Consensus guidelines on perioperative management of malignant hyperthermia suspected or susceptible patients from the European Malignant Hyperthermia Group.

Malignant hyperthermia is a potentially fatal condition, in which genetically predisposed individuals develop a hypermetabolic reaction to potent inhalation anaesthetics or succinylcholine. Because of the rarity of malignant hyperthermia and ethical limitations, there is no evidence from interventional trials to inform the optimal perioperative management of patients known or suspected with malignant hyperthermia who present for surgery. Furthermore, as the concentrations of residual volatile anaesthetics that might trigger a malignant hyperthermia crisis are unknown and manufacturers' instructions differ considerably, there are uncertainties about how individual anaesthetic machines or workstations need to be prepared to avoid inadvertent exposure of susceptible patients to trigger anaesthetic drugs. The present guidelines are intended to bundle the available knowledge about perioperative management of malignant hyperthermia-susceptible patients and the preparation of anaesthesia workstations. The latter aspect includes guidance on the use of activated charcoal filters. The guidelines were developed by members of the European Malignant Hyperthermia Group, and they are based on evaluation of the available literature and a formal consensus process. The most crucial recommendation is that malignant hyperthermia-susceptible patients should receive anaesthesia that is free of triggering agents. Providing that this can be achieved, other key recommendations include avoidance of prophylactic administration of dantrolene; that preoperative management, intraoperative monitoring, and care in the PACU are unaltered by malignant hyperthermia susceptibility; and that malignant hyperthermia patients may be anaesthetised in an outpatient setting.

BMI and malignant hyperthermia pathogenic ryanodine receptor type 1 sequence variants in Switzerland: A retrospective cohort analysis.

BACKGROUND: Ryanodine receptor type 1 (RYR1) sequence variants are pathogenic for malignant hyperthermia. Variant carriers have a subtle increase in resting myoplasmic calcium concentration compared with nonaffected individuals, but whether this has metabolic effects in daily life is unknown. OBJECTIVES: We analysed the potential effect of malignant hyperthermia-pathogenic RYR1 sequence variants on BMI as a single factor. Due to the heterogeneity of genetic variants predisposing to malignant hyperthermia, and to incomplete information about their regional distribution, we describe the prevalence of RYR1 variants in our population. DESIGN: A retrospective cohort study. SETTING: A single University hospital. PATIENTS: Patients from malignant hyperthermia families with pathogenic RYR1 sequence variants were selected if BMI was available. OUTCOME MEASURES: BMI values were compared amongst malignant hyperthermia susceptible (MHS) and malignant hyperthermia-negative individuals using hierarchical multivariable analyses adjusted for age and sex and considering family clustering. Variant prevalence was calculated. RESULTS: The study included 281 individuals from 42 unrelated malignant hyperthermia families, 109 of whom were MHS and carriers of the familial RYR1 sequence variants. Median [IQR] BMI in MHS individuals with pathogenic RYR1 variants was 22.5 kg m-2 [21.3 to 25.6 kg m-2]. In malignant hyperthermia-negative individuals without variants, median BMI was 23.4 kg m-2 [21.0 to 26.3 kg m-2]. Using multivariable regression adjusted for age and sex, the mean difference was -0.73 (95% CI -1.51 to 0.05). No carrier of a pathogenic RYR1 sequence variant was found to have BMI higher than 30 kg m-2. Only 10 RYR1 variants from the list of the European MH Group were found in our cohort, the most common being p.Val2168Met (39% of families), p.Arg2336His (24%) and p.Arg614Cys (12%). CONCLUSION: The observed tendency towards lower BMI values in carriers of malignant hyperthermia-pathogenic RYR1 sequence variants points to a possible protective effect on obesity. This study confirms regional differences of the prevalence of malignant hyperthermia-pathogenic RYR1 sequence variants, with just three variants covering 75% of Swiss MHS families. TRIAL REGISTRATION: This manuscript is based on a retrospective analysis.

Availability of dantrolene for the management of malignant hyperthermia crises: European Malignant Hyperthermia Group guidelines.

Faced with a malignant hyperthermia crisis, the immediate access to sufficient dantrolene is essential to achieve the best possible outcome for the patient. However, malignant hyperthermia crises are rare, and there may be administrative pressures to limit the amount of dantrolene stocked or, in some countries, not to stock dantrolene at all. There are no published guidelines to support anaesthetic departments in their effort to ensure availability of sufficient dantrolene for the management of malignant hyperthermia crises. After a literature review that confirmed a lack of clinical trials to inform this guideline, we undertook a formal consensus development process, in which 25 members of the European Malignant Hyperthermia Group participated. The consensus process used a modified web-based Delphi exercise, in which participants rated the appropriateness of statements that covered the dosing regimen for dantrolene in a malignant hyperthermia crisis, the types of facility that should stock dantrolene, and the amount of dantrolene that should be stocked. The resulting guidelines are based on available evidence and the opinions of international malignant hyperthermia experts representing a large group of malignant hyperthermia laboratories from around the world. Key recommendations include: the dosing regimen of dantrolene should be based on actual body weight, dantrolene should be available wherever volatile anaesthetics or succinylcholine are used, and 36 vials of dantrolene should be immediately available with a further 24 vials available within 1 h.

Effect of L-carnitine supplementation on the body carnitine pool, skeletal muscle energy metabolism and physical performance in male vegetarians.

PURPOSE: More than 95% of the body carnitine is located in skeletal muscle, where it is essential for energy metabolism. Vegetarians ingest less carnitine and carnitine precursors and have lower plasma carnitine concentrations than omnivores. Principle aims of the current study were to assess the plasma and skeletal muscle carnitine content and physical performance of male vegetarians and matched omnivores under basal conditions and after L-carnitine supplementation. RESULTS: Sixteen vegetarians and eight omnivores participated in this interventional study with oral supplementation of 2 g L-carnitine for 12 weeks. Before carnitine supplementation, vegetarians had a 10% lower plasma carnitine concentration, but maintained skeletal muscle carnitine stores compared to omnivores. Skeletal muscle phosphocreatine, ATP, glycogen and lactate contents were also not different from omnivores. Maximal oxygen uptake (VO2max) and workload (P max) per bodyweight (bicycle spiroergometry) were not significantly different between vegetarians and omnivores. Sub-maximal exercise (75% VO2max for 1 h) revealed no significant differences between vegetarians and omnivores (respiratory exchange ratio, blood lactate and muscle metabolites). Supplementation with L-carnitine significantly increased the total plasma carnitine concentration (24% in omnivores, 31% in vegetarians) and the muscle carnitine content in vegetarians (13%). Despite this increase, P max and VO2max as well as muscle phosphocreatine, lactate and glycogen were not significantly affected by carnitine administration. CONCLUSIONS: Vegetarians have lower plasma carnitine concentrations, but maintained muscle carnitine stores compared to omnivores. Oral L-carnitine supplementation normalizes the plasma carnitine stores and slightly increases the skeletal muscle carnitine content in vegetarians, but without affecting muscle function and energy metabolism.

Contractile function and energy metabolism of skeletal muscle in rats with secondary carnitine deficiency.

The consequences of carnitine depletion upon metabolic and contractile characteristics of skeletal muscle remain largely unexplored. Therefore, we investigated the effect of N-trimethyl-hydrazine-3-propionate (THP) administration, a carnitine analog inhibiting carnitine biosynthesis and renal reabsorption of carnitine, on skeletal muscle function and energy metabolism. Male Sprague-Dawley rats were fed a standard rat chow in the absence (CON; n = 8) or presence of THP (n = 8) for 3 wk. Following treatment, rats were fasted for 24 h prior to excision of their soleus and EDL muscles for biochemical characterization at rest and following 5 min of contraction in vitro. THP treatment reduced the carnitine pool by ∼80% in both soleus and EDL muscles compared with CON. Carnitine depletion was associated with a 30% decrease soleus muscle weight, whereas contractile function (expressed per gram of muscle), free coenzyme A, and water content remained unaltered from CON. Muscle fiber distribution and fiber area remained unaffected, whereas markers of apoptosis were increased in soleus muscle of THP-treated rats. In EDL muscle, carnitine depletion was associated with reduced free coenzyme A availability (-25%, P < 0.05), impaired peak tension development (-44%, P < 0.05), and increased glycogen hydrolysis (52%, P < 0.05) during muscle contraction, whereas PDC activation, muscle weight, and water content remained unaltered from CON. In conclusion, myopathy associated with carnitine deficiency can have different causes. Although muscle atrophy, most likely due to increased apoptosis, is predominant in muscle composed predominantly of type I fibers (soleus), disturbance of energy metabolism appears to be the major cause in muscle composed of type II fibers (EDL).

JP-45/JSRP1 variants affect skeletal muscle excitation-contraction coupling by decreasing the sensitivity of the dihydropyridine receptor.

JP-45 (also JP45; encoded by JSRP1) is an integral protein constituent of the skeletal muscle sarcoplasmic reticulum junctional face membrane interacting with Ca(v) 1.1 (the α.1 subunit of the voltage-sensing dihydropyridine receptor, DHPR) and the luminal calcium-binding protein calsequestrin. Two JSRP1 variants have been found in the human population: c.323C>T (p.P108L) in exon 5 and c.449G>C (p.G150A) in exon 6, but nothing is known concerning the incidence of these polymorphisms in the general population or in patients with neuromuscular diseases nor the impact of the polymorphisms on excitation-contraction (EC) coupling. In the present report, we investigated the frequencies of these two JSRP1 polymorphisms in the Swiss malignant hyperthermia population and studied the functional impact of the variants on EC coupling. Our results show that the polymorphisms are equally distributed among malignant hyperthermia negative, malignant hyperthermia equivocal, and malignant hyperthermia susceptible individuals. Interestingly, however, the presence of either one of these JP-45 variants decreased the sensitivity of the DHPR to activation. The presence of a JSRP1 variant may explain the variable phenotype seen in patients with malignant hyperthermia carrying the same mutation and, more importantly, may counteract the hypersensitivity of EC coupling caused by mutations in the RYR1 gene.

Enhanced excitation-coupled Ca(2+) entry induces nuclear translocation of NFAT and contributes to IL-6 release from myotubes from patients with central core disease.

Prolonged depolarization of skeletal muscle cells induces entry of extracellular calcium into muscle cells, an event referred to as excitation-coupled calcium entry. Skeletal muscle excitation-coupled calcium entry relies on the interaction between the 1,4-dihydropyridine receptor on the sarcolemma and the ryanodine receptor on the sarcoplasmic reticulum membrane. In this study, we directly measured excitation-coupled calcium entry by total internal reflection fluorescence microscopy in human skeletal muscle myotubes harbouring mutations in the RYR1 gene linked to malignant hyperthermia (MH) and central core disease (CCD). We found that excitation-coupled calcium entry is strongly enhanced in cells from patients with CCD compared with individuals with MH and controls. Furthermore, excitation-coupled calcium entry induces generation of reactive nitrogen species and enhances nuclear localization of NFATc1, which in turn may be responsible for the increased IL-6 released by myotubes from patients with CCD.

Analgesic and antihyperalgesic properties of propofol in a human pain model.

BACKGROUND: Propofol (Disoprivan, AstraZeneca AG, Zug, Switzerland) has long been considered to be nonanalgesic. However, accumulating evidence shows that propofol possesses modulatory action on pain processing and perception. In this study, the authors investigated the modulatory effects of propofol and a formulation similar to the solvent of propofol (10% Intralipid; Fresenius Kabi, Stans, Switzerland) on pain perception and central sensitization in healthy volunteers. METHODS: Fourteen healthy volunteers were included in this randomized, double-blind, placebo-controlled, crossover study. Intracutaneous electrical stimulation (48.8 +/- 25.8 mA) induced spontaneous acute pain (Numeric Rating Scale, 6 of 10) and stable areas of hyperalgesia and allodynia. Pain intensities and areas of hyperalgesia were assessed regularly before, during, and after a 45-min target-controlled infusion (2 microg/ml) of propofol, the solvent 10% Intralipid, and saline. RESULTS: During administration, propofol significantly decreased pain scores and areas of hyperalgesia and allodynia compared with both 10% Intralipid and saline (placebo-corrected mean Numerical Rating Scale score reduction by propofol: 38 +/- 28%). This difference disappeared shortly after cessation of the infusion. Thereafter, no significant group differences were observed in the Numerical Rating Scale score and the areas of hyperalgesia or allodynia. However, there was a trend to reduced hyperalgesia and allodynia after propofol treatment. Pharmacodynamic modeling regarding the analgesic effect of propofol showed an EC50 (half-maximum effect site concentration) of 3.19 +/- 0.37 microg/ml. Ten percent Intralipid was free of pain-modulatory effects in the authors' experiments. CONCLUSIONS: Propofol showed short-lasting analgesic properties during its administration, whereas the solvent-like formulation 10% Intralipid had no effect on pain perception.

Increasing the number of diagnostic mutations in malignant hyperthermia.

Malignant hyperthermia (MH) is an autosomal dominant disorder characterized by abnormal calcium homeostasis in skeletal muscle in response to triggering agents. Today, genetic investigations on ryanodine receptor type 1 (RYR1) gene and alpha1 subunit of the dihydropyridine receptor (DHPR) (CACNA1S) gene have improved the procedures associated with MH diagnosis. In approximately 50% of MH cases a causative RYR1 mutation was found. Molecular genetic testing based on RYR1 mutations for MH diagnosis is challenging, because the causative mutations, most of which are private, are distributed throughout the RYR1 gene. A more comprehensive genetic testing procedure is needed. Therefore, we aim to expand the genetic information related to MH and to evaluate the effect of mutations on the MH phenotype. Performing an in-depth mutation screening of the RYR1 transcript sequence in 36 unrelated MH susceptible (MHS) patients, we identified 17 novel, five rare, and eight non-disease-causing variants in 23 patients. The 13 remaining MHS patients presented no known variants, neither in RYR1 nor in the CACNA1S binding regions to RYR1. The 17 novel variants were found to affect highly conserved amino acids and were absent in 100 controls. Excellent genotype-phenotype correlations were found by investigating 21 MHS families-a total of 186 individuals. Epstein-Barr virus (EBV) lymphoblastoid cells carrying four of these novel mutations showed abnormal calcium homeostasis. The results of this study contribute to the establishment of a robust genetic testing procedure for MH diagnosis.

A mathematical model to improve on phenotyping for molecular genetic research in malignant hyperthermia.

BACKGROUND: The in-vitro contracture test is the standard test to diagnose malignant hyperthermia (MH) susceptibility. Maximum sensitivity is important for patient safety. For scientific purposes, the reduced specificity of contracture testing is a major drawback, and precise phenotyping is of utmost importance. Our study aimed to improve phenotyping for MH susceptibility to more accurately select patients for molecular genetic research in MH, thus, improving the probability to detect novel MH associated variants. METHODS: Patients who underwent contracture and molecular genetic testing were selected from the database of two MH investigation centres (Basel and Leipzig). The area under the curve of halothane and caffeine contracture tests was calculated and a logistic regression model was applied to determine the odds of carrying a MH associated genetic variant. This model was subsequently applied to patients without familial MH related genetic variant. RESULTS: Validation of the logistic regression model showed 98% concordance with molecular genetic results. Among patients with unclear in-vitro contracture test diagnosis (MH equivocal), half of the mutation carriers were classified as positive by the model, whereas 86% of those without familial mutation were classified as negative. Excluding the MH equivocal group, the model showed sensitivity of 0.99 (95% confidence interval: 0.95-0.99) and specificity 0.98 (95% confidence interval: 0.94-0.99), respectively, to identify genetically positive MH individuals. CONCLUSION: Our model is a valuable tool to select patients from MH families for further molecular genetic research. This preselection increases the probability of successful molecular genetic research and is important when available resources are limited.

Serious complications associated with external intrathecal catheters used in cancer pain patients: a systematic review and meta-analysis.

BACKGROUND: Potential risks of intrathecal catheters in cancer patients include infection, bleeding, and neurologic injury. METHODS: A systematic review and a pooled analysis of observational studies were performed. Articles reporting on adverse events (infections, bleeding, granuloma, and death) associated with intrathecal catheters and external pumps in cancer patients were identified. Electronic searches of PubMed, MEDLINE, and EMBASE were conducted. Observations from different studies were pooled using a generalized mixed-effect model. Model estimates and their standard errors (SEs) were used for calculating 95% confidence intervals (CIs) on the overall proportion. RESULTS: The analysis identified 10 articles, including a total of 821 patients. Twenty catheter-related infections were identified. Of these, 10 were superficial and 10 were deep infections, with rates of 2.3% (95% CI, 0.8-6.1) and 1.4% (95% CI, 0.5-3.8), respectively. Furthermore, the authors calculated that every 71st patient had a deep infection after an average catheter duration of 54 days. The risk of bleeding was found to be 0.9% (95% CI, 0-2.0), and for neurologic injury 0.4% (95% CI, 0-1.0). The infection rates are comparable to other intrathecal catheter techniques. CONCLUSIONS: Serious complications are rare in both hospitalized and homebound patients with intrathecal catheters. This analysis supports the reasoning that the potential benefit of intrathecal catheters in the treatment of severe cancer pain is likely to outweigh the potential for serious complications associated with this technique. Therefore, an external intrathecal catheter can be considered an effective and low-cost solution for the control of pain in such patients.

In vitro effects of propofol and volatile agents on pharmacologically induced chloride channel myotonia.

BACKGROUND: Anesthetic choice for patients with chloride channel myotonia remains under debate. The authors have, therefore, investigated the in vitro effects of various anesthetic agents on pharmacologically induced chloride channel myotonia. METHODS: Functionally viable (> 10 mN force generation) rectus abdominis muscle preparations obtained from normal swine were investigated using in vitro muscle contracture test baths. During continuous 0.1-Hz supramaximal electrical stimulation, the chloride channel blocker 9-anthracenecarboxylic acid (64 microM) was added before the addition of propofol or one of three volatile anesthetics. The concentration of propofol in either Intralipid (n = 11) or dimethyl sulfoxide (n = 10) was doubled every 10 min (from 4-512 microM). The concentration of halothane (n = 8), isoflurane (n = 8), and sevoflurane (n = 8) was doubled from 0.25 vol% up to the maximum dose according to calibrated vaporizers. Control muscle bundles were either untreated (n = 30) or exposed to 9-anthracenecarboxylic acid (n = 19). RESULTS: The myotonic reactions induced by 9-anthracenecarboxylic acid were reversed by high-dose (> 64 microM) propofol (P < 0.01). Halothane, isoflurane, or sevoflurane each enhanced the myotonic reactions at 5.4 (P < 0.001), 0.21 (P < 0.01), and 0.5 minimum alveolar concentrations (P < 0.05), respectively. CONCLUSIONS: The authors' in vitro data imply that propofol administration for general anesthesia may be better suited for patients with chloride channel myotonia versus volatile anesthetics. In isolated swine skeletal muscle bundles, propofol elicited a reversal of 9-anthracenecarboxylic acid-induced chloride channel myotonia, whereas volatile anesthetics further increased the associated myotonic reactions.

Rapid and accurate detection of atypical and Kalow variants in the butyrylcholinesterase gene using denaturing high performance liquid chromatography.

BACKGROUND: Variations in the butyrylcholinesterase (BCHE) gene can prolong neuromuscular block after the administration of the neuromuscular blocking drugs succinylcholine and mivacurium. The most frequent variations in the BCHE gene are the atypical (A) and Kalow (K) variants. We, therefore, developed a detection approach for these most common variants based on the method of denaturing high-performance liquid chromatography (dHPLC). METHODS: Forty-six subjects were included. Sixteen were known to carry either the normal sequence or different combinations of A- and K-variants and 30 test subjects were randomly selected from the general population. Three samples of the 16 were used to establish the dHPLC protocols. Results from dHPLC were blindly compared with the automated sequencing data. RESULTS: All A- and K-variants in their heterozygous and homozygous forms were unequivocally identified by dHPLC. For all 86 tested alleles, dHPLC results were 100% concordant with DNA sequencing results. Additional genetic variations were also detected, which included G344A encoding for the silent variant (S) and a known polymorphism, A1914G. CONCLUSIONS: The described dHPLC protocols offer a rapid and accurate screening method for the most common variants of BCHE. This screening tool might be useful in pharmacokinetic studies investigating drugs metabolized by BCHE, such as mivacurium and succinylcholine.

Use of non-invasive-stimulated muscle force assessment in long-term critically ill patients: a future standard in the intensive care unit?

BACKGROUND: This study's main purpose was to test the feasibility of employing a non-invasive-stimulated muscle force assessment approach in long-term critically ill patients. METHODS: A case series was performed over a 4-year period in the intensive care unit (ICU). Of the 25 patients initially recruited, eight patients required long-time mechanical ventilation for a median of 3.8 weeks (range 2-10 weeks) and were immobilized for 5 weeks (range 2-10 weeks). With a previously tested non-invasive measuring device, we weekly assessed peak torques and rates of force development and relaxation of patients' ankle dorsiflexor contractile responses, induced via peroneal nerve stimulation. Subsequently, we derived each patient's time course of observed progressive weakness and/or recovery. RESULTS: During their critical illnesses, seven out of eight patients elicited significant decreases in measured peak torques. In survivors (n = 6) during their recovery periods, torques gradually recovered. In the two patients who died, their strengths decreased continuously until death. The rate of force development data elicited similar trends as peak torque responses, whereas relative relaxation rates differed more widely between individuals. CONCLUSION: This approach of non-invasive-stimulated muscle force assessment can be used in long-term critically ill patients and may eventually become a standard in the intensive care unit, e.g. for assessing recovery. This method is easy to employ, reproducible, provides important phenotypic quantification of skeletal muscle contractile function, and can be used for long-term outcomes assessment.

High dose amino acid administration achieves an anabolic response in type 2 diabetic patients that is independent of glycaemic control: A randomized clinical trial.

BACKGROUND & AIMS: Surgical stress provokes protein catabolism and hyperglycaemia that is enhanced in patients with type 2 diabetes (T2DM), and increases perioperative morbidity. This study hypothesized that perioperative administration of high dose intravenous (IV) amino acids (AA) will augment protein balance in T2DM patients receiving tight plasma glucose control via continuous IV insulin compared to standard plasma glucose control via subcutaneous (SC) insulin sliding scale. METHODS: Eighteen patients with well-controlled T2DM (HbA1C% < 7.1) undergoing colorectal surgery were assigned randomly to receive standard glucose control (6-10 mmol/l, SC insulin, n = 9) or tight glucose control (4-6 mmol/l, IV insulin, n = 9). Both groups received general anaesthesia and epidural analgesia. AA (1 ml/kg h Aminoven™ 10%, ∼2.4 g/kg d) were infused via a peripheral vein for two 3-h periods: at the beginning of surgery and in the post-operative care unit. Whole-body protein and glucose kinetics were assessed by stable isotope tracers, L-[1-13C]leucine and [6,6-2H2]glucose. RESULTS: Whole-body protein balance was positive after surgery in all patients. Since protein synthesis, breakdown and leucine oxidation were comparable in both groups, whole body protein balance was not different (p = 0.605). Tight glucose control suppressed endogenous glucose production (EGP, p < 0.001) and increased glucose clearance (p < 0.001) compared to standard glucose control during both study periods. No episode of hypoglycaemia occurred in either group. CONCLUSION: High-dose perioperative AA administration under optimal anti-catabolic care with epidural analgesia was effective in achieving a positive protein balance in T2DM patients undergoing surgery that was independent of glycaemic control strategy. Continuous IV insulin maintained normoglycaemia by inhibiting EGP and increasing glucose clearance. Improved glucose control, without a pronounced increase in protein balance with the intravenous insulin regimen, suggests perioperative protein metabolism may be less sensitive to insulin than is glucose.

Evaluation of a standardized internet-based and telephone-based patient monitoring system for pain therapy with transdermal fentanyl.

The aim of the present observational 4-week study was to document the feasibility and utility of telephone-based or Internet-based pain monitoring in patients with chronic cancer or noncancer pain, such as nociceptive or neuropathic pain, using transdermal fentanyl. Pain intensity, treatment tolerability, activities of daily living, quality of life, and patient and physician satisfaction were evaluated in 60 (60% women, 42% opioid-naive) chronic pain patients who were switched from oral pain therapy to transdermal fentanyl therapy because of persisting severe pain. When the total dataset of all patient entries was analyzed, treatment with transdermal fentanyl led to decreases in maximal and mean pain scores as reported by the patients (-14% and -19%, respectively, last observation carried forward vs. baseline). Pain reduction was more pronounced in opioid-naive than in opioid-experienced patients (-35% and -25% vs. baseline, respectively; P=0.03). Overall, impairment of daily activities was reduced by 23% with transdermal fentanyl. No effect was observed with regard to quality of life and use of rescue pain medication. Transdermal fentanyl was generally well tolerated. Most patients (60%) preferred the telephone-based to the Internet-based or Internet combined with telephone questionnaires. Patient preference was driven by age, whereby younger patients tended to prefer the Internet and older patients the telephone (mean age, 45 and 54 y, respectively; difference n.s.). Internet-based and telephone-based monitoring of the efficacy and tolerability of opioid treatment for chronic pain was feasible in daily practice and generally well accepted by patients and physicians. Future research will determine the relative contribution of these 2 new options for patient-physician interaction and delineate their role in improving chronic pain control.

Resequencing array for gene variant detection in malignant hyperthermia and butyrylcholinestherase deficiency.

Malignant hyperthermia (MH) and butyrylcholinestherase (BCHE) deficiency are two relevant pharmacogenetic disorders in anesthetic practice linked with sequence variants, the former in the RyR1 and CACNA1S genes, the latter in the BCHE gene. Genotyping for known pathogenic variants in these genes is useful to help identify susceptible individuals, and others may exist but remain unknown, because full-length sequence of these genes is, in general, not investigated. To facilitate this task, we developed a resequencing DNA array, the perioperative patient safety (POPS) array, to be able to screen the entire coding sequences of the RyR1, CACNA1S and BCHE genes. MH-susceptible individuals (n = 121) identified with the in vitro contracture test, the standard diagnostic tool for MH susceptibility, were genotyped with the arrays. Compared with capillary sequencing, call rates with the arrays could achieve 100% at maximal sensitivity, although to reduce false positive rates, sensitivity was adjusted to 0.85, 0.87 and 0.66 for RyR1, CACNA1S and BCHE respectively, with overall base call specificity exceeding 99%. Detection of 29 predetermined RyR1 variants in 44 individuals was successful in 97% of the cases, among them all 16 variants of established diagnostic value. In a trial application of the arrays, 21 MH-susceptible subjects with no known RyR1 or CACNA1S variants were screened, resulting in the discovery of new variants, all confirmed by capillary sequencing. In conclusion, arrays offer an efficient high-throughput alternative for diagnostic genotyping of candidate genes affecting MH susceptibility, BCHE deficiency and other neuromuscular disorders, simultaneously enabling a comprehensive search for rare variants in these genes.