Ensemble-Based Virtual Screening Led to the Discovery of Novel Lead Molecules as Potential NMBAs.

Neuromuscular blocking agents (NMBAs) are routinely used during anesthesia to relax skeletal muscle. Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels; NMBAs can induce muscle paralysis by preventing the neurotransmitter acetylcholine (ACh) from binding to nAChRs situated on the postsynaptic membranes. Despite widespread efforts, it is still a great challenge to find new NMBAs since the introduction of cisatracurium in 1995. In this work, an effective ensemble-based virtual screening method, including molecular property filters, 3D pharmacophore model, and molecular docking, was applied to discover potential NMBAs from the ZINC15 database. The results showed that screened hit compounds had better docking scores than the reference compound d-tubocurarine. In order to further investigate the binding modes between the hit compounds and nAChRs at simulated physiological conditions, the molecular dynamics simulation was performed. Deep analysis of the simulation results revealed that ZINC257459695 can stably bind to nAChRs' active sites and interact with the key residue Asp165. The binding free energies were also calculated for the obtained hits using the MM/GBSA method. In silico ADMET calculations were performed to assess the pharmacokinetic properties of hit compounds in the human body. Overall, the identified ZINC257459695 may be a promising lead compound for developing new NMBAs as an adjunct to general anesthesia, necessitating further investigations.

Epidemiology of perioperative anaphylaxis in France in 2017-2018: the 11th GERAP survey.

BACKGROUND: Perioperative anaphylaxis is rare but is associated with significant morbidity. This complication has been well described in France by the GERAP (Groupe d'Etude des Réactions Anaphylactiques Périopératoires), a network focused on its study. The epidemiology of perioperative anaphylaxis is evolving, influenced by environmental factors and clinical practice. The aim of this study was to update the epidemiology of perioperative anaphylaxis in France. METHODS: This multicentre retrospective study was performed in 26 allergy clinics of the GERAP network in 2017-8. RESULTS: There were 765 patients with perioperative anaphylaxis included. Most cases were severe, with 428 (56%) reactions graded as 3 or 4 according to the Ring and Messmer classification. Skin test results were available for 676 patients, with a culprit agent identified in 471 cases (70%). Neuromuscular blocking agents were the main cause of perioperative anaphylaxis (n=281; 60%), followed by antibiotics (n=118; 25%) and patent blue dye (n=11; 2%). Cefazolin was the main antibiotic responsible for perioperative anaphylaxis (52% of antibiotic-related reactions). Suxamethonium and rocuronium were the main neuromuscular blocking agents responsible for perioperative anaphylaxis with 7.1 (6.1-8.4) and 5.6 (4.2-7.4) reactions per 100,000 vials sold, respectively, whereas cefazolin-related cases were estimated at 0.7 (0.5-0.9) reactions per 100,000 vials sold. CONCLUSIONS: Our results confirm that most commonly identified triggering agents remain neuromuscular blocking agents. Reactions to antibiotics, particularly cefazolin, are becoming increasingly frequent. The origin of sensitisation to cefazolin is unknown, as no cross-sensitisation has been described, and it should be the subject of further study. Perioperative anaphylaxis should be followed over the years and understood given the changing triggers. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT04654923).

Trapping and reversing neuromuscular blocking agent by anionic pillar[5]arenes: Understanding the structure-affinity-reversal effects.

Selective relaxant binding agents (SRBA) have great potential in clinical surgeries for the precise reversal of neuromuscular blockades. Understanding the relationship between the structure-affinity-reversal effects of SRBA and neuromuscular blockade is crucial for the design of new SRBAs, which has rarely been explored. Seven anionic pillar[5]arenes (AP5As) with different aliphatic chains and anionic groups at both edges were designed. Their binding affinities to the neuromuscular blocking agent decamonium bromide (DMBr) were investigated using 1H NMR, isothermal titration calorimetry (ITC), and theoretical calculations. The results indicate that the capture of DMBr by AP5As is primarily driven by electrostatic interactions, ion-dipole interactions and C-H‧‧‧π interactions. The optimal size matching between the carboxylate AP5As and DMBr was ∼0.80. The binding affinity increased with an increase in the charge quantity of AP5As. Further animal experiments indicated that the reversal efficiency increased with increasing binding affinity for carboxylate or phosphonate AP5As. However, phosphonate AP5As exhibited lower reversal efficiencies than carboxylate AP5As, despite having stronger affinities with DMBr. By understanding the structure-affinity-reversal relationships, this study provides valuable insights into the design of innovative SRBAs for reversing neuromuscular blockade.

Expiratory Muscle Activity Counteracts Positive End-Expiratory Pressure and Is Associated with Fentanyl Dose in Patients with Acute Respiratory Distress Syndrome.

Rationale: Hypoxemia during mechanical ventilation might be worsened by expiratory muscle activity, which reduces end-expiratory lung volume through lung collapse. A proposed mechanism of benefit of neuromuscular blockade in acute respiratory distress syndrome (ARDS) is the abolition of expiratory efforts. This may contribute to the restoration of lung volumes. The prevalence of this phenomenon, however, is unknown. Objectives: To investigate the incidence and amount of end-expiratory lung impedance (EELI) increase after the administration of neuromuscular blocking agents (NMBAs), clinical factors associated with this phenomenon, its impact on regional lung ventilation, and any association with changes in pleural pressure. Methods: We included mechanically ventilated patients with ARDS monitored with electrical impedance tomography (EIT) who received NMBAs in one of two centers. We measured changes in EELI, a surrogate for end-expiratory lung volume, before and after NMBA administration. In an additional 10 patients, we investigated the characteristic signatures of expiratory muscle activity depicted by EIT and esophageal catheters simultaneously. Clinical factors associated with EELI changes were assessed. Measurements and Main Results: We included 46 patients, half of whom showed an increase in EELI of >10% of the corresponding Vt (46.2%; IQR, 23.9-60.9%). The degree of EELI increase correlated positively with fentanyl dosage and negatively with changes in end-expiratory pleural pressures. This suggests that expiratory muscle activity might exert strong counter-effects against positive end-expiratory pressure that are possibly aggravated by fentanyl. Conclusions: Administration of NMBAs during EIT monitoring revealed activity of expiratory muscles in half of patients with ARDS. The resultant increase in EELI had a dose-response relationship with fentanyl dosage. This suggests a potential side effect of fentanyl during protective ventilation.

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.

Performance of closed-loop systems for intravenous drug administration: a systematic review and meta-analysis of randomised controlled trials.

Closed-loop drug delivery systems are autonomous computers able to administer medication in response to changes in physiological parameters (controlled variables). While limited evidence suggested that closed-loop systems can perform better than manual drug administration in certain settings, this technology remains a research tool with an uncertain risk/benefit profile. Our aim was comparing the performance of closed-loop systems with manual intravenous drug administration in adults. We searched MEDLINE, CENTRAL, and Embase from inception until November 2022, without restriction to language. We assessed for inclusion randomised controlled trials comparing closed-loop and manual administration of intravenous drugs in adults, intraoperatively or in the Intensive Care Unit. We identified 32 studies on closed-loop administration of propofol, noradrenaline, phenylephrine, insulin, neuromuscular blockers, and vasodilators. Most studies were at moderate or high risk of bias. The results showed that closed-loop systems reduced the duration of blood pressure outside prespecified targets during noradrenaline (MD 14.9%, 95% CI 9.6-20.2%, I2 = 66.6%) and vasodilators administration (MD 7.4%, 95% CI 5.2-9.7%, I2 = 62.3%). Closed-loop systems also decreased the duration of recovery after propofol (MD 1.3 min, 95% CI 0.4-2.1 min, I2 = 58.6%) and neuromuscular blockers (MD 9.0 min, 95% CI 7.9-10.0 min, I2 = 0%). The certainty of the evidence was low or very low for most outcomes. Automatic technology may be used to improve the hemodynamic profile during noradrenaline and vasodilators administration and reduce the duration of postanaesthetic recovery.Registration: This systematic review was registered with PROSPERO (CRD42022336950) on the 7th of June 2022.

An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline.

Background: This document updates previously published Clinical Practice Guidelines for the management of patients with acute respiratory distress syndrome (ARDS), incorporating new evidence addressing the use of corticosteroids, venovenous extracorporeal membrane oxygenation, neuromuscular blocking agents, and positive end-expiratory pressure (PEEP). Methods: We summarized evidence addressing four "PICO questions" (patient, intervention, comparison, and outcome). A multidisciplinary panel with expertise in ARDS used the Grading of Recommendations, Assessment, Development, and Evaluation framework to develop clinical recommendations. Results: We suggest the use of: 1) corticosteroids for patients with ARDS (conditional recommendation, moderate certainty of evidence), 2) venovenous extracorporeal membrane oxygenation in selected patients with severe ARDS (conditional recommendation, low certainty of evidence), 3) neuromuscular blockers in patients with early severe ARDS (conditional recommendation, low certainty of evidence), and 4) higher PEEP without lung recruitment maneuvers as opposed to lower PEEP in patients with moderate to severe ARDS (conditional recommendation, low to moderate certainty), and 5) we recommend against using prolonged lung recruitment maneuvers in patients with moderate to severe ARDS (strong recommendation, moderate certainty). Conclusions: We provide updated evidence-based recommendations for the management of ARDS. Individual patient and illness characteristics should be factored into clinical decision making and implementation of these recommendations while additional evidence is generated from much-needed clinical trials.

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.

Delirium in patients with COVID-19 treated in the intensive care unit.

Coronavirus disease 2019 (COVID-19) can lead to acute organ dysfunction, and delirium is associated with long-term cognitive impairment and a prolonged hospital stay. This retrospective single-center study aimed to investigate the risk factors for delirium in patients with COVID-19 infection receiving treatment in an intensive care unit (ICU). A total of 111 patients aged >18 years with COVID-19 pneumonia who required oxygen therapy from February 2021 to April 2022 were included. Data on patient demographics, past medical history, disease severity, delirium, and treatment strategies during hospitalization were obtained from electronic health records. Patient characteristics and risk factors for delirium were analyzed. Old age (P < 0.001), hypertension (P < 0.001), disease severity (Sequential Organ Failure Assessment score) (P < 0.001), mechanical ventilator support (P < 0.001), neuromuscular blocker use (P < 0.001), and length of stay in the ICU (P < 0.001) showed statistically significant differences on the univariable analysis. Multivariable analysis with backward selection revealed that old age (odds ratio, 1.149; 95% confidence interval, 1.037-1.273; P = 0.008), hypertension (odds ratio, 8.651; 95% confidence interval, 1.322-56.163; P = 0.024), mechanical ventilator support (odds ratio, 226.215; 95% confidence interval, 15.780-3243.330; P < 0.001), and length of stay in the ICU (odds ratio, 30.295; 95% confidence interval, 2.539-361.406; P = 0.007) were significant risk factors for delirium. In conclusion, old age, ICU stay, hypertension, mechanical ventilator support, and neuromuscular blocker use were predictive factors for delirium in COVID-19 patients in the ICU. The study findings suggest the need for predicting the occurrence of delirium in advance and preventing and treating delirium.

[¿Anafilaxia perioperatoria? Serie de casos].

Objective: Identify the causative agent of POH, to avoid re-exposure and assess the use of alternative treatment. Methods: 10 cases of immediate POH are described, in all of them a history of previous surgical procedures, carrying out a 3-step protocol: 1st documenting the surgical record to identify exposures, 2nd performing skin and/or epicutaneous tests and 3rd searching for an alternative treatment. treatment if a new surgical procedure is required and in selected cases challenge tests. Results: Of a total of 10 patients with immediate POH, tests were performed according to the case: neuromuscular blockers, anesthetics, opioids, NSAIDs, anti- biotics, diuretics, latex, isodine, and chlorhexidine; finding positive tests in 7 (70%) patients: in 4 (40%) neuromuscular blockers, one of them also positive for latex, in 2 (20%) anesthetics and finally finding a pharmacological alternative in 2 (2%) and recommending free operating room latex in 2 cases (20%), the rest (30%) were classified as related to the surgical procedure and medication management. Conclusions: The study of POH is focused on ensuring safety in subsequent exposures, so in addition to identifying the causative agent, the role of the allergist also leads to a search for a safe alternative in patient management.

Objetivo: Identificar agente causal de POH, para evitar reexposición y valorar uso de alternativa de tratamiento. Métodos: Se describen 10 casos de POH inmediata, en todos antecedente de procedimientos quirúrgicos previos, realizándose protocolo de 3 pasos: 1°docu- mentar registro quirúrgico para identificar exposiciones, 2° realización de pruebas cutáneas y/o epicutáneas y 3° búsqueda de alternativa de tratamiento en caso de requerir nuevo procedimiento quirúrgico y en casos seleccionados pruebas de reto. Resultados: De un total de 10 pacientes con POH inmediata, se realizaron pruebas según el caso: bloqueadores neuromusculares, anestésicos, opioides, AINE, antibióticos, diuréticos, látex, isodine y clorhexidina; encontrando pruebas positivas en 7 pacientes (70%): en 4 (40%) bloqueadores neuromusculares, uno de ellos también positivo para látex, en 2 (20%) anestésicos y finalmente encontrando alternativa farmacológica en 2 (2%) y recomendando quirófano libre de látex en 2 casos (20%), el resto (30%) fueron catalogados como relacionados con procedimiento quirúrgico y manejo de medicamentos. Conclusiones: El estudio de las POH está enfocado en asegurar seguridad en exposiciones posteriores, por lo que además de la identificación de agente causal, el papel del alergólogo también conlleva a una búsqueda de alternativa segura en el manejo del paciente.

El bloqueo del plano del músculo erector espinal antes de la litotricia extracorpórea por ondas de choque reduce el tiempo de fluoroscopia y facilita el tratamiento de la litiasis renal: estudio prospectivo aleatorizado / Erector spinae plane block prior to extracorporeal shock wave lithotripsy decreases fluoroscopy time and promise a comfortable procedure for renal stones: a prospective randomized study

Introducción y objetivos Comparar la eficacia del bloqueo del plano del erector espinal (BPEE) y el diclofenaco sódico intramuscular (IM) en términos del manejo del dolor y su impacto sobre el estado libre de cálculos en pacientes sometidos a litotricia extracorpórea de ondas de choque (LEOCh). Pacientes y materiales El estudio incluyó a pacientes sometidos a LEOCh por litiasis renal en nuestro centro. Los pacientes fueron asignados aleatoriamente a los grupos de BPEE (Grupo 1: n = 31) y de 75 mg de diclofenaco sódico IM (Grupo 2: n = 30). Se registraron los datos demográficos de los pacientes, el tiempo de fluoroscopia durante la LEOCh, el número de focalizaciones, el total de disparos administrados, el voltaje, las tasas libre de cálculos (TLC), el método de analgesia, el número de sesiones de LEOCh, la puntuación de la Escala Visual Analógica (EVA) la localización de los cálculos, el tamaño máximo de los cálculos, el volumen de los cálculos y las unidades Hounsfield (UH). Resultados Un total de 61 pacientes fueron incluidos en el estudio. No hubo diferencias estadísticamente significativas entre los dos grupos en cuanto al tamaño, el volumen y la densidad de los cálculos, la duración de la LEOCh, el total de disparos administradas, el voltaje, el índice de masa corporal (IMC), el estado libre de cálculos y la localización de los cálculos. El tiempo de fluoroscopia y el número de veces que fue necesario focalizar el cálculo fueron significativamente inferiores en el grupo 1 con respecto al grupo 2 (p:0,002, p:0,021, respectivamente). La puntuación EVA fue significativamente inferior en el grupo 1 en comparación con el grupo 2 (p<0,001). Conclusiones Observamos que la puntuación EVA del grupo BPEE era menor que la del grupo de diclofenaco sódico IM y, aunque no de manera estadísticamente significativa, conseguimos una tasa libre de cálculos más alta en la primera sesión en el grupo BPEE. ... (AU)

Introduction and Objectives To compare the efficacy of erector spinae plane block (ESPB) and intramuscular (i.m.) diclofenac sodium in regard to pain management and impact on stone-free status in patients undergoing SWL. Patients or Materials The study included patients who underwent SWL for kidney stones in our institution. The patients were randomly assigned to the ESPB (Group 1: n = 31) and i.m. 75 mg diclofenac sodium (Group 2: n = 30) groups. The demographic data of the patients, fluoroscopy time during SWL, number of need of targeting, total shocks given, voltage, stone free rates (SFR), analgesy method, number of SWL sessions, VAS score, stone location, maximum stone size, stone volume and Hounsfield unit (HU) were also recorded. Results A total of 61 patients were included the study. There was no statistically significant difference between the two groups according to stone size, volume and density, SWL duration, total shocks given, voltage, BMI, stone-free status and stone location. Fluoroscopy time and number of need for stone targeting were significantly lower in group 1 than group 2 (p:0.002, p:0.021, respectively). The VAS score was significantly lower for group 1 compared to group 2 (p<0.001). Conclusions We observed that the VAS score was lower in the ESPB group compared to i.m. diclofenac sodium group and although it was not statistically significant, we achieved a higher rate of stone-free status in the first session in ESPB group. Most importantly, the patients in the ESPB group were exposed to less fluoroscopy and radiation. (AU)

Thigh ultrasound monitoring identifies muscle atrophy in mechanically ventilated pediatric patients.

Over the last decade, ultrasonography has taken on an increasingly important role in the daily management of critically patients and has recently been proposed as a means of measuring muscle volume and architecture. This study had two main aims: to monitor for the onset of muscle atrophy in mechanically ventilated pediatric patients during stays in a pediatric intensive care unit based on quadriceps femoris muscle thickness measurements and to study whether demographic and clinical variables have an impact on muscle loss in critically children. The study followed a prospective, observational, single-center design. The sample included all children admitted to our pediatric intensive care unit (PICU) who required mechanical ventilation for more than 48 h. Two trained clinicians measured the thickness of the quadriceps using a 12-MHz linear ultrasound transducer within 24 h of initiating invasive mechanical ventilation and again at 72 h, 1 week, and weekly thereafter until extubation. For the entire cohort, quadriceps femoris muscle thickness decreased by 4.67% on average (IQR = -13.4 to -0.59) between the first two assessments and 13% by the time of the final measurement (IQR = -24 to -0.5%) or 1.57%/day (p < 0.001). Approximately half of all the children (23/41; 56%) experienced muscle atrophy (defined a priori as a decrease in thickness of 10% or more). Bivariate analyses revealed that increasing age, being a child (vs. infant), cumulative energy and protein deficit, highest C-reactive protein value, exposure to neuromuscular blockers, and a longer stay in the PICU were all predictive of a greater decrease in thickness. In a multivariate model, exposure to neuromuscular blockers was linked with greater muscle loss.       Conclusion: In mechanically ventilated children, point-of-care ultrasonography can identify skeletal muscle atrophy. Muscle atrophy of limbs is strongly associated with the use of neuromuscular blockers. Ultrasound-based monitoring of the quadriceps femoris is a clinically useful tool for assessing muscle mass that can provide information on nutritional status and guide rehabilitation. What is Known: • ICU-acquired muscle atrophy is common and has a deleterious effect on adult outcomes. The prevalence and severity of muscular atrophy in critically ill children, however, are poorly understood. • Point-of-care ultrasonography has been put forward as an accurate, reliable method for monitoring variations in muscle mass.. What is New: • The quadriceps femoris muscle tends to suffer an intense loss of thickness early on in most critically ill children. • Quadriceps femoris ultrasound monitoring is a helpful tool for measuring muscle thickness and could lead to the development of novel therapies for critically ill children.

Allosteric inhibition of muscle-type nicotinic acetylcholine receptors by a neuromuscular blocking agent pancuronium.

Muscle relaxants are indispensable for surgical anesthesia. Early studies suggested that a classical non-depolarizing muscle relaxant pancuronium competitively binds to the ligand binding site to block nicotinic acetylcholine receptors (nAChR). Our group recently showed that nAChR which has two distinct subunit combinations are expressed in zebrafish muscles, αßδε and αßδ, for which potencies of pancuronium are different. Taking advantage of the distinct potencies, we generated chimeras between two types of nAChRs and found that the extracellular ACh binding site is not associated with the pancuronium sensitivity. Furthermore, application of either 2 µM or 100 µM ACh in native αßδε or αßδ subunits yielded similar IC50 of pancuronium. These data suggest that pancuronium allosterically inhibits the activity of zebrafish nAChRs.

Neuromuscular blocking agent re-exposure in a retrospective cohort with neuromuscular blocking agent-associated anaphylaxis.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are one of the most common causes of perioperative anaphylaxis. Although skin test positivity may help identify reactive NMBAs, it is unclear whether skin test negativity can guarantee the safety of systemically administered NMBAs. OBJECTIVE: This study aimed to evaluate the real-world safety of alternative NMBAs screened using skin tests in patients with suspected NMBA-induced anaphylaxis. METHODS: A retrospective cohort of suspected NMBA-induced anaphylaxis were recruited among patients at Seoul National University Hospital from June 2009 to May 2021, and their characteristics and outcomes were assessed. RESULTS: A total of 47 cases (0.017%) of suspected anaphylaxis occurred in 282,707 patients who received NMBAs. Cardiovascular manifestations were observed in 95.7%, whereas cutaneous findings were observed in 59.6%. Whereas 83% had a history of undergoing general anesthesia, 17% had no history of NMBA use. In skin tests, the overall positivity to any NMBA was 94.6% (81.1% to culprit NMBAs) and the cross-reactivity was 75.7%, which is related to the chemical structural similarity among NMBAs; the cross-reactivity and chemical structure similarity of rocuronium were 85.3% and 0.814, respectively, with vecuronium; this is in contrast to 50% and 0.015 with cisatracurium and 12.5% and 0.208 with succinylcholine. There were 15 patients who underwent subsequent surgery with a skin test-negative NMBA; whereas 80.0% (12/15) safely completed surgery, 20.0% (3/15) experienced hypotension. CONCLUSION: Similarities in chemical structure may contribute to the cross-reactivity of NMBAs in skin tests. Despite the high negative predictability of skin tests for suspected NMBA-induced anaphylaxis, the potential risk of recurrent anaphylaxis has not been eliminated.

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.