A case of wheat-dependent exercise-induced anaphylaxis after specific oral immunotherapy

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The severity of sevoflurane-induced malignant hyperthermia.

BACKGROUND: Malignant hyperthermia (MH) is a potentially fatal complication of general anesthesia triggered by volatile anesthetics. In animal studies, sevoflurane has been reported to be a weak triggering agent. The aim of this study was to evaluate the clinical severity of sevoflurane-induced MH compared to isoflurane. METHODS: From the Japanese MH database containing information for 520 MH cases since 1961, we analyzed 147 cases classified by the MH Clinical Grading Scale (CGS) as 'very likely' or 'almost certain', accumulated from 1990 to 2009. Sevoflurane without succinylcholine (S-SCh (-) group) was given to 48 cases, and isoflurane without succinylcholine (I-SCh (-) group) was given to 30. Variables studied were outcome, CGS score, CGS rank, the first MH sign, and time from induction to onset of MH (occurrence time). Clinical signs and maximum laboratory data from six processes of the CGS were also analyzed. Each of the Mann-Whitney U-test or the unpaired t-test was used for group comparisons. RESULTS: Mortality was 8.3% in the S-SCh (-) group and 10.0% in the I-SCh (-) group (P = 0.803). The CGS scores were 53.4 (SD, 12.2) and 52.3 (11.7) (P = 0.691), respectively. The five processes of the CGS did not differ between groups. Median occurrence times were 72.5 minutes (range, 36.3-127.5) and 65.0 minutes (30.0-131.3), respectively (P = 0.890). CONCLUSION: There were no clinically apparent differences between MH triggered by sevoflurane and isoflurane, and thus no evidence to support the postulate that sevoflurane is a weak or weaker MH triggering agent.

Analysis of human cultured myotubes responses mediated by ryanodine receptor 1.

Malignant hyperthermia is a life-threatening condition caused by autosomal dominant mutations in the ryanodine receptor type 1 gene. Identifying patients predisposed to malignant hyperthermia is done through the Ca-induced Ca release test in Japan. We examined the intracellular calcium concentration in human cultured muscle cells and compared the sensitivity of myotubes to ryanodine receptor type 1 activators based on the Ca-induced Ca release rate. We assessed the utility of this method as an identifying test for predisposition to malignant hyperthermia. Muscle specimens were obtained from 34 individuals undergoing the Ca-induced Ca release test. We cultured myotubes from residual material and monitored changes in intracellular calcium concentration after exposure to the ryanodine receptor type 1 activators caffeine, halothane and 4-chloro-m-cresol by measuring fura-2 fluorescence. We determined the half maximal effective concentrations (EC50) for the test compounds in each myotube and calculated cut-off points using receiver operating characteristic curves. Seventeen patients each were classified into the accelerated and non-accelerated groups based on their Ca-induced Ca release rate. The EC50 values for caffeine, halothane and 4-chloro-m-cresol of the accelerated group were significant lower than those of the non-accelerated group (P < 0.001, P < 0.001 and P < 0.001, respectively). The calculated cut-off points of EC50 values for caffeine, halothane and 4-CmC were 3.62 mM, 2.28 mM and 197 microM, respectively. An increased sensitivity to ryanodine receptor type 1 activators was seen in myotubes in the accelerated group. This functional test on human cultured myotubes indicates that the alteration of their intracellular Ca2+ homeostasis may identify the predisposition to malignant hyperthermia.

Effects of propofol on calcium homeostasis in human skeletal muscle.

Malignant hyperthermia is a pharmacogenetic skeletal muscle disorder of intracellular calcium (Ca2+) homeostasis with an autosomal dominant inheritance. The objective of this study was to investigate the safety of propofol by investigating its effects on calcium homeostasis and its effect sites in human skeletal muscles. Muscle specimens were obtained from 10 individuals with predisposition to malignant hyperthermia. In skinned fibre experiments, we measured the effects of propofol on the Ca(2+)-induced Ca2+ release and the uptake of Ca2+ into the sarcoplasmic reticulum. Ca2+ imaging in primary myotubes was employed to analyse propofol-mediated alternations in the Ca2+ regulation and propofol-induced Ca2+ responses in the presence of Ca2+ channel blocker or Ca(2+)-induced Ca2+ release inhibitor. Increased Ca2+ release from the sarcoplasmic reticulum and inhibition of Ca2+ uptake into the sarcoplasmic reticulum were not observed with 100 microM propofol. A rise of Ca2+ was not seen under 100 microM propofol and the EC50 value for propofol was 274.7 +/- 33.9 microM, which is higher than the clinical levels for anaesthesia. Propofol-induced Ca2+ responses were remarkably attenuated in the presence of Ca2+ channel blocker or Ca(2+)-induced Ca+ release inhibitor compared with the results obtained with caffeine. We conclude firstly that propofol is safe for individuals with predisposition to malignant hyperthermia when it is used within the recommended clinical dosage range, and secondly that its mode of action upon ryanodine receptors is likely to be different from that of caffeine.

Propofol-induced changes in myoplasmic calcium concentrations in cultured human skeletal muscles from RYR1 mutation carriers.

Malignant hyperthermia is a pharmacogenetic disorder caused by autosomal dominant mutations in the ryanodine receptor type 1 gene. Propofol has been reported as a safe anaesthetic for malignant hyperthermia susceptible patients but has not been tested on cultured cells from patients with the ryanodine receptor type 1 mutation. The aim of this study was to determine whether propofol could trigger abnormal calcium fluxes in human myotubes isolated from malignant hyperthermia susceptible patients harbouring the native ryanodine receptor type 1 mutation. Muscle specimens were obtained from the patients to diagnose malignant hyperthermia disposition and the calcium-induced calcium release test and molecular genetic analyses were performed. Using the calcium sensitive probe Fura 2, we determined the 340/380 nm wave-length ratios by measuring alterations in calcium homeostasis in isolated myotubes from cultured skeletal muscle specimens. Two patients, one with ryanodine receptor type 1 R2508C and one with the L4838V mutation had accelerated calcium-induced calcium release rates. The 340/380 nm ratios increased when the propofol concentration exceeded 100 microM. The half-maximal activation concentrations (EC50) for propofol from patients 1 and 2 were 181.1 and 420.5 microM, respectively. Increases in calcium concentrations in response to propofol dosage were limited to doses at least 100-fold greater than those used in clinical settings. These observations correlate well with clinical observations that propofol does not trigger malignant hyperthermia in susceptible humans.

Nociceptin system does not affect MAC of volatile anaesthetics.

BACKGROUND: Nociceptin is the endogenous agonist of the opioid receptor-like (ORL) 1 receptor (NOP), and both nociceptin and NOP are widely expressed in the brain and spinal cord, which are target organs of general anaesthetics. As nociceptin has been reported to be involved in modulating pain mechanisms and stress responses, it is possible that the activity of the nociceptin system affects the anaesthetic potency of general anaesthetics. To address this possibility, we investigated the minimum alveolar concentrations (MACs) of various volatile anaesthetics in nociceptin receptor knockout mice (NOP-/-) and wild-type mice (NOP+/+). METHODS: We used male NOP-/- mice and NOP+/+ mice. MACs for halothane, isoflurane and sevoflurane were determined by the tail-clamp method. RESULTS: MACs for halothane, isoflurane and sevoflurane in NOP-/- mice were 1.60 (SD 0.06), 1.68 (0.08) and 3.36 (0.07)%, respectively. In NOP+/+ mice, MACs for halothane, isoflurane and sevoflurane were 1.59 (SD 0.07), 1.72 (0.07) and 3.38 (0.09)%, respectively. CONCLUSION: MACs in NOP-/- mice did not significantly differ from those in NOP+/+ mice for halothane, isoflurane and sevoflurane. This result suggests that the nociceptin system does not affect the anaesthetic potency of volatile anaesthetics.

Prediction of accelerated Ca-induced Ca release rate by clinical findings in malignant hyperthermia susceptible subjects.

BACKGROUND: An abnormally accelerated Ca-induced Ca release (CICR) rate is known to be correlated with malignant hyperthermia susceptibility (MHS). OBJECTIVE: To analyze significant clinical findings concerning CICR rate and develop a computer program for its prediction in human MHS. PATIENTS AND METHOD: Using data from 146 subjects who had received a muscle biopsy for the determination of CICR rate, because of their anesthesia-related MHS history, we analyzed 23 different clinical features. There were 71 subjects with an abnormally accelerated CICR rate and 75 with a normal rate. Accelerated CICR rate was used as the objective variable whilst clinical findings and ages were used as independent variables and control variables, respectively. A multiple logistic regression model was employed for the analyses and the most suitable formulae for prediction were determined for use in the development of a computer program. RESULTS: The following 8 clinical findings were determined to be the most significant: the presence of muscle rigidity, the most serious PaCO2 reading (mmHg), peak body temperature (degree C), body temperature rate of increase over 15 minutes (degree C/15 minutes), most serious arterial pH reading, administration of dantrolene, improvement of acidosis with dantrolene, and time elapsed to peak body temperature after administration of anesthetics (minutes). By ranking the subject ages into 14 groups, we were able to minimize the prediction error rate with each corresponding formula. The computer program developed for prediction whilst consisted of these formulae yielded a sensitivity of 80% and a specificity of 86%. CONCLUSION: This method of prediction may contribute to the accurate prediction of CICR rate at the bedside. For clinical convenience, we will distribute the computer program upon request.

The McCoy laryngoscope, external laryngeal pressure, and their combined use.

The efficacy of the McCoy laryngoscope, external laryngeal pressure, and their combination to improve the laryngoscopic view was evaluated in 219 patients and compared with the Macintosh laryngoscope. An experienced laryngoscopist performed laryngoscopy twice using the Macintosh laryngoscope and the McCoy laryngoscope in a random sequence, and external laryngeal pressure was applied in each laryngoscopy with the laryngoscopist's right hand. The laryngoscopic view obtained was graded on our modified Cormack's method. Without external laryngeal pressure, the McCoy laryngoscope provided a better laryngoscopic view than that obtained by the Macintosh laryngoscope (P < 0.001, signed rank test), but the view was worse than that with the Macintosh laryngoscope under external laryngeal pressure (P < 0.001). The McCoy laryngoscope combined with external laryngeal pressure provided a better view than the Macintosh laryngoscope with external laryngeal pressure (P < 0.001).

Comparison of the in vitro caffeine-halothane contracture test with the Ca-induced Ca release rate test in patients suspected of having malignant hyperthermia susceptibility.

PURPOSE: We compared the results of the in vitro caffeine-halothane contracture test (CHCT) according to the protocols of the North American Malignant Hyperthermia Group (NAMHG) and the European Malignant Hyperthermia Group (EMHG) with the Ca-induced Ca release (CICR) rate test in the same patients with suspected malignant hyperthermia (MH). METHODS: Five normal controls and 16 patients suspected of having MH susceptibility were studied. Muscle biopsies were usually obtained from the musculus vastus lateralis. Diagnostic cutoff points and procedures for CHCT protocols were as described in the original and renewal versions of NAMHG and EMHGs. The CICR rate test was performed according to the protocol reported by Endo et al. RESULTS: All five normal controls and two patients with abortive MH, two with postoperative hyperthermia, and three with high serum creatine kinase levels were normal in the three tests. Three patients with MH reactions and one patient with a history of masseter spasm were classified as MH positive according to NAMHG criteria and MH susceptible and MH equivocal according to EMHG criteria. There were five cases with discordant results between the CHCT and CICR rate tests. CONCLUSION: We propose that muscle biopsy for diagnosis of MH susceptibility should combine the CHCT with the CICR rate test, which may identify the defective site of Ca release channels.

Genetic analysis with calcium-induced calcium release test in Japanese malignant hyperthermia susceptible (MHS) families.

Some genetic studies have shown a linkage between malignant hyperthermia susceptibility (MHS) and chromosome 19q or the skeletal muscle ryanodine receptor (RYR1) gene. Some types of MHS seem to be caused by an abnormality of calcium-induced calcium release (CICR). We analyzed the linkage of RYR1 gene polymorphisms in Japanese MHS families and investigated the correlation between genetic evidence of RYR1 gene mutations and an accelerated rate of CICR. We studied 63 subjects who were referred to our institute for investigation of MHS. CICR rates were measured by the skinned fiber method in 23 subjects. DNA samples were collected from 63 individuals belonging to 22 unrelated families. Restriction fragment length polymorphism (RFLP) analyses on the RYR1 locus and hypervariable microsatellite analysis were performed. We found one family with a linkage between acceleration of the CICR mechanism and a group of RFLPs. In CICR tests, ten of the 11 patients who had presented with fulminant MH showed accelerated rates of CICR. Analysis for the mutation C1840T, which was performed in 63 samples, did not demonstrate an alteration in any of the patients. Although we found heterozygotes in RFLP studies, we did not recognize a specific relationship between the acceleration of CICR and the RFLPs. We suggest a linkage between the acceleration of CICR and an abnormal human RYR1 gene in MHS. These results also suggest that heterogeneity exists for MH. We conclude that genetic tests cannot replace CICR tests or caffeine-halothane contracture tests with muscle biopsy as a diagnosing test for MH in the near future.

[General anesthesia with propofol and fentanyl for adult cardiac surgery].

We employed propofol anesthesia with a restricted dose of fentanyl in adult cardiac surgery with the aim of early tracheal extubation and evaluated its effects on the intraoperative factors and postoperative recovery compared with those of a previous benzodiazepine-fentanyl regimen. During surgery, control group patients (n = 17) received intermittent bolus of benzodiazepines and fentanyl without restriction, whereas propofol group patients (n = 17) received continuous administration of propofol and the restricted dose of fentanyl (20 micrograms.kg-1). There were no significant differences in the times to eye opening (average 2.4 hr vs 1.6 hr, respectively, P = 0.30) and tracheal extubation (average 5.4 hr vs 4.0 hr, P = 0.25) between the groups. Both groups had similar postanesthetic circulatory status: cardiac index (average 3.6 l.min-1.m-2 vs 3.4 l.min-1.m-2, P = 0.46). The propofol group patients required smaller doses of vasodilators during cardiopulmonary bypass (average PGE1: 0.096 microgram.kg-1.min-1 vs 0.047 microgram.kg-1.min-1, P = 0.046, NTG: 0.69 microgram.kg-1.min-1 vs 0.31 microgram.kg-1.min-1, P = 0.009). It is suggested that propofol-based anesthesia could replace the previous regimen with no adverse hemodynamic effects and might have a potential to provide faster recovery and improve peripheral circulatory status in adult cardiac surgery.

[Living related liver transplantation for patients with ornithine transcarbamylase deficiency].

Ornithine transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis inherited as an X-linked trait, a clinical manifestation of which is a repeated episodes of hyperammonemic coma. Recently, liver transplantations have been performed in these patients in the USA and Europe. We experienced the anesthetic managements of liver transplantations in two OTCD patients, who had been suffering from several episodes of hyperammonemic decompensation despite a restricted protein diet with administration of sodium benzoate. Anesthesia was induced and maintained with a combination of fentanyl and midazolam in both cases. Their postoperative courses were good without any neurological damages, though one patient had hyperammonemic attack during the operation.

[Anesthetic management of patients with pheochromocytoma for adrenalectomy using balanced anesthesia with continuous infusion of nicardipine and nitroglycerin].

Four patients underwent surgical removal of pheochromocytoma under balanced anesthesia with fentanyl, sevoflurane and epidural anesthesia combined with continuous infusion of nicardipine and nitroglycerin. Circulation was stable during the operation in all the patients. There were no serious hypertension and hypotension, arrhythmia and pulmonary edema during the postoperative period. We conclude that the anesthetic management of patients with pheochromocytoma for adrenalectomy using balanced anesthesia with continuous infusion of nicardipine and nitroglycerin is one of the most useful anesthetic methods.

[Comparative study of in vitro diagnosis by the skinned fiber test and clinical diagnosis of malignant hyperthermia].

Skeletal muscles from twenty patients suspected of malignant hyperthermia during general anesthesia were examined with the skinned fiber test for abnormality in the Ca2+ release function of their sarcoplasmic reticulum, and the result was correlated with the classifications of the patients in accordance with the clinical criteria now used in Japan. Among them, fourteen patients were diagnosed as clinical malignant hyperthermia syndrome (fulminant syndrome: 4, abortive syndrome: 10). Three out of four fulminant cases showed potentiated Ca-induced Ca release mechanism of the sarcoplasmic reticulum in their skeletal muscles. The others including six patients not diagnosed as malignant hyperthermia were normal in the sarcoplasmic reticulum function. This suggests that the skinned fiber test has comparatively high sensitivity to fulminant malignant hyperthermia syndrome. The present paper discusses, based on the present results, the problems resulting from the difference in diagnostic concept between in vitro criteria by the skinned fiber test to detect a specific pathogenetical factor in the skeletal muscle of a single abnormality and clinical criteria to pick up a series of relatively non-specific symptoms and signs of a clinical syndrome.

Biotransformation of isoflurane: urinary and serum fluoride ion and organic fluorine.

The serum and urinary concentrations of fluorinated metabolites of isoflurane after inhalation of three different concentrations of isoflurane were studied in 18 ASA physical status 1 or 2 patients, scheduled for orthopedic or otolaryngeal surgery. Isoflurane was administered for 60 min during fentanyl-nitrous oxide-oxygen, and its end-tidal concentration was maintained at 0.3, 0.6, or 1.15% (groups I, II, and III). The organic fluorine was determined by combustion and fluoride ions were analyzed by ion chromatography. The amounts were expressed in terms of fluoride ion. The concentrations of serum fluoride ion and organic fluorine increased significantly 15 min after the onset of inhalation of isoflurane. The mean peak values of fluoride ions were 3.8 +/- 1.1, 3.9 +/- 1.4, and 4.2 +/- 0.9 mumole/1 (M +/- SD) in patients in groups I, II, and III, respectively. The half-lives of fluoride ion and of organic fluorine as metabolites of isoflurane, calculated from the amounts excreted in urine, were 36 h and 41 h, respectively. The cumulative amounts of fluoride ion and organic fluorine excreted up to the 6th postoperative day were 548 +/- 230 and 785 +/- 452 mumoles in group I, 594 +/- 138 and 1,378 +/- 807 mumoles in group II, and 1,032 +/- 496 and 728 +/- 265 mumoles (M +/- SD) in group III, respectively. The urinary excreted fluoride ion increased in proportion to the dose of isoflurane and approximately 1.3 mmol was excreted per 1 MAC X hour inhalation of isoflurane. The authors concluded that isoflurane might be biotransformed to a greater extent than reported previously, although the serum fluoride ion level was found to be low.