ClC-1 Inhibition as a Mechanism for Accelerating Skeletal Muscle Recovery After Neuromuscular Block in Rats.

Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents.

Area under the curve and amplitude of the compound motor action potential are clinically interchangeable quantitative measures of neuromuscular block: a method comparison study.

Background: Current guidelines recommend quantitative neuromuscular block monitoring during neuromuscular blocking agent administration. Monitors using surface electromyography (EMG) determine compound motor action potential (cMAP) amplitude or area under the curve (AUC). Rigorous evaluation of the interchangeability of these methods is lacking but necessary for clinical and research assurance that EMG interpretations of the depth of neuromuscular block are not affected by the methodology. Methods: Digitised EMG waveforms were studied from 48 patients given rocuronium during two published studies. The EMG amplitudes and AUCs were calculated pairwise from all cMAPs classified as valid by visual inspection. Ratios of the first twitch (T1) to the control T1 before administration of rocuronium (T1c) and train-of-four ratios (TOFRs) were compared using repeated measures Bland-Altman analysis. Results: Among the 2419 paired T1/T1c differences where the average T1/T1c was ≤0.2, eight (0.33%) were outside prespecified clinical limits of agreement (-0.148 to 0.164). Among the 1781 paired TOFR differences where the average TOFR was ≥0.8, 70 (3.93%) were outside the prespecified clinical limits of agreement ((-0.109 to 0.134). Among all 7286 T1/T1c paired differences, the mean bias was 0.32 (95% confidence interval 0.202-0.043), and among all 5559 paired TOFR differences, the mean bias was 0.011 (95% confidence interval 0.0050-0.017). Among paired T1/T1c and TOFR differences, Lin's concordance correlation coefficients were 0.98 and 0.995, respectively. Repeatability coefficients for T1/T1c and TOFR were <0.08, with no differences between methods. Conclusions: Quantitative assessment neuromuscular block depth is clinically interchangeable when calculated using cMAP amplitude or the AUC.

Pediatric Intraoperative Electromyographic Responses at the Adductor Pollicis and Flexor Hallucis Brevis Muscles: A Prospective, Comparative Analysis.

BACKGROUND: Peripheral nerve stimulation with a train-of-four (TOF) pattern can be used intraoperatively to evaluate the depth of neuromuscular block and confirm recovery from neuromuscular blocking agents (NMBAs). Quantitative monitoring can be challenging in infants and children due to patient size, equipment technology, and limited access to monitoring sites. Although the adductor pollicis muscle is the preferred site of monitoring, the foot is an alternative when the hands are unavailable. However, there is little information on comparative evoked neuromuscular responses at those 2 sites. METHODS: Pediatric patients undergoing inpatient surgery requiring NMBA administration were studied after informed consent. Electromyographic (EMG) monitoring was performed simultaneously in each participant at the hand (ulnar nerve, adductor pollicis muscle) and the foot (posterior tibial nerve, flexor hallucis brevis muscle). RESULTS: Fifty patients with a mean age of 3.0 ± standard deviation (SD) 2.9 years were studied. The baseline first twitch amplitude (T1) of TOF at the foot (12.46 mV) was 4.47 mV higher than at the hand (P <.0001). The baseline TOF ratio (TOFR) before NMBA administration and the maximum TOFR after antagonism with sugammadex were not different at the 2 sites. The onset time until the T1 decreased to 10% or 5% of the baseline value (T1) was delayed by approximately 90 seconds (both P =.014) at the foot compared with the hand. The TOFR at the foot recovered (TOFR ≥0.9) 191 seconds later than when this threshold was achieved at the hand (P =.017). After antagonism, T1 did not return to its baseline value, a typical finding with EMG monitoring, but the fractional recovery (maximum T1 at recovery divided by the baseline T1) at the hand and foot was not different, 0.81 and 0.77, respectively (P =.68). The final TOFR achieved at recovery was approximately 100% and was not different between the 2 sites. CONCLUSIONS: Although this study in young children demonstrated the feasibility of TOF monitoring, interpretation of the depth of neuromuscular block needs to consider the delayed onset and the delayed recovery of TOFR at the foot compared to the hand. The delay in achieving these end points when monitoring the foot may impact the timing of tracheal intubation and assessment of adequate recovery of neuromuscular block to allow tracheal extubation (ie, TOFR ≥0.9).

The Incidence of Residual Neuromuscular Block in Pediatrics: A Prospective, Pragmatic, Multi-institutional Cohort Study.

Introduction Residual neuromuscular block, defined as a quantitatively measured train-of-four ratio (TOFr) <0.9, is common postoperatively. Using a pragmatic trial design, we hypothesized that qualitative and/or clinical assessment of neuromuscular block would inadequately detect residual block following antagonism with neostigmine or sugammadex. Method After IRB approval and written informed consent, 74 children (aged 2-17 years), undergoing elective surgery and receiving rocuronium, were prospectively enrolled in the study at Children's Hospital Colorado and Children's Healthcare of Atlanta. Routine clinical practice at both institutions consisted of clinical signs and/or qualitative assessment with peripheral nerve stimulators. Children at the Colorado hospital routinely received sugammadex antagonism; whereas children at the Atlanta hospital received neostigmine. Residual neuromuscular block was assessed postoperatively using quantitative electromyography. If TOFr was <0.9, patients received sugammadex until TOFr ≥0.9. Result Qualitative and clinical assessment failed to detect residual block in 29.7% of patients in the neostigmine reversal cohort (adjusted odds ratio (aOR) 29.8, 95% confidence interval (CI): 2.7 to 5,559.5, p-value = 0.002). No residual block was detected in the sugammadex reversal cohort. A correlation between increasing patient weight and incidence of postoperative residual block was observed in the neostigmine cohort (aOR 1.05, 95% CI: 1.02 to 1.10, p-value = 0.002). Conclusion Qualitative and/or clinical assessment of neuromuscular block inadequately detects residual block following neostigmine antagonism.

Machine learning based analysis and detection of trend outliers for electromyographic neuromuscular monitoring.

PURPOSE: Neuromuscular monitoring is frequently plagued by artefacts, which along with the frequent unawareness of the principles of this subtype of monitoring by many clinicians, tends to lead to a cynical attitute by clinicians towards these monitors. As such, the present study aims to derive a feature set and evaluate its discriminative performance for the purpose of Train-of-Four Ratio (TOF-R) outlier analysis during continuous intraoperative EMG-based neuromuscular monitoring. METHODS: Patient data was sourced from two devices: (1) Datex-Ohmeda Electromyography (EMG) E-NMT: a dataset derived from a prospective observational trial including 136 patients (21,891 TOF-R observations), further subdivided in two based on the type of features included; and (2) TetraGraph: a clinical case repository dataset of 388 patients (97,838 TOF-R observations). The two datasets were combined to create a synthetic set, which included shared features across the two. This process led to the training of four distinct models. RESULTS: The models showed an adequate bias/variance balance, suggesting no overfitting or underfitting. Models 1 and 2 consistently outperformed the others, with the former achieving an F1 score of 0.41 (0.31, 0.50) and an average precision score (95% CI) of 0.48 (0.35, 0.60). A random forest model analysis indicated that engineered TOF-R features were proportionally more influential in model performance than basic features. CONCLUSIONS: Engineered TOF-R trend features and the resulting Cost-Sensitive Logistic Regression (CSLR) models provide useful insights and serve as a potential first step towards the automated removal of outliers for neuromuscular monitoring devices. TRIAL REGISTRATION: NCT04518761 (clinicaltrials.gov), registered on 19 August 2020.

Corrigendum to "Validation of a convolutional neural network that reliably identifies electromyographic compound motor action potentials following train-of-four stimulation: an algorithm development experimental study" [BJA Open 8 (2023) 100236].

[This corrects the article DOI: 10.1016/j.bjao.2023.100236.].

Validation of a convolutional neural network that reliably identifies electromyographic compound motor action potentials following train-of-four stimulation: an algorithm development experimental study.

Background: International guidelines recommend quantitative neuromuscular monitoring when administering neuromuscular blocking agents. The train-of-four count is important for determining the depth of block and appropriate reversal agents and doses. However, identifying valid compound motor action potentials (cMAPs) during surgery can be challenging because of low-amplitude signals and an inability to observe motor responses. A convolutional neural network (CNN) to classify cMAPs as valid or not might improve the accuracy of such determinations. Methods: We modified a high-accuracy CNN originally developed to identify handwritten numbers. For training, we used digitised electromyograph waveforms (TetraGraph) from a previous study of 29 patients and tuned the model parameters using leave-one-out cross-validation. External validation used a dataset of 19 patients from another study with the same neuromuscular block monitor but with different patient, surgical, and protocol characteristics. All patients underwent ulnar nerve stimulation at the wrist and the surface electromyogram was recorded from the adductor pollicis muscle. Results: The tuned CNN performed highly on the validation dataset, with an accuracy of 0.9997 (99% confidence interval 0.9994-0.9999) and F1 score=0.9998. Performance was equally good for classifying the four individual responses in the train-of-four sequence. The calibration plot showed excellent agreement between the predicted probabilities and the actual prevalence of valid cMAPs. Ten-fold cross-validation using all data showed similar high performance. Conclusions: The CNN distinguished valid cMAPs from artifacts after ulnar nerve stimulation at the wrist with >99.5% accuracy. Incorporation of such a process within quantitative electromyographic neuromuscular block monitors is feasible.

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision.

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59-74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51, 789-808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.

Comparison of visual and electromyographic assessments with train-of-four stimulation of the ulnar nerve: a prospective cohort study.

PURPOSE: The use of a peripheral nerve stimulator to assess the level of neuromuscular blockade tasks the anesthesia clinician with subjectively assessing the response to neurostimulation. In contrast, objective neuromuscular monitors provide quantitative information. The purpose of this study was to compare subjective evaluations from a peripheral nerve stimulator with objective measurements of neurostimulation responses from a quantitative monitor. METHODS: Patients were enrolled preoperatively, and intraoperative neuromuscular blockade management was at the discretion of the anesthesiologist. Electromyography electrodes were placed over the dominant or nondominant arm in a randomized fashion. Following onset of nondepolarizing neuromuscular blockade, the ulnar nerve was stimulated, the response was measured with electromyography, and anesthesia clinicians, who were blinded to the objective measurements, subjectively (visually) evaluated the response to neurostimulation. RESULTS: Fifty patients were enrolled and 666 neurostimulations were performed at 333 different time points. Anesthesia clinicians subjectively overestimated the response of the adductor pollicis muscle following neurostimulation of the ulnar nerve 155/333 (47%) of the time when compared with objective electromyographic measurements. When subjective evaluations and objective measurements differed to any degree, subjective evaluations were higher than objective measurements 155/166 (92%) of the time (95% CI, 87 to 95; P < 0.001), representing significant evidence that subjective evaluation overestimates the response to train-of-four stimulation. CONCLUSIONS: Subjective observations of a "twitch" do not consistently correspond to objective measurements of neuromuscular blockade with electromyography. Subjective evaluation overestimates the response to neurostimulation and may be unreliable for determining the depth of block or confirming adequate recovery.

RéSUMé: OBJECTIF: Lors de l'utilisation d'un stimulateur nerveux périphérique pour évaluer le niveau de bloc neuromusculaire, le clinicien en anesthésie doit évaluer de manière subjective la réponse à la neurostimulation. Les moniteurs neuromusculaires objectifs fournissent quant à eux des informations quantitatives. L'objectif de cette étude était de comparer les évaluations subjectives d'un stimulateur nerveux périphérique avec des mesures objectives des réponses de neurostimulation provenant d'un moniteur quantitatif. MéTHODE: Les patients ont été recrutés avant leur opération, et la gestion du bloc neuromusculaire peropératoire était à la discrétion de l'anesthésiologiste. Des électrodes d'électromyographie ont été placées sur le bras dominant ou non dominant de manière aléatoire. Après l'amorce du bloc neuromusculaire non dépolarisant, le nerf cubital a été stimulé, la réponse a été mesurée par électromyographie, et les cliniciens en anesthésie, qui n'avaient pas accès aux mesures objectives, ont évalué subjectivement (visuellement) la réponse à la neurostimulation. RéSULTATS: Cinquante patients ont été recrutés et 666 neurostimulations ont été réalisées à 333 moments différents. Les cliniciens en anesthésie ont subjectivement surestimé la réponse du muscle adducteur du pouce après neurostimulation du nerf cubital 155/333 (47 %) fois par rapport aux mesures électromyographiques objectives. Lorsque les évaluations subjectives et les mesures objectives différaient à quelque degré que ce soit, les évaluations subjectives étaient plus élevées que les mesures objectives 155/166 (92 %) du temps (IC 95 %, 87 à 95; P < 0,001), ce qui représente une preuve significative que l'évaluation subjective surestime la réponse à la stimulation par train-de-quatre. CONCLUSION: Les observations subjectives d'une « contraction ¼ ne correspondent pas systématiquement aux mesures objectives d'un bloc neuromusculaire telles qu'obtenues par électromyographie. L'évaluation subjective surestime la réponse à la neurostimulation et pourrait ne pas être fiable pour déterminer la profondeur du bloc ou confirmer une récupération adéquate.

A survey on the availability, usage and perception of neuromuscular monitors in Europe.

PURPOSE: Neuromuscular blocking agents (NMBAs) are routinely administered to patients in a multiplicity of anesthetic settings. Absence of postoperative residual neuromuscular block is widely considered an anesthetic patient safety mandate. Despite the increasing availability of a wider range of commercial quantitative neuromuscular monitors, the availability and use of neuromuscular monitoring devices is deemed to be suboptimal even in countries with above-average health system ratings. The present study aims to more precisely characterize the perceived availability, cost sensitivity and usability of neuromuscular monitoring devices within European anesthesia departments. METHODS: A pre-registered internet-based survey assessing the availability, cost sensitivity and usability of neuromuscular monitoring devices was distributed as e-mail newsletter by the European Society of Anaesthesiology and Intensive Care (ESAIC) to all of its active full members. The survey was available online for a total of 120 days. RESULTS: Having targeted a total of 7472 ESAIC members, the survey was completed by a total of 692 anesthesiologists (9.3%) distributed across 37 different European countries. Quantitative monitors were reported to be proportionally more available than qualitative ones (87.6% vs. 62.6%, respectively), as well as in greater monitor-per-operating room ratios. Most anesthesiologists (60.5%) expressed moderate confidence in quantitative monitors, with artifactual recordings and inaccurate measurements being the most frequently encountered issues (25.9%). The commercial pricing of quantitative devices was considered more representative of a device's true value, when compared to qualitative instruments (average cost of €4.500 and €1.000 per device, respectively). CONCLUSION: The availability of quantitative NMM in European operating theaters has increased in comparison with that reported in previous decades, potentially indicating increasing monitoring rates. European anesthesiologists express moderate confidence in quantitative neuromuscular monitors, along with a sentiment of adequate pricing when compared to their qualitative counterparts. Trust in quantitative monitors is marked by caution and awareness for artifactual recordings, with a consequent expectation that developments focusing on accuracy, reliability and ergonomics of neuromuscular monitors be prioritized.