Under-dosing and over-dosing of neuromuscular blocking drugs and reversal agents: beware of the risks.

The phenomena of residual curarisation and recurarisation after the use of long-acting non-depolarising neuromuscular blocking drugs such as tubocurarine and pancuronium were well recognised 60 years ago. But the incidence seemed to decline with the introduction of atracurium and vecuronium. However, recently there have been an increasing number of reports of residual and recurrent neuromuscular block. Some of these reports are a result of inappropriate doses of rocuronium, sugammadex or both, together with inadequate neuromuscular monitoring. We urge clinicians to review their practice to ensure the highest standards of clinical care when using neuromuscular blocking drugs and reversal agents. This includes the use of quantitative neuromuscular monitoring whenever neuromuscular blocking drugs are administered.

Is adamgammadex the brother of sugammadex or the next generation of reversal agent?

Sugammadex is now in widespread use to reverse the neuromuscular blocking effects of rocuronium. Adverse effects from sugammadex are rare, but anaphylactic and cardiovascular reactions to the drug have been reported. In an attempt to reduce such side-effects, a modified gamma-cyclodextrin, adamgammadex, has been developed. Phase 3 clinical trials suggest that it is slightly less potent than sugammadex and has a non-inferior speed of onset. In a multicentre trial of 310 patients, there was a suggestion of a lower incidence of allergic responses and recurarisation after adamgammadex compared with sugammadex. The clinical implications of this study are discussed in this editorial.

'To see ourselves as others see us'.

Shaw and colleagues, who are medical historians, have published a detailed review of the social history of the British Journal of Anaesthesia (BJA) to celebrate its first 100 years. In this editorial, we note some additional contributions and financial details that are relevant to the development of the BJA into the international high-impact journal it is today.

Educating anaesthetists on neuromuscular monitoring: the challenges continue.

The need to introduce guidelines on neuromuscular monitoring emphasising the use of quantitative techniques that record the train-of-four ratio is now recognised by an increasing number of national anaesthetic societies in the Western world. But the challenge of convincing individual anaesthetists to adopt and use this practice routinely remains. For >10 yr, it has been recognised that all staff in anaesthetic departments need to have regular training in modern neuromuscular monitoring techniques. We discuss a publication in this journal that describes the challenges of setting up multicentre training in Spain to expand the use of quantitative neuromuscular monitoring and their short-term results.

How robust are the STRONGER and STIL-STRONGER studies?

In 2020, the Sugammadex vs Neostigmine for Reversal of Neuromuscular Blockade and Postoperative Pulmonary Complications (STRONGER) study provided evidence for the first time that use of sugammadex is associated with fewer postoperative pulmonary complications than use of neostigmine. In a recent publication in the British Journal of Anaesthesia, a secondary analysis of the same data, the Association Between Neuromuscular Blockade Reversal Agent Choice and Postoperative Pulmonary Complications (STIL-STRONGER) study, has produced similar evidence of the advantages of sugammadex over neostigmine in high-risk and older patients undergoing prolonged, elective surgery. Here we consider the implications of the detailed statistical analysis used in these two studies and how its limitations could possibly have enhanced the statistical differences between the two drugs with respect to postoperative pulmonary complications.

The evolution of the British Journal of Anaesthesia: the first 100 years.

At this centenary of the British Journal of Anaesthesia (BJA) in 2023, six of its 12 editors/editors-in-chief detail developments over the decades that have led to the BJA becoming a high-impact international scientific journal. As a charity, the BJA supports academic research and training in anaesthesia, critical care, and pain medicine including funding of research grants and postgraduate education. Building on this foundation, the BJA continues to innovate as it aims to become fully electronic, expand into open access publishing, and increase the diversity of its editorial board.

Use of a train-of-four ratio of 0.95 versus 0.9 for tracheal extubation: an exploratory analysis of POPULAR data.

BACKGROUND: The prospective observational European multicentre cohort study (POPULAR) of postoperative pulmonary complications (NCT01865513) did not demonstrate that adherence to the recommended train-of-four ratio (TOFR) of 0.9 before extubation was associated with better pulmonary outcomes from the first postoperative day up to hospital discharge. We re-analysed the POPULAR data as to whether there existed a better threshold for TOFR recovery before extubation to reduce postoperative pulmonary complications in patients who had quantitative neuromuscular monitoring (87% acceleromyography). METHODS: To identify the optimal TOFR, the complete case cohort of patients with quantitative neuromuscular monitoring (n=3150) was split into several pairs of sub-cohorts related to TOFR values from 0.86 to 0.96; values of 0.97 and higher could not be used as the sub-cohorts were too small. The optimal TOFR was considered to have the lowest P-value from multivariate logistic regression calculated for each of the TOFR values. Data are presented as adjusted absolute risk reduction or median difference with 95% confidence interval. RESULTS: Extubating patients with TOFR >0.95 rather than >0.9 reduced the adjusted risk of postoperative pulmonary complications by 3.5% (0.7-6.0%) from that reported in POPULAR (11.3%). Increasing the recommended TOFR from 0.9 to 0.95 reduced the adjusted risk by 4.9% (1.2-8.5%). Sub-cohorts resulting from 1:1 propensity score matching revealed that sugammadex had been given in higher doses by 0.30 (0.13-0.48) mg kg-1 in the sub-cohort with TOFR > 0.95. CONCLUSIONS: A post hoc analysis of patients receiving quantitative monitoring of neuromuscular function suggests that postoperative pulmonary complications are reduced for TOFR > 0.95 before tracheal extubation compared with TOFR > 0.9. TRIAL REGISTRATION NUMBER: NCT01865513.

Anesthesiologists' Overconfidence in Their Perceived Knowledge of Neuromuscular Monitoring and Its Relevance to All Aspects of Medical Practice: An International Survey.

BACKGROUND: In patients who receive a nondepolarizing neuromuscular blocking drug (NMBD) during anesthesia, undetected postoperative residual neuromuscular block is a common occurrence that carries a risk of potentially serious adverse events, particularly postoperative pulmonary complications. There is abundant evidence that residual block can be prevented when real-time (quantitative) neuromuscular monitoring with measurement of the train-of-four ratio is used to guide NMBD administration and reversal. Nevertheless, a significant percentage of anesthesiologists fail to use quantitative devices or even conventional peripheral nerve stimulators routinely. Our hypothesis was that a contributing factor to the nonutilization of neuromuscular monitoring was anesthesiologists' overconfidence in their knowledge and ability to manage the use of NMBDs without such guidance. METHODS: We conducted an Internet-based multilingual survey among anesthesiologists worldwide. We asked respondents to answer 9 true/false questions related to the use of neuromuscular blocking drugs. Participants were also asked to rate their confidence in the accuracy of each of their answers on a scale of 50% (pure guess) to 100% (certain of answer). RESULTS: Two thousand five hundred sixty persons accessed the website; of these, 1629 anesthesiologists from 80 countries completed the 9-question survey. The respondents correctly answered only 57% of the questions. In contrast, the mean confidence exhibited by the respondents was 84%, which was significantly greater than their accuracy. Of the 1629 respondents, 1496 (92%) were overconfident. CONCLUSIONS: The anesthesiologists surveyed expressed overconfidence in their knowledge and ability to manage the use of NMBDs. This overconfidence may be partially responsible for the failure to adopt routine perioperative neuromuscular monitoring. When clinicians are highly confident in their knowledge about a procedure, they are less likely to modify their clinical practice or seek further guidance on its use.

Consensus Statement on Perioperative Use of Neuromuscular Monitoring.

A panel of clinician scientists with expertise in neuromuscular blockade (NMB) monitoring was convened with a charge to prepare a consensus statement on indications for and proper use of such monitors. The aims of this article are to: (a) provide the rationale and scientific basis for the use of quantitative NMB monitoring; (b) offer a set of recommendations for quantitative NMB monitoring standards; (c) specify educational goals; and (d) propose training recommendations to ensure proper neuromuscular monitoring and management. The panel believes that whenever a neuromuscular blocker is administered, neuromuscular function must be monitored by observing the evoked muscular response to peripheral nerve stimulation. Ideally, this should be done at the hand muscles (not the facial muscles) with a quantitative (objective) monitor. Objective monitoring (documentation of train-of-four ratio ≥0.90) is the only method of assuring that satisfactory recovery of neuromuscular function has taken place. The panel also recommends that subjective evaluation of the responses to train-of-four stimulation (when using a peripheral nerve stimulator) or clinical tests of recovery from NMB (such as the 5-second head lift) should be abandoned in favor of objective monitoring. During an interim period for establishing these recommendations, if only a peripheral nerve stimulator is available, its use should be mandatory in any patient receiving a neuromuscular blocking drug. The panel acknowledges that publishing this statement per se will not result in its spontaneous acceptance, adherence to its recommendations, or change in routine practice. Implementation of objective monitoring will likely require professional societies and anesthesia department leadership to champion its use to change anesthesia practitioner behavior.

Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance.

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver.

Aberrant DNA methylation is a common feature of neoplastic lesions, and early detection of such changes may provide powerful mechanistic insights and biomarkers for carcinogenesis. Here, we investigate dynamic changes in the mouse liver DNA methylome associated with short (1 day) and prolonged (7, 28 and 91 days) exposure to the rodent liver non-genotoxic carcinogen, phenobarbital (PB). We find that the distribution of 5mC/5hmC is highly consistent between untreated individuals of a similar age; yet, changes during liver maturation in a transcriptionally dependent manner. Following drug treatment, we identify and validate a series of differentially methylated or hydroxymethylated regions: exposure results in staged transcriptional responses with distinct kinetic profiles that strongly correlate with promoter proximal region 5hmC levels. Furthermore, reciprocal changes for both 5mC and 5hmC in response to PB suggest that active demethylation may be taking place at each set of these loci via a 5hmC intermediate. Finally, we identify potential early biomarkers for non-genotoxic carcinogenesis, including several genes aberrantly expressed in liver cancer. Our work suggests that 5hmC profiling can be used as an indicator of cell states during organ maturation and drug-induced responses and provides novel epigenetic signatures for non-genotoxic carcinogen exposure.

Comparative analysis of affinity-based 5-hydroxymethylation enrichment techniques.

The epigenetic modification of 5-hydroxymethylcytosine (5hmC) is receiving great attention due to its potential role in DNA methylation reprogramming and as a cell state identifier. Given this interest, it is important to identify reliable and cost-effective methods for the enrichment of 5hmC marked DNA for downstream analysis. We tested three commonly used affinity-based enrichment techniques; (i) antibody, (ii) chemical capture and (iii) protein affinity enrichment and assessed their ability to accurately and reproducibly report 5hmC profiles in mouse tissues containing high (brain) and lower (liver) levels of 5hmC. The protein-affinity technique is a poor reporter of 5hmC profiles, delivering 5hmC patterns that are incompatible with other methods. Both antibody and chemical capture-based techniques generate highly similar genome-wide patterns for 5hmC, which are independently validated by standard quantitative PCR (qPCR) and glucosyl-sensitive restriction enzyme digestion (gRES-qPCR). Both antibody and chemical capture generated profiles reproducibly link to unique chromatin modification profiles associated with 5hmC. However, there appears to be a slight bias of the antibody to bind to regions of DNA rich in simple repeats. Ultimately, the increased specificity observed with chemical capture-based approaches makes this an attractive method for the analysis of locus-specific or genome-wide patterns of 5hmC.