Oral Dantrolene for Myopathic Symptoms in Malignant Hyperthermia-Susceptible Patients: A 25-Year Retrospective Cohort Study of Adverse Effects and Tolerability.

BACKGROUND: Patients susceptible to malignant hyperthermia (MH) may experience disabling manifestations of an unspecified myopathy outside the context of anesthesia, including myalgia, fatigue, or episodic rhabdomyolysis. Clinical observations suggest that oral dantrolene may relief myopathic symptoms in MH-susceptible (MHS) patients. However, high-dose oral dantrolene has been associated with severe hepatotoxicity. METHODS: In a retrospective database review (1994-2018), we investigated a cohort of patients who were diagnosed as MHS by a positive caffeine-halothane contracture test (CHCT), had myopathic manifestations, and received oral dantrolene. Our aim was to investigate the occurrence of serious adverse effects and the adherence to oral dantrolene therapy. We also explored factors associated with self-reported clinical improvement, considering as nonresponders patients with intolerable adverse effects or who reported no improvement 8 weeks after starting treatment. RESULTS: Among 476 MHS patients with positive CHCT, 193 had muscle symptoms, 164 started oral dantrolene, 27 refused treatment, and 2 were excluded due to abnormal liver function before starting therapy. There were no serious adverse effects reported. Forty-six of 164 patients (28%; 95% confidence interval [CI], 22%-35%) experienced mild to moderate adverse effects. Twenty-two patients (22/164, 13%; 95% CI, 9%-19%) discontinued treatment, among which 16 due to adverse effects and 6 due to lack of improvement. One hundred forty-two patients (87%; 95% CI, 80%-90%) adhered to therapy and reported improvement of myalgia (n = 78), fatigue (n = 32), or rhabdomyolysis/hiperCKemia (n = 32). The proportion of responders was larger among patients with MH history than among those referred due to a clinical myopathy with nonpertinent anesthetic history (97% vs 79%, respectively; 95% CI of the difference, 8.5-28; P < .001). Patients with a sarcoplasmic reticulum Ca2+ release channel ryanodine receptor gene ( RYR1 ) variant had higher odds of responding to dantrolene treatment (OR, 6.4; 95% CI, 1.3-30.9; P = .013). Dantrolene median dose was 50 (25-400) and 200 (25-400) mg·day -1 in responders and nonresponders, respectively. CONCLUSIONS: We found that oral dantrolene produced no serious adverse effects within the reported dose range, and was well tolerated by most MH-susceptible patients presenting myopathic symptoms. Our study provides dosing and adverse effect data as a basis for further randomized controlled clinical trials to determine the efficacy of oral dantrolene for symptomatic relief in MHS-related myopathies.

Analysis of clinically-reported, memantine-induced cardiovascular adverse responses using the halothane-anesthetized dogs: Reverse translational study.

Although NMDA receptor antagonist memantine is considered to be better tolerated than cholinesterase inhibitors on treating Alzheimer's disease, several types of cardiovascular adverse events have been associated with memantine treatment, including hypertension, myocardial infarction, severe bradycardia and QT-interval prolongation. In order to clarify how memantine induces these cardiovascular adverse events, we assessed its electropharmacological effects using the halothane-anesthetized dogs (n = 4). Memantine hydrochloride was intravenously administered in doses of 0.01, 0.1 and 1 mg/kg over 10 min, providing subtherapeutic, clinically-relevant and supratherapeutic concentrations, respectively. The low to high doses increased the mean blood pressure and left ventricular contraction and enhanced the atrioventricular nodal conduction, suggesting an increase of sympathicotonic output from the central nervous system similarly to donepezil, which might induce myocardial ischemia in patients with coronary artery disease. Meanwhile, the high dose suppressed the intra-atrial conduction and the low to high doses inhibited the intra-ventricular conduction, indicating potential to induce severe bradycardic adverse event by advanced cardiac conduction block in susceptible patients. Memantine alone did not induce repolarization delay, indicating lack of risk for inducing torsade de pointes. Thus, these in vivo experimental findings may provide basic information to better understand the clinically observed adverse events of memantine.

The Effects of Volatile Anesthetics on Lung Ischemia-Reperfusion Injury: Basic to Clinical Studies.

Case reports from as early as the 1970s have shown that intravenous injection of even a small dose of volatile anesthetics result in fatal lung injury. Direct contact between volatile anesthetics and pulmonary vasculature triggers chemical damage in the vessel walls. A wide variety of factors are involved in lung ischemia-reperfusion injury (LIRI), such as pulmonary endothelial cells, alveolar epithelial cells, alveolar macrophages, neutrophils, mast cells, platelets, proinflammatory cytokines, and surfactant. With a constellation of factors involved, the assessment of the protective effect of volatile anesthetics in LIRI is difficult. Multiple animal studies have reported that with regards to LIRI, sevoflurane demonstrates an anti-inflammatory effect in immunocompetent cells and an anti-apoptotic effect on lung tissue. Scattered studies have dismissed a protective effect of desflurane against LIRI. While a single-center randomized controlled trial (RCT) found that volatile anesthetics including desflurane demonstrated a lung-protective effect in thoracic surgery, a multicenter RCT did not demonstrate a lung-protective effect of desflurane. LIRI is common in lung transplantation. One study, although limited due to its small sample size, found that the use of volatile anesthetics in organ procurement surgery involving "death by neurologic criteria" donors did not improve lung graft survival. Future studies on the protective effect of volatile anesthetics against LIRI must examine not only the mechanism of the protective effect but also differences in the effects of different types of volatile anesthetics, their optimal dosage, and the appropriateness of their use in the event of marked alveolar capillary barrier damage.

Dietary Caffeine Synergizes Adverse Peripheral and Central Responses to Anesthesia in Malignant Hyperthermia Susceptible Mice.

Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (EEG) total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF ± HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single-channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MH susceptibility exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations. SIGNIFICANCE STATEMENT: Dietary caffeine at a human-relevant dose synergizes adverse peripheral and central responses to anesthesia in malignant hyperthermia susceptible mice. Synergism of these drugs can be attributed to their actions at ryanodine receptors.

Sensitivity of inhalation anesthetics isoflurane and sevoflurane for the drug-induced QT-interval prolongation in guinea pigs.

We investigated effects of isoflurane and sevoflurane on sparfloxacin-induced QT-interval prolongation in guinea pigs under the monitoring of electrocardiogram and monophasic action potential (MAP), which was compared with those of halothane or non-inhaled anesthetics ketamine/xylazine. Intravenous administration of sparfloxacin at 3 and 10 mg/kg prolonged the QT interval and MAP duration together with bradycardic action under 4 different anesthetic conditions. The order of extent of prolongation of corrected QT interval after the administration of sparfloxacin was isoflurane ≈ sevoflurane ≈ halothane >> ketamine/xylazine, whereas that of the MAP90 at a pacing cycle length of 300 ms was halothane ≥ isoflurane ≈ sevoflurane >> ketamine/xylazine. These results suggest that isoflurane and sevoflurane as well as halothane could sensitize the heart to sparfloxacin-induced QT interval prolongation in guinea pigs.

Thymic stromal lymphopoietin and interleukin-4 mediate the pathogenesis of halothane-induced liver injury in mice.

UNLABELLED: Liver eosinophilia has been associated with incidences of drug-induced liver injury (DILI) for more than 50 years, although its role in this disease has remained largely unknown. In this regard, it was recently shown that eosinophils played a pathogenic role in a mouse model of halothane-induced liver injury (HILI). However, the signaling events that drove hepatic expression of eosinophil-associated chemokines, eotaxins, eosinophil infiltration, and subsequent HILI were unclear. We now provide evidence implicating hepatic epithelial-derived cytokine thymic stromal lymphopoietin (TSLP) and type 2 immunity, in particular, interleukin-4 (IL-4) production, in mediating hepatic eosinophilia and injury during HILI. TSLP was constitutively expressed by mouse hepatocytes and increased during HILI. Moreover, the severity of HILI was reduced in mice deficient in either the TSLP receptor (TSLPR) or IL-4 and was accompanied by decreases in serum levels of eotaxins and hepatic eosinophilia. Similarly, concanavalin A-induced liver injury, where type 2 cytokines and eosinophils play a significant role in its pathogenesis, was also reduced in TSLPR-deficient mice. Studies in vitro revealed that mouse and human hepatocytes produce TSLP and eotaxins in response to treatment with combinations of IL-4 and proinflammatory cytokines IL-1ß and tumor necrosis factor alpha. CONCLUSION: This report provides the first evidence implicating roles for hepatic TSLP signaling, type 2 immunity, and eosinophilia in mediating liver injury caused by a drug.

Malignant hyperthermia testing in probands without adverse anesthetic reaction.

BACKGROUND: Malignant hyperthermia (MH) is triggered by reactions to anesthetics. Reports link nonanesthetic-induced MH-like reactions to a variety of disorders. The objective of the authors was to retrospectively investigate the reasons for referrals for MH testing in nonanesthetic cases and assess their phenotype. In addition, the response to the administration of oral dantrolene in nonanesthetic probands with positive caffeine-halothane contracture test (CHCT) was investigated. METHODS: Following institutional research ethics board approval, probands without reaction to anesthesia, who underwent CHCT, were selected. Clinical details and response to dantrolene were analyzed. RESULTS: In total, 87 of 136 (64%) patients referred for nonanesthetic indications tested positive to the CHCT. Of these, 47 with a high creatine kinase (CK), 9 with exercise-induced rhabdomyolysis and/or exercise intolerance, 2 with high CK and exercise-induced rhabdomyolysis and/or exercise intolerance, 15 with postviral chronic fatigue, and 14 with muscle weakness of unknown etiology had a positive CHCT. These patients had a higher CK compared with those with negative CHCT. Oral dantrolene improved the musculoskeletal symptoms in 28 of 34 (82%) CHCT-positive patients. Response to treatment was associated with a significantly higher pretreatment CK and a greater posttreatment CK reduction. CONCLUSIONS: A positive CHCT may represent more than simply an anesthetic-related disorder. Individuals with positive CHCTs may exhibit muscle symptoms without exposure to MH-triggering anesthetics. Oral dantrolene may be useful in alleviating these symptoms.

Eosinophils mediate the pathogenesis of halothane-induced liver injury in mice.

UNLABELLED: Drug-induced liver injury (DILI) is a major health issue, as it remains difficult to predict which new drugs will cause injury and who will be susceptible to this disease. This is due in part to the lack of animal models and knowledge of susceptibility factors that predispose individuals to DILI. In this regard, liver eosinophilia has often been associated with DILI, although its role remains unclear. We decided to investigate this problem in a murine model of halothane-induced liver injury (HILI). When female Balb/cJ mice were administered halothane, eosinophils were detected by flow cytometry in the liver within 12 hours and increased thereafter proportionally to liver damage. Chemokines, eotaxin-1 (CCL11) and eotaxin-2 (CCL24), which are known to attract eosinophils, increased in response to halothane treatment. The severity of HILI was decreased significantly when the study was repeated in wildtype mice made deficient in eosinophils with a depleting antibody and in eosinophil lineage-ablated ΔdblGata(-/-) mice. Moreover, depletion of neutrophils by pretreating animals with Gr-1 antibody prior to halothane administration failed to reduce the severity of HILI at antibody concentrations that did not affect hepatic eosinophils. Immunohistochemical staining for the granule protein, major basic protein, revealed that eosinophils accumulated exclusively around areas of hepatocellular necrosis. CONCLUSION: Our findings indicate that eosinophils have a pathologic role in HILI in mice and suggest that they may contribute similarly in many clinical cases of DILI.

Anesthetic drugs and onset of malignant hyperthermia.

BACKGROUND: The time between the beginning of anesthetic administration and recognition of the first sign of malignant hyperthermia (MH) (MH onset time) could differ among anesthetic drugs. METHODS: We examined the time of the first signs of suspected MH, anesthetic drugs administered, subject age, and year of event in Adverse Metabolic/Musculoskeletal Reaction to Anesthesia reports in the North American Malignant Hyperthermia Registry. Inclusion criteria were judgment by the reporting clinician that the event was possible or fulminant MH, documentation of the time when anesthetic administration began, and the time when the first MH sign was noted. Descriptive statistics, Kruskal-Wallis analysis, and nonparametric correlation were used to assess the difference in MH onset times under different conditions. RESULTS: Four hundred seventy-seven cases met inclusion criteria; 58.5% were possible MH and 41.5% fulminant MH. Inhaled anesthetic and succinylcholine were given in 53.9% of cases, inhaled anesthetic only in 41.7%, and succinylcholine without inhaled anesthetics in 2.9%. No causative anesthetic drugs were reported in 7 MH cases. In 394 patients exposed to only 1 of the 4 inhaled anesthetics, without regard for subject age, MH onset time was shorter in the presence of halothane than any of the other anesthetics and shorter after succinylcholine in all anesthetics. If succinylcholine was not given, MH onset was shorter during sevoflurane anesthesia than during desflurane or isoflurane. In 322 cases, 1 rather than multiple first signs of MH were reported with masseter spasm as the earliest MH sign. In 339 cases in which masseter spasm was not reported, there was no difference in MH onset time with or without succinylcholine. In 146 cases in which masseter spasm was not reported and succinylcholine was not given, MH onset was shorter during halothane anesthesia, than during exposure to desflurane, or isoflurane. MH onset time during sevoflurane was shorter than during desflurane or isoflurane. MH was reported later in the course of anesthesia after 1998, when halothane and succinylcholine were less often reported. MH occurred after succinylcholine administration in the absence of inhaled anesthetics. We could not separate an effect of age from that of other variables. CONCLUSION: The onset of MH has been observed later during desflurane and isoflurane anesthesia than during exposure to sevoflurane. Since 1998, MH signs have more often appeared later, in the second or third hour of anesthesia, than they did before 1998.

Malignant hyperthermia in Canada: characteristics of index anesthetics in 129 malignant hyperthermia susceptible probands.

BACKGROUND: Between 1992 and 2011, 373 Canadian individuals with adverse anesthetic reaction were referred to the Malignant Hyperthermia Unit in Toronto, Ontario, Canada for malignant hyperthermia (MH) diagnostic testing. We analyzed the epidemiologic characteristics of the index adverse anesthetics for those probands who were confirmed to be MH susceptible. METHODS: One hundred twenty-nine proband survivors of adverse anesthetic reactions, whose MH susceptible status was confirmed by caffeine-halothane contracture testing were selected. Individuals were excluded if the index anesthetic record was not available for review. Data regarding demographics, clinical signs, laboratory findings, treatment, and complications were retrospectively compiled and analyzed. A Fisher exact test and χ test were applied to compare categorical variables. The Wilcoxon rank-sum test was applied with continuous variables. RESULTS: Young males (61.2%) dominated among selected patients. Seventeen of 129 (13.2%) patients had prior unremarkable anesthesia. Anesthetic triggers were volatile-only (n = 58), succinylcholine-only (n = 20), or both volatile and succinylcholine (n = 51). Eight (6.2%) cases occurred in the postanesthetic care unit. There were no reactions after discharge from the postanesthetic care unit. The most frequent clinical signs were hyperthermia (66.7%), sinus tachycardia (62.0%), and hypercarbia (51.9%). Complications occurred in 20.1% of patients, the most common complication being renal dysfunction. When 20 or more minutes between the first adverse sign and dantrolene treatment elapsed, complication rates increased to ≥30%. CONCLUSIONS: This is the first Canadian study in 3 decades to report nationwide data on MH epidemiology. Features that differ from earlier reports include a 15.5% incidence of reactions triggered by succinylcholine alone and lower complication rates. In agreement with previously published studies, we confirmed in this independent dataset that increased complication rates were associated with an increased time interval between the first adverse clinical sign and dantrolene treatment. This underscores the need for early diagnosis and rapid dantrolene access and administration in anesthetizing locations using either succinylcholine or volatile anesthetic drugs.

Effects of sevoflurane versus other general anaesthesia on emergence agitation in children.

BACKGROUND: Sevoflurane is an inhaled volatile anaesthetic that is widely used in paediatric anaesthetic practice. Since its introduction, postoperative behavioural disturbance known as emergence agitation (EA) or emergence delirium (ED) has been recognized as a problem that may occur during recovery from sevoflurane anaesthesia. For the purpose of this systematic review, EA has been used to describe this clinical entity. A child with EA may be restless, may cause self-injury or may disrupt the dressing, surgical site or indwelling devices, leading to the potential for parents to be dissatisfied with their child's anaesthetic. To prevent such outcomes, the child may require pharmacological or physical restraint. Sevoflurane may be a major contributing factor in the development of EA. Therefore, an evidence-based understanding of the risk/benefit profile regarding sevoflurane compared with other general anaesthetic agents and adjuncts would facilitate its rational and optimal use. OBJECTIVES: To compare sevoflurane with other general anaesthetic (GA) agents, with or without pharmacological or non-pharmacological adjuncts, with regard to risk of EA in children during emergence from anaesthesia. The primary outcome was risk of EA; secondary outcome was agitation score. SEARCH METHODS: We searched the following databases from the date of inception to 19 January 2013: CENTRAL, Ovid MEDLINE, Ovid EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCOhost), Evidence-Based Medicine Reviews (EBMR) and the Web of Science, as well as the reference lists of other relevant articles and online trial registers. SELECTION CRITERIA: We included all randomized (or quasi-randomized) controlled trials investigating children < 18 years of age presenting for general anaesthesia with or without surgical intervention. We included any study in which a sevoflurane anaesthetic was compared with any other GA, and any study in which researchers investigated adjuncts (pharmacological or non-pharmacological) to sevoflurane anaesthesia compared with no adjunct or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently searched the databases, decided on inclusion eligibility of publications, ascertained study quality and extracted data. They then resolved differences between their results by discussion. Data were entered into RevMan 5.2 for analyses and presentation. Comparisons of the risk of EA were presented as risk ratios (RRs) with 95% confidence intervals (CIs). Sevoflurane is treated as the control anaesthesia in this review. Sensitivity analyses were performed as appropriate, to exclude studies with a high risk of bias and to investigate heterogeneity. MAIN RESULTS: We included 158 studies involving 14,045 children. Interventions to prevent EA fell into two broad groups. First, alternative GA compared with sevoflurane anaesthesia (69 studies), and second, use of an adjunct with sevoflurane anaesthesia versus sevoflurane without an adjunct (100 studies). The overall risk of bias in included studies was low. The overall Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE) assessment of the quality of the evidence was moderate to high. A wide range of EA scales were used, as were different levels of cutoff, to determine the presence or absence of EA. Some studies involved children receiving potentially inadequate or no analgesia intraoperatively during painful procedures.Halothane (RR 0.51, 95% CI 0.41 to 0.63, 3534 participants, high quality of evidence) and propofol anaesthesia were associated with a lower risk of EA than sevoflurane anaesthesia. Propofol was effective when used throughout anaesthesia (RR 0.35, 95% CI 0.25 to 0.51, 1098 participants, high quality of evidence) and when used only during the maintenance phase of anaesthesia after sevoflurane induction (RR 0.59, 95% CI 0.46 to 0.76, 738 participants, high quality of evidence). No clear evidence was found of an effect on risk of EA of desflurane (RR 1.46, 95% CI 0.92 to 2.31, 408 participants, moderate quality of evidence) or isoflurane (RR 0.76, 95% CI 0.46 to 1.23, 379 participants, moderate quality of evidence) versus sevoflurane.Compared with no adjunct, effective adjuncts for reducing the risk of EA during sevoflurane anaesthesia included dexmedetomidine (RR 0.37, 95% CI 0.29 to 0.47, 851 participants, high quality of evidence), clonidine (RR 0.45, 95% CI 0.31 to 0.66, 739 participants, high quality of evidence), opioids, in particular fentanyl (RR 0.37, 95% CI 0.27 to 0.50, 1247 participants, high quality of evidence) and a bolus of propofol (RR 0.58, 95% CI 0.38 to 0.89, 394 participants, moderate quality of evidence), ketamine (RR 0.30, 95% CI 0.13 to 0.69, 231 participants, moderate quality of evidence) or midazolam (RR 0.57, 95% CI 0.41 to 0.81, 116 participants, moderate quality of evidence) at the end of anaesthesia. Midazolam oral premedication (RR 0.81, 95% CI 0.59 to 1.12, 370 participants, moderate quality of evidence) and parental presence at emergence (RR 0.91, 95% CI 0.51 to 1.60, 180 participants, moderate quality of evidence) did not reduce the risk of EA.One or more factors designated as high risk of bias were noted in less than 10% of the included studies. Sensitivity analyses of these studies showed no clinically relevant changes in the risk of EA. Heterogeneity was significant with respect to these comparisons: halothane; clonidine; fentanyl; midazolam premedication; propofol 1 mg/kg bolus at end; and ketamine 0.25 mg/kg bolus at end of anaesthesia. With investigation of heterogeneity, the only clinically relevant changes to findings were seen in the context of potential pain, namely, the setting of adenoidectomy/adenotonsillectomy (propofol bolus; midazolam premedication) and the absence of a regional block (clonidine). AUTHORS' CONCLUSIONS: Propofol, halothane, alpha-2 agonists (dexmedetomidine, clonidine), opioids (e.g. fentanyl) and ketamine reduce the risk of EA compared with sevoflurane anaesthesia, whereas no clear evidence shows an effect for desflurane, isoflurane, midazolam premedication and parental presence at emergence. Therefore anaesthetists can consider several effective strategies to reduce the risk of EA in their clinical practice. Future studies should ensure adequate analgesia in the control group, for which pain may be a contributing or confounding factor in the diagnosis of EA. Regardless of the EA scale used, it would be helpful for study authors to report the risk of EA, so that this might be included in future meta-analyses. Researchers should also consider combining effective interventions as a multi-modal approach to further reduce the risk of EA.

Effect of the halothane genotype on intramuscular fat deposition in swine.

Intramuscular fat (IMF) content has been identified as an important factor in determining the quality of pork. Previous studies have suggested that IMF deposition may be associated with the presence of the halothane (HAL) gene. This study aimed to evaluate the effect of the HAL gene on IMF deposition in crossbred pigs of commercial lines, which were killed at a slaughterhouse under official inspection. The genotype of the HAL gene was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. IMF was analyzed from longissimus dorsi samples. Among all animals analyzed, 42.36% were of the HalNN genotype and 57.64% were of the HalNn genotype. The average IMF content of all samples was 2.14%. Variation in IMF between genotypes was evaluated by analysis of variance. No significant difference in IMF deposition, which could be based on the presence of the halothane allele, was observed, at least in heterozygotes.

Urinary lipid and protein oxidation products upon halothane, isoflurane, or sevoflurane anesthesia in humans: potential biomarkers for a subclinical nephrotoxicity.

OBJECTIVE: To investigate whether lipid and protein oxidation products are elevated and correlated with routine clinical markers of hepatic and renal function in patients anesthetized with halothane, isoflurane, or sevoflurane. METHODS: Urine and blood samples were collected from patient groups. Excretion of aldehydes, acetone, and o,o'-dityrosine was measured before and after anesthesia. Blood samples were analysed for clinical markers. RESULTS: Urinary concentrations of aldehydes, acetone, o,o'-dityrosine and glucose were significantly increased after anesthesia in halothane and sevoflurane groups earlier than clinical markers. Significant correlations were found in sevoflurane group. CONCLUSION: Lipid and protein oxidation contributes to subclinical sevoflurane nephrotoxicity. Oxidation products may serve as early biomarkers.

Ryanodine receptor type 1 gene variants in the malignant hyperthermia-susceptible population of the United States.

BACKGROUND: Mutations in the ryanodine receptor type 1 gene (RYR1) that encodes the skeletal muscle-specific intracellular calcium (Ca(2+)) release channel are a cause of malignant hyperthermia (MH). In this study, we examined RYR1 mutations in a large number of North American MH-susceptible (MHS) subjects without prior genetic diagnosis. METHODS: RYR1 was examined in 120 unrelated MHS subjects from the United States in a tiered manner. The α-1 subunit of the dihydropyridine receptor gene (CACNA1S) was screened for 4 variants in subjects in whom no abnormality was found in ≥ 100 exons of RYR1. RESULTS: Ten known causative MH mutations were found in 26 subjects. Variants of uncertain significance in RYR1 were found in 36 subjects, 16 of which are novel. Novel variants in both RYR1 and CACNA1S were found in the 1 subject who died of MH. Two RYR1 variants were found in 4 subjects. Variants of uncertain significance were found outside and inside the hotspots of RYR1. Maximal contractures in the caffeine-halothane contracture test were greater in those who had a known MH mutation or variant of uncertain significance in RYR1 than in those who did not. CONCLUSIONS: The identification of novel RYR1 variants and previously observed RYR1 variants of uncertain significance in independent MHS families is necessary for demonstrating the significance of these variants for MH susceptibility and supports the need for functional studies of these variants. Continued reporting of the clinical phenotypes of MH is necessary for interpretation of genetic findings, especially because the pathogenicity of most of these genetic variants associated with MHS remains to be elucidated.

A family with discordance between malignant hyperthermia susceptibility and rippling muscle disease.

Rippling muscle disease (RMD) is a disorder that affects striated muscle and involves disturbances in calcium homeostasis. Malignant hyperthermia susceptibility (MHS) is a potentially lethal disorder, characterized by extreme hypermetabolism and muscle rigidity/rhabdomyolysis during anesthesia with potent inhalational agents, in otherwise healthy individuals. The aim of this report was to search for a correlation between RMD and MHS in members of a family in which both disorders were present. Ten members of a large Swedish family segregating RMD were tested for MHS prior to establishing an RMD diagnosis. Results from diagnostic RMD investigations and anesthesia outcomes were collected and cross-referenced to evaluate whether phenotype variations could be predicted by in vitro contracture test (IVCT) results suggestive of MHS. No correlation was found between individual RMD phenotypes and the IVCT results. There were no recorded adverse reactions to anesthesia, and RMD and MHS did not co-segregate. We conclude that RMD patients should not, on the basis of our present knowledge, be classified as having MHS; however, an increased surveillance for MH reactions is recommended in these patients.

Novel double and single ryanodine receptor 1 variants in two Austrian malignant hyperthermia families.

BACKGROUND: Malignant hyperthermia (MH) is a potentially lethal genetic disorder in response to volatile anesthetics and depolarizing muscle relaxants. To support the claim that a novel genetic variant causes MH, it is necessary to demonstrate that it has significant effects on the sensitivity of the ryanodine receptor (RYR1) calcium channel. In this study we focused on 2 Austrian families with strong MH disposition and new RYR1 variants. METHODS: We sequenced the entire coding region of the RYR1 from 2 Austrian MH individuals. Genotype-phenotype segregation and evolutionary conservation of the variants were considered. On a functional level, Ca(2+) release experiments with fura-2-acetoxymethyl ester were performed in cultured skeletal muscle cells derived from individuals carrying the new variants and compared with control cells from nonsusceptible individuals. Caffeine, 4-chloro-m-cresole (4-CmC), and halothane were used as specific Ca(2+) releasing agents. RESULTS: The variant p.A612P in family A segregated with an MH-susceptible phenotype and cells showed an increased sensitivity for all Ca(2+)-releasing substances tested. In family B, 2 variants (p.R2458H/p.R3348C) were identified. While p.R2458H and p.R2458H/p.R3348C segregated with an MH-susceptible diagnosis, p.R3348C alone showed an MH equivocal diagnosis. Ca(2+)-release experiments showed that exchanges of these highly conserved amino acids increased the sensitivities for the substances tested (except 4-CmC with p.R2458H and p.R3348C) when compared with the MH-negative control group. CONCLUSIONS: Our results suggest that these variants are new causative MH variants.

Halothane: how should it be used in a developing country?

The anaesthetic agent halothane is still widely used in developing countries including the Islamic Republic of Iran because of its low price. Because of halothane-induced hepatitis, a rare complication, it has been replaced by other inhalation anaesthetics in Western countries; it has been suggested by some Iranian professionals that the Islamic Republic of Iran should do the same. We evaluated various dimensions of this replacement through a literature review to assess the incidence of halothane-induced hepatitis and costs of anaesthetics in the country. We also conducted a questionnaire survey of 30 anaesthesiology/gastroenterology experts about their views on the subject. The results indicate that the incidence of halothane hepatitis in the Islamic Republic of Iran is very low and could mostly be avoided by strict adherence to guidelines. Complete withdrawal of halothane in the Islamic Republic of Iran might not be appropriate at present. Comprehensive cost-effectiveness studies are needed before a decision is made on complete replacement of halothane with other anaesthetics.

[Drug-induced liver injury]. / Il danno epatico da farmaci.

Drug-induced liver injury represents the principal cause of acute liver failure and orthotopic liver transplantation in western country. A very large number of different drugs and medicinal herbs has been associated with liver injury but just for few of them we know the process that causes liver disease. All the people which ingest a large number of drugs present a risk of developing liver injury. Diagnosis is very difficult because a specific biomarker of damage is absent and the clinical picture is common to other liver diseases. A therapeutic approach is efficacy only in few cases. When a drug-induced liver injury is suspected, cessation of the drug is the first step in their management.