in the family, but before IVCT. CONCLUSION: The clinical expressivity of the MHS phenotype was found to be 34%-54%.

Adolescent↗
PubMed1997

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

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 4-chloro-m-cresol may be a suitable aid to clarify puzzling results of standard testing of MH susceptibility.

Biopsy↗
PubMed1996

Osteogenesis imperfecta and malignant hyperthermia. Is there a relationship?

We describe a patient with osteogenesis imperfecta who developed tachycardia, metabolic and respiratory acidosis (pH 7.14, PCO2 8.4 kPa, BE -8.5 mmol.l-1) and hyperthermia up to 40 degrees C during anaesthesia with barbiturates, fentanyl, pancuronium, and nitrous oxide. Malignant hyperthermia was suspected and the patient treated accordingly. Two years later the in-vitro contracture test for malignant hyperthermia was completely normal. We conclude that hypermetabolism in patients with osteogenesis imperfecta is due to unknown mechanisms other than malignant hyperthermia.

Anesthesia, Intravenous↗
PubMed1996

RYR mutation G1021A (Gly341Arg) is not frequent in Danish and Swedish families with malignant hyperthermia susceptibility.

Malignant hyperthermia (MH) is a pharmacogenetic disorder. Susceptibility to MH (MHS) is presumed to be inherited in an autosomal dominant way. MH crises are triggered by halogenated inhalational anaesthetics and suxamethonium, and may be lethal if not treated early and adequately. Until now, eight mutations in the RYR1 gene have been described as causes of MHS phenotype in various MH families. The mutation RYR1 G1021A (Gly341Arg) has been reported to account for approximately 10% of Caucasian MHS cases. However, in our study this mutation was discovered in only 1 out of 89 Scandinavian families, indicating that this mutation may be the cause of MHS in only about 1% of MHS families in those populations. The mutation may have been brought to Scandinavia by an immigrant.

Calcium Channels↗
PubMed1996

Results of in vitro contracture testing of both parents of malignant hyperthermia susceptible probands.

BACKGROUND: Malignant Hyperthermia (MH) is regarded as a dominantly inherited condition. Therefore, most investigators do not test the second parent if the first parent is found to be MH susceptible (MHS). The purpose of this study was to validate this policy. METHODS: In vitro contracture tests (IVCT) have been performed in both parents of 101 MH susceptible probands. Diagnoses were made according to the European MH group protocol and include MH susceptible (MHS), MH equivocal (MHE) and MH negative (MHN). Our control material consists of 60 patients without any personal or family history of MH. RESULTS: Thirty-seven pairs of parents were MHS-MHN, 20 were MHE-MHN, 6 were MHS-MHS, 20 were MHS-MHE, 6 were MHE-MHE, and 12 were MHN-MHN. The frequency of MHE was greater in the parents than in the controls (26% versus 8%, P < 0.05). Several possible explanations exist: the IVCT produces false positive and/or false negative results; the MH genes may be more frequent in the population than previously expected; MH susceptibility may have more than one mode of inheritance; the mutation rate may not be negligible. Our test results in controls and fulminants point at a combination of these explanations. CONCLUSIONS: We conclude that both parents should be tested whenever possible. For genetic research it is important that labelling any parent "presumed normal" may give misleading results.

Biopsy↗
PubMed1994

Search for three known mutations in the RYR1 gene in 48 Danish families with malignant hyperthermia.

We have examined 48 Danish families in which malignant hyperthermia reactions have occurred, with respect to three of six published mutations in the gene for the calcium release channel of sarcoplasmic reticulum (the RYR1 gene) believed to cause malignant hyperthermia susceptibility in man. The mutations are Arg614Cys, also known as the "pig mutation"; Arg163Cys; and Ile403Met. The only mutation found was Arg163Cys, which was detected in only one family. The results of this study indicate that other mutations must underlie the disorder in most Danish malignant hyperthermia-susceptible families, and that the "pig mutation" is not a frequent cause of malignant hyperthermia susceptibility in Denmark.

Arginine↗
PubMed1994

Lignocaine gel used for lubrication of intranasal and endotracheal tubes in premature neonates.

In this study, we have measured the plasma concentration of lignocaine and its metabolite, monoethylglycinxylidin, in 19 premature neonates (gestational age < or = 33 weeks) when lignocaine gel was used for lubrication of an intranasal tube (during continuous positive airway pressure treatment) or an endotracheal tube (for intubation). We did not find any correlation between plasma concentration of lignocaine or monoethylglycinxylidin and weight of the infant (range 795-2530 g). None of the neonates had toxic levels of lignocaine. One neonate had an exceptionally high but not toxic plasma level of monoethylglycinxylidin. However, this neonate had been treated for severe seizures with an iv infusion of lignocaine up to 13 h before the study. In conclusion, we found it safe to use moderate amounts of lignocaine (i.e. 0.3 ml/kg of lignocaine gel 20 mg/ml) for lubricating both intranasal and endotracheal tubes.

Female↗
PubMed1992

[Malignant hyperthermia].

Malignant hyperthermia (MH) is a life threatening complication following anaesthesia with potent inhalational agents and suxamethonium. The signs of MH are caused by increased metabolism and secondary stimulation of the sympathetic nervous system due to uncontrolled, high intracellular concentrations of calcium in skeletal muscle. The hyperthermia is secondary to the increased energy turnover. Calcium release from the sarcoplasmic reticulum is increased due to a low threshold for release and prolonged opening of the calcium channel upon normal stimulation. The gene encoding the calcium channel is localized on chromosome 19 in humans, and a substitution of cysteine for arginine has recently been described in one family with MH.

Calcium↗
PubMed1992

Sources of variability in halothane and caffeine contracture tests for susceptibility to malignant hyperthermia.

In vitro contracture tests for susceptibility to malignant hyperthermia (MH) were performed in 96 patients according to the protocol of the European MH Group. In addition, tests were performed with halothane 0.44 mmol l-1 and 0.66 mmol l-1, and caffeine 2 mmol l-1, each added as a single bolus dose to fresh specimens. For all tests the size of contractures were recorded, and for the diagnostic tests the halothane and caffeine threshold concentrations were determined (i.e. the minimal concentrations eliciting a contracture of 0.2 g). The caffeine specific concentration (CSC, i.e. the concentration increasing force 1.0 g) and the % increase with caffeine 2 mmol l-1 were calculated from the dose response curves. Various diagnostic criteria in use by the North American MH Group were applied, and diagnostic outcome compared with the result obtained by the protocol of the European MH Group. Thirty-five patients were susceptible to MH (MHS), 33 were non-susceptible (MHN), and 28 had equivocal results of the tests (MHE). Additional tests were made in 34 MHS, 32 MHN, and 26 MHE patients. Contractures elicited by bolus addition of halothane or caffeine were significantly larger than those observed following the same dose of drug added cumulatively (P less than 0.05). Contractures greater than or equal to 0.7 g following halothane 3% (bolus dose) were seen in 78% of MHS patients and 18% of MHN patients, A CSC less than 4 mmol l-1 was elicited in 86% of MHS and 30% of MHN patients, whereas an increase in force greater than or equal to 4% or greater than or equal to 7% was seen in 71% and 34% of MHS patients, respectively, and in none of the MHN patients. Using the criterion of greater than or equal to 0.7 g in the halothane test and greater than or equal to 4% increase in the caffeine test gave the best agreement between diagnostic outcome with the European and North American protocols: All 34 MHS patients (100%) were positive to one or more tests, but so were eight of 32 MHN patients (25%), giving an overall diagnostic agreement of 88%. We conclude that, in our laboratory, the results obtained with the two major protocols for investigation of MH susceptibility are not identical. Patients surviving fulminant MH, however, react abnormally to nearly all the tests. For validation and possibly further standardization of the tests each laboratory must investigate a large number of normal controls and as many patients surviving fulminant MH as possible.

Adolescent↗
PubMed1990

Influence of salbutamol on the in vitro muscle response to caffeine and halothane in malignant hyperthermia.

In vitro contracture tests for susceptibility to malignant hyperthermia (MH) were performed with halothane and caffeine in 34 patients, according to the protocol of the European MH Group. Additional halothane and caffeine tests were performed in the presence of salbutamol 50 micrograms/l. Contractures after exposure to halothane were seen only in MH-susceptible (MHS) patients (n = 16), and were not changed by salbutamol. Salbutamol did not influence the caffeine dose-response curves in any of the groups (n = 14 in the MH-non-susceptible (MHN) group). The caffeine threshold concentration was significantly increased by salbutamol in the MHS group.

Adult↗
PubMed1989

[Use of the APACHE II scoring method for registering patients receiving intensive care at a central hospital].

The APACHE II scoring method was employed prospectively for registration of patients in intensive care in a central hospital. Scoring was performed in a total of 390 patients. Seventy-three patients (20.2%) of the patients died in hospital. A significant difference in the APACHE II score was found in the surviving patients (9 points) as compared with those who died (19 points). A significant linear connection was found between the frequency of death observed and the estimated risk of death in hospital. The APACHE II score could not be correlated to the number of bed-days in the intensive care unit but to the resources employed measured as the number of therapeutic procedures carried out. The APACHE II scoring method was found to be employable in the prognosis for survival as a control of quality, as a tool for description of the degree of severity of illness and as an indirect measurement of the resources required.

Adult↗