Structure-Activity Relationship Studies Leading to the Discovery of Highly Water-Soluble and Biocompatible Acyclic Cucurbit[n]uril FY-3451 as a Universal Antagonist That Rapidly Reverses Neuromuscular Blocking Agents In Vivo.

The development of a reversal agent that can rapidly reverse clinically used nondepolarizing neuromuscular blocking agents (NMBAs) has long been a challenge. Here, we report the synthesis of a series of highly water-soluble acyclic cucurbit[n]urils (acCBs). Systematic structure-activity relationship studies reveal that introducing two propylidene units on the peripheral benzene rings not only remarkably improves the activity of the corresponding derivative acCB6 (FY 3451) in reversing the neuromuscular block of rocuronium, cisatracurium, vecuronium, and pancuronium, the four clinically used NMBAs, through stable inclusion, but also allows for high water-solubility as well as a maximum tolerated dose (2000 mg/kg on rats). In vivo experiments with rats show that, at the identical dose of 25 mg/kg, for rocuronium, vecuronium, and pancuronium, acCB6 can achieve a recovery time shorter than that of sugammadex for rocuronium and, at the dose of 100 mg/kg, realize comparably rapid reversal for cisatracurium.

An Experimental Study to Optimize Neuromuscular Blockade Protocols in Cynomolgus Macaques: Monitoring, Doses, and Antagonism.

BACKGROUND: Neuromuscular blocking agents (NMBAs) are a crucial component of anesthesia and intensive care through the relaxation of skeletal muscles. They can lead to adverse reactions such as postoperative residual neuromuscular block. Only one agent is capable of an instant block reversal in deep block situations, but is restricted to aminosteroid agents. Among animal models, non-human primates are an essential model for a great diversity of human disease models. The main objective of this study was to establish a model for NMBA monitoring with current available drugs before testing new reversal agents. METHODS: Seven healthy male cynomolgus macaques were randomly assigned to this study. Experiments using macaques were approved by the local ethical committee (CEtEA #44). All animals were anesthetized according to institutional guidelines, with ketamine and medetomidine, allowing IV line placement and tracheal intubation. Anesthesia was maintained with isoflurane. Either rocuronium bromine (with or without sugammadex reversal) or atracurium besylate was evaluated. Monitoring was performed with two devices, TOF-Watch and ToFscan, measuring the T4/T1 and the T4/Tref ratios, respectively. Nonparametric Mann-Whitney statistical analyses were done when indicated. RESULTS: NMBA monitoring required adaptation compared to humans, such as stimulus intensity and electrode placement, to be efficient and valid in cynomolgus macaques. When administered, both NMBAs induced deep and persistent neuro-muscular block at equivalent doses to clinical doses in humans. The rocuronium-induced profound neuromuscular block could be reversed using the cyclodextrin sugammadex as a reversal agent. We report no adverse effects in these models by clinical observation, blood chemistry, or complete blood count. CONCLUSION: These results support the use of non-human primate models for neuromuscular block monitoring. This represented the first step before the forthcoming testing of new NMBA-reversal agents.

Amide naphthotube as a novel supramolecular sequestration agent for tetracaine and decamethonium.

RATIONALE: Anesthetics are widely used for optimizing surgical conditions, postoperative pain management, and treating various chronic pain conditions. Tetracaine and decamethonium are representative drugs of local anesthetics and neuromuscular blocking agents, respectively. However, overdose and toxicity of the drugs always lead to serious adverse events. Thus, there is a strong demand for effective antidotes. METHODS: The binding interactions of amide naphthotubes with tetracaine and decamethonium were systematically studied using 1H NMR, ITC, and DFT calculations. The antidotal effects of amide naphthotube to tetracaine toxicity were assessed in vitro and in vivo, and the mechanism of detoxification was explored at a cellular level. Additionally, mouse models were established to evaluate the reversal activities of amide naphthotube on decamethonium-induced mortality and muscle relaxation, and the reversal mechanism was investigated through pharmacokinetic experiments. RESULTS: We have demonstrated that the anti-isomer of amide naphthotube exhibits significant binding affinities towards tetracaine (K a = 1.89×107 M-1) and decamethonium (K a = 1.01×107 M-1) in water. The host displayed good biocompatibility both in vitro and in vivo. The administration of amide naphthotube following tetracaine overdose in mouse models notably increased the overall survival rate, indicating its effective antidotal properties. The host could reverse the tetracaine-induced Na+ channels blockage at the cellular level. Moreover, the injection of amide naphthotube also reversed the mortality and paralysis induced by decamethonium in mouse models following a pharmacokinetic mechanism. CONCLUSION: An emerging artificial receptor, amide naphthotube, has strong binding affinities towards tetracaine and decamethonium. It functions as a supramolecular antidote for tetracaine poisoning and a reversal agent for decamethonium by selectively sequestering these compounds in vivo.

Navigating Anesthesia: Muscle Relaxants and Reversal Agents in Patients with Renal Impairment.

This comprehensive review explores the interaction between neuromuscular blocking agents, reversal agents, and renal function, focusing on various drugs commonly used in anesthesia and their effects on kidney health. Succinylcholine, commonly used for anesthesia induction, can trigger elevated potassium levels in patients with specific medical conditions, leading to serious cardiac complications. While studies suggest the use of succinylcholine in patients with renal failure is safe, cases of postoperative hyperkalemia warrant further investigation. Some agents, such as atracurium and mivacurium, are minimally affected by impaired kidney function, whereas others, such as cisatracurium and rocuronium, can have altered clearance, necessitating dose adjustments in patients with renal failure. The reversal agents neostigmine and sugammadex affect renal markers, while cystatin C levels remain relatively stable with sugammadex use, indicating its milder impact on glomerular function, compared with neostigmine. Notably, the combination of rocuronium and sugammadex in rat studies shows potential nephrotoxic effects, cautioning against the simultaneous use of these agents. In conclusion, understanding the interplay between neuromuscular blocking agents and renal function is crucial for optimizing patient care during anesthesia. While some agents can be used safely in patients with renal failure, others can require careful dosing and monitoring. Further research is needed to comprehensively assess the long-term impact of these agents on kidney health, especially in high-risk patient populations. This article aims to review the use of muscle relaxants and reversal for anesthesia in patients with impaired renal function.

[Neuromuscular Blockade in the Critically Ill]. / Muskelrelaxanzien in der Intensivmedizin.

The management of sedation in intensive care medicine has changed substantially in the last few years. Neuromuscular blocking agents (NMBA) are only rarely indicated in modern intensive care medicine. In this review, the mechanism of action, potential side effects, and special considerations for the application of NMBA to critically ill patients will be discussed. We further present the rationale for the use of NMBA for the remaining indications, such as endotracheal intubation, selected cases of severe acute respiratory distress syndrome, and shivering during temperature control after cardiac arrest. The review will close with a description of potential side effects of NMBA use in the intensive care setting, such as awareness, acquired skeletal muscle weakness as well as corneal injuries, and how monitoring of sedation and peripheral muscle blockade may be handled.

[Neuromuscular Blockade in Geriatric Patients]. / Muskelrelaxierung bei geriatrischen Patient*innen.

The administration of neuromuscular blocking agents has been used in anesthesia for decades and continues to play an important role in modern anesthesia. Special patient populations, such as very young or very old patients, require adapted use. The following article discusses the specifics of neuromuscular blocking agents administration in geriatric patients.

[Update: Neuromuscular Blockade during General Anesthesia]. / Update: Muskelrelaxierung in der Anästhesie.

The correct use of muscle relaxants and neuromuscular monitoring during anesthesia has been subject of controversial discussions for decades. Particularly important in clinical practice are identification and management of residual neuromuscular blockages and avoidance of associated complications. Despite the differences in the molecular mechanisms of action between depolarizing and non-depolarizing muscle relaxants the blockade of the postsynaptic nicotinic acetylcholine receptor remains a common ending pathway. Due to its unfavorable side effect profile, succinylcholine should only be used in justified exceptional cases. The use of muscle relaxants generally reduces the complication rate in airway management. However, even the single use of muscle relaxants increases the likelihood of postoperative pulmonary complications. These complications associated with the use of muscle relaxants, such as residual neuromuscular blockade, must be anticipated. The application of guideline-based approaches, including continuous neuromuscular monitoring and the application of muscle relaxant reversal agents, may significantly reduce the rate of adverse events associated with the use of muscle relaxants.

[Role of neuromuscular blocking agents in the development of polyneuropathy and myopathy in critically ill patients]. / Rol de los bloqueantes neuromusculares en el desarrollo de polineuropatía y miopatía del enfermo crítico.

BACKGROUND: Acquired critical illness weakness (AWCIP) is the most frequent neuromuscular disease in intensive care medicine departments. Its importance is given by the prolongation of hospital stay and the delayed recovery it causes to patients after hospitalization. The main objective of this study was to investigate the association between neuromuscular blocking agents and the development of acquired weakness in critically ill patients. MATERIAL AND METHODS: We conducted a prospective study of 103 critically ill patients who were periodically monitored with electromyography. RESULTS: The development of AWCIP was observed in 63 patients. The group of patients who developed AWCIP had a significantly higher utilization of neuromuscular blocking agents than the group who did not develop AWCIP [79.4% vs 50%, OR:3.85 (1.63-9.39), p <0.02]; likewise, this group of patients had a longer ICU stay [32 days vs 14 days, OR: 1.11 (1.06-1.17), p <0. 001] and a longer mechanical ventilation time [24 days vs 9 days, OR:1.2 (1.11-1.32), p <0.001]. CONCLUSION: Neuromuscular blocking agents are a factor associated with the occurrence of AWCIP.

The Influence of Acid-Base Balance on Anesthetic Muscle Relaxants: A Comprehensive Review on Clinical Applications and Mechanisms.

Muscle relaxants have broad application in anesthesiology. They can be used for safe intubation, preparing the patient for surgery, or improving mechanical ventilation. Muscle relaxants can be classified based on their mechanism of action into depolarizing and non-depolarizing muscle relaxants and centrally acting muscle relaxants. Non-depolarizing neuromuscular blocking drugs (NMBDs) (eg, tubocurarine, atracurium, pipecuronium, mivacurium, pancuronium, rocuronium, vecuronium) act as competitive antagonists of nicotine receptors. By doing so, these drugs hinder the depolarizing effect of acetylcholine, thereby eliminating the potential stimulation of muscle fibers. Depolarizing drugs like succinylcholine and decamethonium induce an initial activation (depolarization) of the receptor followed by a sustained and steady blockade. These drugs do not act as competitive antagonists; instead, they function as more enduring agonists compared to acetylcholine itself. Many factors can influence the duration of action of these drugs. Among them, electrolyte disturbances and disruptions in acid-base balance can have an impact. Acidosis increases the potency of non-depolarizing muscle relaxants, while alkalosis induces resistance to their effects. In depolarizing drugs, acidosis and alkalosis produce opposite effects. The results of studies on the impact of acid-base balance disturbances on non-depolarizing relaxants have been conflicting. This work is based on the available literature and the authors' experience. This article aimed to review the use of anesthetic muscle relaxants in patients with acid-base disturbances.

Neuromuscular blocking agent drug challenge: a literature review and protocol proposal with biological evaluation.

BACKGROUND: Drug challenge is the gold standard for identifying causative agents of drug allergies. Although clinical guidelines have recently been published, they do not recommend neuromuscular blocking agent (NMBA) drug challenges. NMBA challenges are rendered difficult by the lack of homogeneity of routine allergy work-ups and the necessity of a specialised setting. Several scenarios support NMBA challenges, such as an ambiguous allergy work-up, a high suspicion of a false-positive skin test or identification of a well tolerated alternative NMBA strategy. Furthermore, routine allergy work-ups may not recognise non-IgE mechanisms, such as IgG or MRGPRX2, whereas drug challenges may reveal them. Finally, if the culprit NMBA is not identified, subsequent anaesthesia regimens will be challenging to implement, resulting in increased risk. OBJECTIVES: This literature review discusses the indications, strategies, doses, monitoring methods, limitations, and unresolved issues related to drug challenges for NMBAs. DESIGN: The literature review included randomised controlled trials, observational studies, reviews, case reports, series, and comments on humans. DATA SOURCES: Studies were retrieved from databases (PubMed) and electronic libraries (OVID, EMBASE, Scopus, etc.). ELIGIBILITY CRITERIA: All studies that referred to the NMBA challenge were included without publication date limitations. RESULTS: NMBA challenge may be considered in NMBA anaphylaxis patients with inconclusive or ambivalent IgE diagnostic work-up under controlled conditions (presence of anaesthetists and allergists with continuous monitoring in a secured environment). To illustrate its utility, a case report of a double NMBA challenge in a patient with NMBA cross-reactivity is presented, along with biological explorations to detect subclinical cellular activation, a novel aspect of this procedure. CONCLUSION: Drug challenges could be implemented during the NMBA allergy work-up under strict safety conditions at specialised centres with close collaboration between anaesthetists and allergists. This could decrease uncertainty and contribute to defining a safer strategy for subsequent anaesthetic drug regimens.

Neuromuscular Blocking Agent Use in Critical Care Transport Not Associated With Intubation.

OBJECTIVE: Variable indications exist for neuromuscular blocking agents (NMBAs) in the critical care transport setting beyond facilitation of intubation. METHODS: This retrospective cohort study included adult patients (≥ 18 years) who underwent critical care transport from July 1, 2020, to May 2, 2023, and received NMBAs during transport that was not associated with intubation. The primary outcome was the indication for NMBA administration. Secondary outcomes included the characterization of NMBA use, mean Richmond Agitation Sedation Scale score before NMBA administration, sedation strategy used, and continuation of NMBAs within 48 hours of hospital admission. RESULTS: One hundred twenty-six patients met the inclusion criteria. The most common indication for NMBA administration was ventilator dyssynchrony (n = 71, 56.4%). The majority of patients received rocuronium during transport (n = 113, 89.7%). The mean pre-NMBA Richmond Agitation Sedation Scale score was -3.7 ± 2.4. The most common sedation strategy was a combination of continuous infusion and bolus sedatives (76.2%). One hundred (79.4%) patients had sedation changes in response to NMBA administration. Seventy-two (57.1%) received NMBAs during the first 48 hours of their intensive care unit admission. CONCLUSION: NMBAs were frequently administered for ventilator dyssynchrony and continuation of prior therapy. Optimization opportunities exist to ensure adequate deep sedation and reassessment of NMBA indication.

Evaluation of the passive mast cell activation test for identifying allergens in perioperative anaphylaxis: a study protocol for a prospective diagnostic accuracy study.

INTRODUCTION: Perioperative anaphylaxis (POA) can lead to significant complications. Therefore, accurate identification of allergens for POA patients is critical to ensure the safety of future surgical and anaesthetic procedures. Existing perioperative allergen detection methods face challenges in sensitivity and specificity. The passive mast cell activation test (pMAT) has recently emerged as a potential diagnostic tool. Our study aims to evaluate the diagnostic efficacy of pMAT for identifying perioperative allergens, with a focus on non-depolarising neuromuscular blocking agents, the most common culprits of POA. METHODS AND ANALYSIS: This prospective diagnostic accuracy study will measure the diagnostic accuracy of pMAT in POA patients. Participants will undergo skin testing (ST), basophil activation testing (BAT) and pMAT. The diagnostic validity of pMAT will be assessed based on the results of ST and BAT. The assessment of diagnostic accuracy will include sensitivity, specificity, likelihood ratios, and false-positive and false-negative rates while measurement of the consistency rate will assess reliability. ETHICS AND DISSEMINATION: This study has been approved by the Institutional Review Board of China-Japan Friendship Hospital (2023-KY-247). Results will be disseminated through academic presentations and peer-reviewed journal publications and will provide valuable scientific data and some new insights into the diagnostic accuracy of pMAT.

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).

Evaluation of the classifications of severity in acute respiratory distress syndrome in childhood by the Berlin Consensus and the Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVE: To compare two methods for defining and classifying the severity of pediatric acute respiratory distress syndrome: the Berlin classification, which uses the relationship between the partial pressure of oxygen and the fraction of inspired oxygen, and the classification of the Pediatric Acute Lung Injury Consensus Conference, which uses the oxygenation index. METHODS: This was a prospective study of patients aged 0 - 18 years with a diagnosis of acute respiratory distress syndrome who were invasively mechanically ventilated and provided one to three arterial blood gas samples, totaling 140 valid measurements. These measures were evaluated for correlation using the Spearman test and agreement using the kappa coefficient between the two classifications, initially using the general population of the study and then subdividing it into patients with and without bronchospasm and those with and without the use of neuromuscular blockers. The effect of these two factors (bronchospasm and neuromuscular blocking agent) separately and together on both classifications was also assessed using two-way analysis of variance. RESULTS: In the general population, who were 54 patients aged 0 - 18 years a strong negative correlation was found by Spearman's test (ρ -0.91; p < 0.001), and strong agreement was found by the kappa coefficient (0.62; p < 0.001) in the comparison between Berlin and Pediatric Acute Lung Injury Consensus Conference. In the populations with and without bronchospasm and who did and did not use neuromuscular blockers, the correlation coefficients were similar to those of the general population, though among patients not using neuromuscular blockers, there was greater agreement between the classifications than for patients using neuromuscular blockers (kappa 0.67 versus 0.56, p < 0.001 for both). Neuromuscular blockers had a significant effect on the relationship between the partial pressure of oxygen and the fraction of inspired oxygen (analysis of variance; F: 12.9; p < 0.001) and the oxygenation index (analysis of variance; F: 8.3; p = 0.004). CONCLUSION: There was a strong correlation and agreement between the two classifications in the general population and in the subgroups studied. Use of neuromuscular blockers had a significant effect on the severity of acute respiratory distress syndrome.

Assessing pain in paralyzed critically ill patients receiving neuromuscular blocking agents: A monocenter prospective cohort.

INTRODUCTION: Given the absence of established recommendations for pain assessment in pharmacologically paralyzed Intensive-Care-Units (ICU) patients under Neuro-Muscular-Blocking Agents (NMBA), this study assessed the validity of various parameters for evaluating pain in this specific population. PATIENTS AND METHODS: Four electrophysiological parameters (instant-Analgesia-Nociception-Index (ANI), Bispectral index (BIS), Heart Rate (HR) and Mean Arterial Blood Pressure (ABP)) and one clinical parameter (Behavioural-Pain-Scale (BPS)) were recorded during tracheal-suctioning in all consecutive ICU patients who required a continuous infusion of cisatracurium, before and just after paralysis recovery measured by Train-of-Four ratio. The validity of the five pain-related parameters was assessed by comparing the values recorded during different situations (before/during/after the nociceptive procedure) (discriminant-validity, primary outcome), and the effect of paralysis was assessed by comparing values obtained during and after paralysis (reliability, secondary outcome). RESULTS: Twenty patients were analyzed. ANI, BIS, and HR significantly changed during the nociceptive procedure in both paralysis and recovery, while BPS changed only post-recovery. ANI and HR were unaffected by paralysis, unlike BIS and BPS (mixed-effect model). ANI exhibited the highest discriminant-validity, with values (min 0/max 100) decreasing from 71 [48-89] at rest to 41 [25-72] during tracheal suctioning in paralyzed patients, and from 71 [53-85] at rest to 40 [31-52] in non-paralyzed patients. CONCLUSIONS: ANI proves the most discriminant parameter for pain detection in both paralyzed and non-paralyzed sedated ICU patients. Its significant and clinically relevant decrease during tracheal suctioning remains unaltered by NMBA use. Pending further studies on analgesia protocols based on ANI, it could be used to assess pain during nociceptive procedures in ICU patients receiving NMBA.

Neuromuscular blocking agents during targeted temperature management for out-of-hospital cardiac arrest patients.

BACKGROUND: Neuromuscular blocking agents (NMBAs) can control shivering during targeted temperature management (TTM) of patients with cardiac arrest. However, the effectiveness of NMBA use during TTM on neurologic outcomes remains unclear. We aimed to evaluate the association between NMBA use during TTM and favorable neurologic outcomes after out-of-hospital cardiac arrest (OHCA). MATERIALS AND METHODS: A multicenter, prospective, observational cohort study from 2019 to 2021. It included OHCA patients who received TTM after hospitalization. We conducted overlap weight propensity-score analyses after multiple imputation to evaluate the effect of NMBAs during TTM. The primary outcome was a favorable neurological outcome, defined as a cerebral performance category of 1 or 2 at discharge. Subgroup analyses were conducted based on initial monitored rhythm and brain computed tomography findings. RESULTS: Of the 516 eligible patients, 337 received NMBAs during TTM. In crude analysis, the proportion of patients with favorable neurological outcome was significantly higher in the NMBA group (38.3% vs. 16.8%; risk difference (RD): 21.5%; 95% confidence interval (CI): 14.0% to 29.1%). In weighted analysis, a significantly higher proportion of patients in the NMBA group had a favorable neurological outcome compared to the non-NMBA group (32.7% vs. 20.9%; RD: 11.8%; 95% CI: 1.2% to 22.3%). In the subgroup with an initial shockable rhythm and no hypoxic encephalopathy, the NMBA group showed significantly higher proportions of favorable neurological outcomes. CONCLUSIONS: The use of NMBAs during TTM was significantly associated with favorable neurologic outcomes at discharge for OHCA patients. NMBAs may have benefits in selected patients with initial shockable rhythm and without poor prognostic computed tomography findings.