Putative malignant hyperthermia mutation CaV1.1-R174W is insufficient to trigger a fulminant response to halothane or confer heat stress intolerance.

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca2+ channel CaV1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, CaV1.1-R174W. Heterozygous (HET) and homozygous (HOM) CaV1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of CaV1.1 by quantitative PCR, Western blot, [3H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible CaV1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the CaV1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca2+ and Na+ measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. CaV1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.

Pholcodine and allergy to neuromuscular blocking agents: where are we and how did we get here?

Despite the purported link between pholcodine and neuromuscular blocking agent allergy, screening for prior pholcodine use offers no practical benefit to patients, and anaesthetists should continue to use a neuromuscular blocking agent where this is clinically indicated.

Peripheral regional anaesthesia and outcomes: a narrative review of the literature from 2013 to 2023.

The use of peripheral regional anaesthesia continues to increase, yet the evidence supporting its use and impact on relevant outcomes often lacks scientific rigour, especially when considering the use of specific blocks for a particular surgical indication. In this narrative review, we consider the relevant literature in a 10-yr period from 2013. We performed a literature search (MEDLINE and EMBASE) for articles reporting randomised controlled trials and other comparative trials of peripheral regional anaesthetic blocks vs systemic analgesia in adult patients undergoing surgery. We evaluated measures of effective treatment and complications. A total of 128 studies met our inclusion criteria. There remains variability in the technical conduct of blocks and the outcomes used to evaluate them. There is a considerable body of evidence to support the use of interscalene blocks for shoulder surgery. Saphenous nerve (motor-sparing) blocks provide satisfactory analgesia after knee surgery and are preferred to femoral nerve blocks which are associated with falls when patients are mobilised early as part of enhanced recovery programmes. There are additional surgical indications where the efficacy of cervical plexus, intercostal nerve, and ilioinguinal/iliohypogastric nerve blocks have been demonstrated. In the past 10 yr, there has been a consolidation of the evidence indicating benefit of peripheral nerve blocks for specific indications. There remains great scope for rigorous, multicentre, randomised controlled trials of many peripheral nerve blocks. These would benefit from an agreed set of patient-centred outcomes.

Myopathic manifestations across the adult lifespan of patients with malignant hyperthermia susceptibility: a narrative review.

Malignant hyperthermia susceptibility (MHS) designates individuals at risk of developing a hypermetabolic reaction triggered by halogenated anaesthetics or the depolarising neuromuscular blocking agent suxamethonium. Over the past few decades, beyond the operating theatre, myopathic manifestations impacting daily life are increasingly recognised as a prevalent phenomenon in MHS patients. At the request of the European Malignant Hyperthermia Group, we reviewed the literature and gathered the opinion of experts to define MHS-related myopathy as a distinct phenotype expressed across the adult lifespan of MHS patients unrelated to anaesthetic exposure; this serves to raise awareness about non-anaesthetic manifestations, potential therapies, and management of MHS-related myopathy. We focused on the clinical presentation, biochemical and histopathological findings, and the impact on patient well-being. The spectrum of symptoms of MHS-related myopathy encompasses muscle cramps, stiffness, myalgias, rhabdomyolysis, and weakness, with a wide age range of onset mainly during adulthood. Histopathological analysis can reveal nonspecific abnormalities suggestive of RYR1 involvement, while metabolic profiling reflects altered energy metabolism in MHS muscle. Myopathic manifestations can significantly impact patient quality of life and lead to functional limitations and socio-economic burden. While currently available therapies can provide symptomatic relief, there is a need for further research into targeted treatments addressing the underlying pathophysiology. Counselling early after establishing the MHS diagnosis, followed by multidisciplinary management involving various medical specialties, is crucial to optimise patient care.

An Association between OXPHOS-Related Gene Expression and Malignant Hyperthermia Susceptibility in Human Skeletal Muscle Biopsies.

Malignant hyperthermia (MH) is a pharmacogenetic condition of skeletal muscle that manifests in hypermetabolic responses upon exposure to volatile anaesthetics. This condition is caused primarily by pathogenic variants in the calcium-release channel RYR1, which disrupts calcium signalling in skeletal muscle. However, our understanding of MH genetics is incomplete, with no variant identified in a significant number of cases and considerable phenotype diversity. In this study, we applied a transcriptomic approach to investigate the genome-wide gene expression in MH-susceptible cases using muscle biopsies taken for diagnostic testing. Baseline comparisons between muscle from MH-susceptible individuals (MHS, n = 8) and non-susceptible controls (MHN, n = 4) identified 822 differentially expressed genes (203 upregulated and 619 downregulated) with significant enrichment in genes associated with oxidative phosphorylation (OXPHOS) and fatty acid metabolism. Investigations of 10 OXPHOS target genes in a larger cohort (MHN: n = 36; MHS: n = 36) validated the reduced expression of ATP5MD and COQ6 in MHS samples, but the remaining 8 selected were not statistically significant. Further analysis also identified evidence of a sex-linked effect in SDHB and UQCC3 expression, and a difference in ATP5MD expression across individuals with MH sub-phenotypes (trigger from in vitro halothane exposure only, MHSh (n = 4); trigger to both in vitro halothane and caffeine exposure, MHShc (n = 4)). Our data support a link between MH-susceptibility and dysregulated gene expression associated with mitochondrial bioenergetics, which we speculate plays a role in the phenotypic variability observed within MH.

What is malignant hyperthermia susceptibility?

The molecular mechanisms of susceptibility to malignant hyperthermia are complex. The malignant hyperthermia susceptibility phenotype should be reserved for patients who have a personal or family history consistent with malignant hyperthermia under anaesthesia and are subsequently demonstrated through diagnostic testing to be at risk.

Suspected perioperative anaphylaxis: are we making the correct diagnosis?

We provide a commentary on aspects of a prospective study of the epidemiology of perioperative anaphylaxis in Japan (Japanese Epidemiologic Study for Perioperative Anaphylaxis [JESPA]). Accurate diagnosis of perioperative anaphylaxis is important for research but essential for clinical safety. We evaluate the diagnostic approach used in the JESPA study and caution against over-reliance on diagnostic tests that lack sensitivity and specificity when clinical data suggest an immediate perioperative hypersensitivity reaction is likely.

Comparison of Transcriptomic Changes in Survivors of Exertional Heat Illness with Malignant Hyperthermia Susceptible Patients.

Exertional heat illness (EHI) is an occupational health hazard for athletes and military personnel-characterised by the inability to thermoregulate during exercise. The ability to thermoregulate can be studied using a standardised heat tolerance test (HTT) developed by The Institute of Naval Medicine. In this study, we investigated whole blood gene expression (at baseline, 2 h post-HTT and 24 h post-HTT) in male subjects with either a history of EHI or known susceptibility to malignant hyperthermia (MHS): a pharmacogenetic condition with similar clinical phenotype. Compared to healthy controls at baseline, 291 genes were differentially expressed in the EHI cohort, with functional enrichment in inflammatory response genes (up to a four-fold increase). In contrast, the MHS cohort featured 1019 differentially expressed genes with significant down-regulation of genes associated with oxidative phosphorylation (OXPHOS). A number of differentially expressed genes in the inflammation and OXPHOS pathways overlapped between the EHI and MHS subjects, indicating a common underlying pathophysiology. Transcriptome profiles between subjects who passed and failed the HTT (based on whether they achieved a plateau in core temperature or not, respectively) were not discernable at baseline, and HTT was shown to elevate inflammatory response gene expression across all clinical phenotypes.

European Neuromuscular Centre consensus statement on anaesthesia in patients with neuromuscular disorders.

BACKGROUND AND PURPOSE: Patients with neuromuscular conditions are at increased risk of suffering perioperative complications related to anaesthesia. There is currently little specific anaesthetic guidance concerning these patients. Here, we present the European Neuromuscular Centre (ENMC) consensus statement on anaesthesia in patients with neuromuscular disorders as formulated during the 259th ENMC Workshop on Anaesthesia in Neuromuscular Disorders. METHODS: International experts in the field of (paediatric) anaesthesia, neurology, and genetics were invited to participate in the ENMC workshop. A literature search was conducted in PubMed and Embase, the main findings of which were disseminated to the participants and presented during the workshop. Depending on specific expertise, participants presented the existing evidence and their expert opinion concerning anaesthetic management in six specific groups of myopathies and neuromuscular junction disorders. The consensus statement was prepared according to the AGREE II (Appraisal of Guidelines for Research & Evaluation) reporting checklist. The level of evidence has been adapted according to the SIGN (Scottish Intercollegiate Guidelines Network) grading system. The final consensus statement was subjected to a modified Delphi process. RESULTS: A set of general recommendations valid for the anaesthetic management of patients with neuromuscular disorders in general have been formulated. Specific recommendations were formulated for (i) neuromuscular junction disorders, (ii) muscle channelopathies (nondystrophic myotonia and periodic paralysis), (iii) myotonic dystrophy (types 1 and 2), (iv) muscular dystrophies, (v) congenital myopathies and congenital dystrophies, and (vi) mitochondrial and metabolic myopathies. CONCLUSIONS: This ENMC consensus statement summarizes the most important considerations for planning and performing anaesthesia in patients with neuromuscular disorders.

Epidemiology of perioperative anaphylaxis in the United States: new insights but more to learn and do.

Gonzalez-Estrada and colleagues report an estimated risk of severe or fatal perioperative anaphylaxis of one in 6,825 procedures during the period 2005-2014. This is slightly higher than that reported previously in France and England. Several predictors of near-fatal and fatal reactions are identified, such as increased age, cancer, and congestive cardiac failure.

Functional analysis of RYR1 variants in patients with confirmed susceptibility to malignant hyperthermia.

BACKGROUND: A major bottleneck to the introduction of noninvasive presymptomatic diagnostic tests for the pharmacogenetic disorder malignant hyperthermia is the lack of functional data for associated variants. METHODS: We screened 50 genes having a potential role in skeletal muscle calcium homeostasis using the HaloPlex™ (Agilent Technologies, Santa Clara, CA, USA) target enrichment system and next-generation sequencing. Twenty-one patients with a history of a clinical malignant hyperthermia reaction together with a positive in vitro contracture test were included. Eight variants in RYR1 were subsequently introduced into the cDNA for the human ryanodine receptor gene and tested in cultured human embryonic kidney (HEK293) cells for their effect on calcium release from intracellular stores in response to the ryanodine receptor-1 agonist 4-chloro-m-cresol using fura-2 as calcium indicator. Each variant was subjected to in silico curation using the European Malignant Hyperthermia Group scoring matrix and ClinGen RYR1 variant curation expert panel guidelines. RESULTS: Potentially causative RYR1 variants were identified in 15 patients. Of these, two families carried two RYR1 variants, five variants had been previously reported as 'pathogenic', two variants had been previously reported as 'likely benign', and eight were of 'uncertain significance'. Of these eight variants, four showed hypersensitivity to 4-chloro-m-cresol. Three variants were reclassified as either 'pathogenic' or 'likely pathogenic'. Two were classified as 'benign', whilst three remained of 'uncertain significance'. CONCLUSIONS: Three (p.Tyr1711Cys, p.Val2280Ile, and p.Arg4737Gln) additional variants can be added to the list of RYR1 disease-associated variants managed by the European Malignant Hyperthermia Group. These can therefore be used diagnostically in the future. Three variants (p.Glu2348Gly, p.Asn2634Lys, and p.Arg3629Trp) that remained classified as of uncertain significance require further family studies or a different functional test to determine clinical relevance in malignant hyperthermia.

Bioenergetic defects in muscle fibers of RYR1 mutant knock-in mice associated with malignant hyperthermia.

Mutations in the skeletal muscle ryanodine receptor gene (RYR1) can cause susceptibility to malignant hyperthermia (MH), a potentially lethal genetic condition triggered by volatile anesthetics. MH is associated with hypermetabolism, which has directed research interest into oxidative phosphorylation and muscle bioenergetics. The most common cause of MH in the United Kingdom is the c.7300G>A RYR1 variant, which is present in ∼16% of MH families. Our study focuses on the MH susceptible G2435R-RYR1 knock-in mouse model, which is the murine equivalent of the human c.7300G>A genotype. Using a combination of transcriptomics, protein expression, and functional analysis, we investigated adult muscle fiber bioenergetics in this mouse model. RNA-Seq data showed reduced expression of genes associated with mitochondria and fatty acid oxidation in RYR1 mutants when compared with WT controls. Mitochondrial function was assessed by measuring oxygen consumption rates in permeabilized muscle fibers. Comparisons between WT and homozygous G2435R-RYR1 mitochondria showed a significant increase in complex I-facilitated oxidative phosphorylation in mutant muscle. Furthermore, we observed a gene-dose-specific increase in reactive oxygen species production in G2435R-RYR1 muscle fibers. Collectively, these findings provide evidence of metabolic defects in G2435R-RYR1 knock-in mouse muscle under basal conditions. Differences in metabolic profile could be the result of differential gene expression in metabolic pathways, in conjunction with mitochondrial damage accumulated from chronic exposure to increased oxidative stress.

Variant curation expert panel recommendations for RYR1 pathogenicity classifications in malignant hyperthermia susceptibility.

PURPOSE: As a ClinGen Expert Panel (EP) we set out to adapt the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) pathogenicity criteria for classification of RYR1 variants as related to autosomal dominantly inherited malignant hyperthermia (MH). METHODS: We specified ACMG/AMP criteria for variant classification for RYR1 and MH. Proposed rules were piloted on 84 variants. We applied quantitative evidence calibration for several criteria using likelihood ratios based on the Bayesian framework. RESULTS: Seven ACMG/AMP criteria were adopted without changes, nine were adopted with RYR1-specific modifications, and ten were dropped. The in silico (PP3 and BP4) and hotspot criteria (PM1) were evaluated quantitatively. REVEL gave an odds ratio (OR) of 23:1 for PP3 and 14:1 for BP4 using trichotomized cutoffs of ≥0.85 (pathogenic) and ≤0.5 (benign). The PM1 hotspot criterion had an OR of 24:1. PP3 and PM1 were implemented at moderate strength. Applying the revised ACMG/AMP criteria to 44 recognized MH variants, 29 were classified as pathogenic, 13 as likely pathogenic, and 2 as variants of uncertain significance. CONCLUSION: Curation of these variants will facilitate classification of RYR1/MH genomic testing results, which is especially important for secondary findings analyses. Our approach to quantitatively calibrating criteria is generalizable to other variant curation expert panels.

Molecular Modification of Transient Receptor Potential Canonical 6 Channels Modulates Calcium Dyshomeostasis in a Mouse Model Relevant to Malignant Hyperthermia.

BACKGROUND: Pharmacologic modulation has previously shown that transient receptor potential canonical (TRPC) channels play an important role in the pathogenesis of malignant hyperthermia. This study tested the hypothesis that genetically suppressing the function of TRPC6 can partially ameliorate muscle cation dyshomeostasis and the response to halothane in a mouse model relevant to malignant hyperthermia. METHODS: This study examined the effect of overexpressing a muscle-specific nonconducting dominant-negative TRPC6 channel in 20 RYR1-p.R163C and 20 wild-type mice and an equal number of nonexpressing controls, using calcium- and sodium-selective microelectrodes and Western blots. RESULTS: RYR1-p.R163C mouse muscles have chronically elevated intracellular calcium and sodium levels compared to wild-type muscles. Transgenic expression of the nonconducting TRPC6 channel reduced intracellular calcium from 331 ± 34 nM (mean ± SD) to 190 ± 27 nM (P < 0.0001) and sodium from 15 ± 1 mM to 11 ± 1 mM (P < 0.0001). Its expression lowered the increase in intracellular Ca2+ of the TRPC6-specific activator hyperforin in RYR1-p.R163C muscle fibers from 52% (348 ± 37 nM to 537 ± 70 nM) to 14% (185 ± 11 nM to 210 ± 44 nM). Western blot analysis of TRPC3 and TRPC6 expression showed the expected increase in TRPC6 caused by overexpression of its dominant-negative transgene and a compensatory increase in expression of TRPC3. Although expression of the muscle-specific dominant-negative TRPC6 was able to modulate the increase in intracellular calcium during halothane exposure and prolonged life (35 ± 5 min vs. 15 ± 3 min; P < 0.0001), a slow, steady increase in calcium began after 20 min of halothane exposure, which eventually led to death. CONCLUSIONS: These data support previous findings that TRPC channels play an important role in causing the intracellular calcium and sodium dyshomeostasis associated with RYR1 variants that are pathogenic for malignant hyperthermia. However, they also show that modulating TRPC channels alone is not sufficient to prevent the lethal effect of exposure to volatile anesthetic malignant hyperthermia-triggering agents.

DALES, Drug Allergy Labels in Elective Surgical patients: a prospective, multicentre cross-sectional study of prevalence, nature and anaesthetists' approach to management.

BACKGROUND: We sought to define the prevalence and nature of patient-reported drug allergies, determine their impact on prescribing, and explore drug allergy knowledge and attitudes amongst anaesthetists. METHODS: We performed a prospective cross-sectional study in 213 UK hospitals in 2018. Elective surgical patients were interviewed, with a detailed allergy history taken in those self-reporting drug allergy. Anaesthetists completed a questionnaire concerning perioperative drug allergy. RESULTS: Of 21 219 patients included, 6214 (29.3 %) (95% confidence interval [CI]: 28.7-29.9) reported drug allergy. Antibiotics, NSAIDs, and opioids were the most frequently implicated agents. Of a total of 8755 reactions, 2462 (28.1%) (95% CI: 29.2-31.1) were categorised as high risk for representing genuine allergy after risk stratification. A history suggestive of chronic spontaneous urticaria significantly increased the risk of reporting drug allergy (odds ratio 2.68; 95% CI: 2.4-3; P<0.01). Of 4756 anaesthetists completing the questionnaire, 1473 (31%) (95% CI: 29.7-32.3) routinely discuss perioperative allergy risk with patients. Prescribing habits in the presence of drug allergy labels differ depending on the implicated agent. Most anaesthetists (4678/4697; 99.6%) (95% CI: 99.4-99.8) prescribe opioids when reactions are consistent with side-effects, although 2269/4697 (48%) (95% CI: 46.9-49.7) would avoid the specific opioid reported. CONCLUSIONS: Almost 30% of UK elective surgical patients report a history of drug allergies, but the majority of reported reactions are likely to be non-allergic reactions. Allergy labels can impact on perioperative prescribing through avoidance of important drugs and use of less effective alternatives. We highlight important knowledge gaps about drug allergy amongst anaesthetists, and the need for improved education around allergy.

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.

Investigating the genetic susceptibility to exertional heat illness.

BACKGROUND: We aimed to identify rare (minor allele frequency ≤1%), potentially pathogenic non-synonymous variants in a well-characterised cohort with a clinical history of exertional heat illness (EHI) or exertional rhabdomyolysis (ER). The genetic link between malignant hyperthermia (MH) and EHI was investigated due to their phenotypic overlap. METHODS: The coding regions of 38 genes relating to skeletal muscle calcium homeostasis or exercise intolerance were sequenced in 64 patients (mostly military personnel) with a history of EHI, or ER and who were phenotyped using skeletal muscle in vitro contracture tests. We assessed the pathogenicity of variants using prevalence data, in silico analysis, phenotype and segregation evidence and by review of the literature. RESULTS: We found 51 non-polymorphic, potentially pathogenic variants in 20 genes in 38 patients. Our data indicate that RYR1 p.T3711M (previously shown to be likely pathogenic for MH susceptibility) and RYR1 p.I3253T are likely pathogenic for EHI. PYGM p.A193S was found in 3 patients with EHI, which is significantly greater than the control prevalence (p=0.000025). We report the second case of EHI in which a missense variant at CACNA1S p.R498 has been found. Combinations of rare variants in the same or different genes are implicated in EHI. CONCLUSION: We confirm a role of RYR1 in the heritability of EHI as well as ER but highlight the likely genetic heterogeneity of these complex conditions. We propose defects, or combinations of defects, in skeletal muscle calcium homeostasis, oxidative metabolism and membrane excitability are associated with EHI.

Generic versus reference listed ropivacaine for peripheral nerve blockade: A randomised, triple-blinded, crossover, equivalence study in volunteers.

BACKGROUND: Generic drug preparations do not require the same degree of scrutiny as the originally licensed preparation before they can be approved for clinical use. The permitted tolerance limits for bioequivalent preparations might be associated with clinically relevant differences for drugs with a narrow therapeutic index, such as local anaesthetics. OBJECTIVE: We compared pharmacokinetic and pharmacodynamic characteristics of generic and reference listed or original preparations of ropivacaine. DESIGN: The current healthy volunteer study used a randomised, triple-blinded, cross-over equivalence design. SETTING: Tertiary university hospital, Medical University of Vienna. SUBJECTS: Healthy male volunteers (N=18) aged 18 to 60 years. INTERVENTIONS: A series of three ultrasound-guided ulnar nerve blocks separated by at least 6 days were carried out on each volunteer. Reference listed ropivacaine (NaropinTM) was used for two blocks and a generic preparation of ropivacaine was used for the other block. Sensory block onset and duration were evaluated using loss of pinprick sensation. MAIN OUTCOME MEASURES: Duration of sensory block was the primary outcome. Secondary outcomes included time-to-onset of sensory block, ropivacaine pharmacokinetics from venous blood samples and pH of the preparations. Equivalence was evaluated using the ratios of means and 90% confidence intervals (CIs) of log transformed data. RESULTS: Equivalence was demonstrated for the primary outcome measure, the duration of sensory block [original : generic ratio 1.01 (90% CI 0.87 to 1.16); P < 0.007] and all pharmacokinetic variables. Equivalence could not be concluded for time-to-onset of sensory block [reference : generic ratio 0.80 (90% CI 0.63 to 1.03); P = 0.27], although reproducibility of this variable using our experimental model was lower than for other variables. The generic preparation was significantly more alkaline [difference 0.06 pH units (95% CI 0.04 to 0.07); P < 0.0001]. CONCLUSION: Our finding of equivalence for sensory block duration and key pharmacokinetic variables between a generic and original preparation of ropivacaine is reassuring. The significant, but small, difference in pH is not clinically important. TRIAL REGISTRATION: EudraCT 2019-003148-61, German Clinical Trials Register (DRKS 00017750).

Genomic Screening for Malignant Hyperthermia Susceptibility.

It is timely to consider the utility and practicability of screening for malignant hyperthermia susceptibility using genomic testing. Here the authors pose a simple, but bold question: what would it take to end deaths from malignant hyperthermia? The authors review recent advances and propose a scientific and clinical pathway toward this audacious goal to provoke discussion in the field.

DALES, Drug Allergy Labels in Elective Surgical patients: a prospective multicentre cross-sectional study of incidence, risks, and attitudes in penicillin de-labelling strategies.

BACKGROUND: Penicillin allergy is associated with a range of poor health outcomes. Allergy testing can be made simpler by using a direct drug provocation test in patients at low risk of genuine allergy. This approach could allow population-level 'de-labelling'. We sought to determine the incidence and nature of penicillin allergy labels in UK surgical patients and define patient and anaesthetist attitudes towards penicillin allergy testing. METHODS: A prospective cross-sectional questionnaire study was performed in 213 UK hospitals. 'Penicillin allergic' patients were interviewed and risk-stratified. Knowledge and attitudes around penicillin allergy were defined in patients and anaesthetists. RESULTS: Of 21 219 patients, 12% (n=2626) self-reported penicillin allergy; 27% reported low-risk histories potentially suitable for a direct drug provocation test; an additional 40% reported symptoms potentially suitable for a direct drug provocation test after more detailed assessment. Of 4798 anaesthetists, 40% claimed to administer penicillin routinely when they judged the label low risk. Only 47% of anaesthetists would be happy to administer penicillin to a patient previously de-labelled by an allergy specialist using a direct drug provocation test; perceived lack of support was the most common reason for not doing so. CONCLUSIONS: At least 27% of patients with a penicillin allergy label may be suitable for a direct drug provocation test. Anaesthetists demonstrated potentially unsafe prescribing in patients with penicillin allergy labels. More than half of anaesthetists lack confidence in the results of a direct drug provocation tests undertaken by a specialist. Our findings highlight significant barriers to the effective implementation of widespread de-labelling in surgical patients.