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Clinical and Translational Science Jan 2022Residual shallow neuromuscular block (NMB) is potentially harmful and contributes to critical respiratory events. Evidence for the optimal dose of sugammadex required to...
Residual shallow neuromuscular block (NMB) is potentially harmful and contributes to critical respiratory events. Evidence for the optimal dose of sugammadex required to reverse vecuronium-induced shallow NMB is scarce. The aims of the present study were to find suitable doses of sugammadex and neostigmine to reverse a residual vecuronium-induced NMB from a time of flight (TOF) ratio of 0.3-0.9 and evaluate their safety and efficacy. In total, 121 patients aged 18-65 years were randomly assigned to 11 groups to receive placebo, sugammadex (doses of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/kg), or neostigmine (doses of 10, 25, 40, 55, or 70 μg/kg). The reversal time of sugammadex and neostigmine to antagonize a vecuronium-induced shallow residual NMB (i.e., TOF ratio of 0.3) and related adverse reactions were recorded. Several statistical models were tested to find an appropriate statistical model to explore the suitable doses of sugammadex and neostigmine required to reverse a residual vecuronium-induced NMB. Based on a monoexponential model with the response variable on a logarithmic scale, sugammadex 0.56 mg/kg may be sufficient to reverse vecuronium-induced shallow residual NMB at a TOF ratio of 0.3 under anesthesia maintained with propofol. Neostigmine may not provide prompt and satisfactory antagonism as sugammadex, even in shallow NMB.
Topics: Delayed Emergence from Anesthesia; Dose-Response Relationship, Drug; Humans; Neostigmine; Sugammadex; Vecuronium Bromide
PubMed: 34435439
DOI: 10.1111/cts.13143 -
Biochemical Pharmacology Oct 2021Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate...
Endogenous neurosteroids and their synthetic analogues-neuroactive steroids-have been found to bind to muscarinic acetylcholine receptors and allosterically modulate acetylcholine binding and function. Using radioligand binding experiments we investigated their binding mode. We show that neuroactive steroids bind to two binding sites on muscarinic receptors. Their affinity for the high-affinity binding site is about 100 nM. Their affinity for the low-affinity binding site is about 10 µM. The high-affinity binding occurs at the same site as binding of steroid-based WIN-compounds that is different from the common allosteric binding site for alcuronium or gallamine that is located between the second and third extracellular loop of the receptor. This binding site is also different from the allosteric binding site for the structurally related aminosteroid-based myorelaxants pancuronium and rapacuronium. Membrane cholesterol competes with neurosteroids/neuroactive steroids binding to both high- and low-affinity binding site, indicating that both sites are oriented towards the cell membrane..
Topics: Allosteric Regulation; Androstanes; Androstenes; Animals; Benzimidazoles; Binding Sites; CHO Cells; Cholesterol; Cricetinae; Cricetulus; Gallamine Triethiodide; Humans; Neuromuscular Nondepolarizing Agents; Neurosteroids; Receptors, Muscarinic; Vecuronium Bromide
PubMed: 34324870
DOI: 10.1016/j.bcp.2021.114699 -
Se Pu = Chinese Journal of... Jul 2021Vecuronium, rocuronium, and pancuronium are widely used as non-depolarizing muscle relaxants. There have been occasional cases of allergic reactions and even death when...
Vecuronium, rocuronium, and pancuronium are widely used as non-depolarizing muscle relaxants. There have been occasional cases of allergic reactions and even death when using such muscle relaxants. Rapid determination of the concentration of these muscle relaxants in blood can provide valuable information for early clinical diagnosis. As quaternary ammonium compounds, these muscle relaxants are highly polar. Hence, they cannot be retained effectively on reversed-phase chromatographic columns with conventional mobile phases. These quaternary ammonium muscle relaxants are mainly separated by ion-pair chromatography. Using an ion-pairing reagent can help improve the retention capabilities of quaternary ammonium muscle relaxants. Nevertheless, the sensitivity of MS detection is significantly decreased because of ionic inhibition caused by the ion-pairing reagent in the mobile phase. Furthermore, ion-pairing reagents can pollute the MS system. A method based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was established for the simultaneous determination of the three quaternary ammonium muscle relaxants in blood. The blood samples were diluted and subjected to high-speed centrifugation. The supernatant was purified on a Bond Elut AL-N solid phase extraction column and then filtered through a 0.45 μm microporous membrane. The quaternary ammonium muscle relaxants were separated on a ZIC-cHILIC analytical column (50 mm×2.1 mm, 3.0 μm) with gradient elution. Acetonitrile and 0.1% formic acid aqueous solution were used as mobile phases. The separated compounds were analyzed by tandem MS with an electrospray ionization (ESI) source in positive and multiple reaction monitoring (MRM) modes. The matrix effects of vecuronium, rocuronium, and pancuronium in blood were 88.1% to 95.4%. The calibration curves for vecuronium, rocuronium, and pancuronium showed good linear relationships in each range, and all correlation coefficients () were > 0.996. The limits of detection of vecuronium, rocuronium, and pancuronium were 0.2-0.8 ng/mL, with the corresponding limits of quantification being 0.5-2.0 ng/mL. The recoveries of vecuronium, rocuronium, and pancuronium were 92.8% to 110.6%, with relative standard deviations (RSDs) of 3.2%-9.4%. This method is sensitive, accurate, and easy to operate, and it can be used to rapidly determine vecuronium, rocuronium, and pancuronium in blood.
Topics: Ammonium Compounds; Chromatography, High Pressure Liquid; Humans; Neuromuscular Agents; Pancuronium; Rocuronium; Solid Phase Extraction; Tandem Mass Spectrometry; Vecuronium Bromide
PubMed: 34227366
DOI: 10.3724/SP.J.1123.2020.09020 -
Anales de Pediatria Oct 2020It has been suggested that neuromuscular blockade (NMB) affects the capacity of bispectral index (BIS) monitoring to measure consciousness in sedated children. Our aim... (Observational Study)
Observational Study
INTRODUCTION
It has been suggested that neuromuscular blockade (NMB) affects the capacity of bispectral index (BIS) monitoring to measure consciousness in sedated children. Our aim was to analyse the impact of NMB on BIS values in critically ill children.
METHODS
We conducted a prospective observational study of children monitored with a BIS system that received a continuous infusion of vecuronium. We analysed data on clinical, diagnostic and haemodynamic variables, sedatives, analgesics, muscle relaxants, and BIS parameters. We compared BIS parameters before the use of a muscle relaxant, during its administration, before its discontinuation and for the 24h following the end of the infusion.
RESULTS
The analysis included 35 patients (median age, 30 months). The most common diagnosis was heart disease (85%). The most frequent indication for initiation of NMB was low cardiac output (45%), followed by adaptation to mechanical ventilation (20%). Neuromuscular blockade did not produce a significant change in BIS values. We found a decrease was observed in electromyography (EMG) values at 6h (34.9±9.4 vs 31.2±7; P=.008) and 12h after initiation of NMB (34.9±9.4 vs 28.6±4.8; P =.006). We observed a small significant increase in BIS after discontinuation of NMB (from 42.7±11 to 48.4±14.5, P=.001), and 6 and 12h later (51.3±16.6; P=.015). There were no differences in the doses of sedatives or analgesics except for fentanyl, of which the dose was lowered after discontinuation of vecuronium.
CONCLUSION
Continuous NMB produces small changes on BIS values that are not clinically significant and therefore does not interfere with BIS consciousness monitoring in critically ill children.
Topics: Child, Preschool; Consciousness Monitors; Critical Illness; Electromyography; Humans; Neuromuscular Blockade; Vecuronium Bromide
PubMed: 34092338
DOI: 10.1016/j.anpede.2019.07.003 -
Lab on a Chip May 2021Engineered three-dimensional models of neuromuscular tissues are promising for use in mimicking their disorder states in vitro. Although several models have been...
Engineered three-dimensional models of neuromuscular tissues are promising for use in mimicking their disorder states in vitro. Although several models have been developed, it is still challenging to mimic the physically separated structures of motor neurons (MNs) and skeletal muscle (SkM) fibers in the motor units in vivo. In this study, we aimed to develop microdevices for precisely compartmentalized coculturing of MNs and engineered SkM tissues. The developed microdevices, which fit a well of 24 well plates, had a chamber for MNs and chamber for SkM tissues. The two chambers were connected by microtunnels for axons, permissive to axons but not to cell bodies. Human iPSC (hiPSC)-derived MN spheroids in one chamber elongated their axons into microtunnels, which reached the tissue-engineered human SkM in the SkM chamber, and formed functional neuromuscular junctions with the muscle fibers. The cocultured SkM tissues with MNs on the device contracted spontaneously in response to spontaneous firing of MNs. The addition of a neurotransmitter, glutamate, into the MN chamber induced contraction of the cocultured SkM tissues. Selective addition of tetrodotoxin or vecuronium bromide into either chamber induced SkM tissue relaxation, which could be explained by the inhibitory mechanisms. We also demonstrated the application of chemical or mechanical stimuli to the middle of the axons of cocultured tissues on the device. Thus, compartmentalized neuromuscular tissue models fabricated on the device could be used for phenotypic screening to evaluate the cellular type specific efficacy of drug candidates and would be a useful tool in fundamental research and drug development for neuromuscular disorders.
Topics: Humans; Lab-On-A-Chip Devices; Motor Neurons; Muscle Fibers, Skeletal; Muscle, Skeletal; Neuromuscular Junction
PubMed: 34008665
DOI: 10.1039/d1lc00048a -
BMC Anesthesiology Feb 2021This randomized, double-blind trial evaluated sugammadex-mediated recovery time from rocuronium- or vecuronium-induced moderate (M-) or deep (D-) neuromuscular block in... (Comparative Study)
Comparative Study Randomized Controlled Trial
Actual versus ideal body weight dosing of sugammadex in morbidly obese patients offers faster reversal of rocuronium- or vecuronium-induced deep or moderate neuromuscular block: a randomized clinical trial.
BACKGROUND
This randomized, double-blind trial evaluated sugammadex-mediated recovery time from rocuronium- or vecuronium-induced moderate (M-) or deep (D-) neuromuscular block in morbidly obese adults dosed by actual (ABW) or ideal body weight (IBW).
METHODS
Adults with BMI ≥40 kg/m were randomized to 1 of 5 groups: M-neuromuscular block, sugammadex 2 mg/kg ABW; M-neuromuscular block, sugammadex 2 mg/kg IBW; M-neuromuscular block, neostigmine 5 mg, and glycopyrrolate 1 mg; D-neuromuscular block, sugammadex 4 mg/kg ABW; or D-neuromuscular block, sugammadex 4 mg/kg IBW. Supramaximal train of four (TOF) stimulation of the ulnar nerve (TOF-watch SX®) monitored recovery. Primary endpoint was time to TOF ratio ≥ 0.9 for ABW and IBW groups pooled across neuromuscular blocking agent (NMBA)/blocking depth, analyzed by log-rank test stratified for agent and depth. Prespecified safety outcomes included treatment-emergent bradycardia, tachycardia, and other arrhythmias, and adjudicated hypersensitivity and anaphylaxis.
RESULTS
Of 207 patients randomized, 188 received treatment (28% male, BMI 47 ± 5.1 kg/m, age 48 ± 13 years). Recovery was 1.5 min faster with ABW vs IBW dosing. The sugammadex 2 mg/kg groups recovered 9-fold faster [time 0.11-fold, 95% CI 0.08 to 0.14] than the neostigmine group. ABW (5.3%) and IBW (2.7%) groups had similar incidences of recovery time > 10 min (95% CI of difference: - 4.8 to 11.0%); 84% for neostigmine group. Re-curarization occurred in one patient each in the 2 mg/kg IBW and neostigmine groups. Prespecified safety outcomes occurred with similar incidences.
CONCLUSIONS
ABW-based sugammadex dosing yields faster reversal without re-curarization, supporting ABW-based sugammadex dosing in the morbidly obese, irrespective of the depth of neuromuscular block or NMBA used.
TRIAL REGISTRATION
Registered on November 17, 2017, at ClinicalTrials.gov under number NCT03346070 .
Topics: Anesthesia Recovery Period; Body Weight; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Ideal Body Weight; Male; Middle Aged; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Obesity, Morbid; Rocuronium; Sugammadex; Time Factors; Vecuronium Bromide
PubMed: 33639839
DOI: 10.1186/s12871-021-01278-w -
Oncology Letters Feb 2021Anaesthetics have been implicated to influence cancer cells and progression. Similarly, crosstalk between cancer cells and stromal components within the microenvironment...
Anaesthetics have been implicated to influence cancer cells and progression. Similarly, crosstalk between cancer cells and stromal components within the microenvironment is also an important factor driving progression. Stromal cell-derived factor-1 (SDF-1) and hepatocyte growth factor (HGF) are key chemokines/cytokines produced by fibroblasts which have been established as influential factors in cancer progression. The present study explored the capacity of anaesthetics to influence the expression of these key molecules in fibroblasts. The anaesthetics rocuronium bromide (RB), vecuronium bromide (VB), suxamethonium chloride CRS (SCC), dexmedetomidine hydrochloride (DH) and lidocaine were used to treat MRC-5 fibroblasts over a range of concentrations. Following treatment, transcript expression of SDF-1 and HGF was quantified using quantitative PCR. Treatment of MRC-5 cells with RB brought about a reduction of SDF-1 expression which was found to be significant in the 45 µg/ml treatment group. Treatment with the other anaesthetics brought about some alterations in SDF-1 expression but these were not found to be statistically significant. Treatment with the tested anaesthetics did not have any significant effect on HGF transcript expression within MRC-5 cells, although again some alterations were observed. The results indicated that anaesthetics may have an impact on the fibroblast component of the tumour microenvironment, potentially influencing SDF-1 and HGF expression which in turn could influence tumour progression.
PubMed: 33552259
DOI: 10.3892/ol.2020.12401 -
Microvascular Research May 2021Several studies report flow disturbance and microcirculation disorders upon anesthesia treatment. These alterations are often related to blood rheology changes. In this...
Several studies report flow disturbance and microcirculation disorders upon anesthesia treatment. These alterations are often related to blood rheology changes. In this work, it was attempted to make a detailed description of the alterations in erythrocyte mechanical properties by the action of propofol, remifentanil, and vecuronium. For this, an in vitro study was performed on red blood cell samples from healthy donors incubated with solutions of propofol (4 μg/mL whole blood), remifentanil (10 ng/mL plasma), and vecuronium (0.15 μg/mL plasma). Erythrocyte viscoelastic parameters were determined by octuplicate using a Reómetro Eritrocitario. Also, a Wilcoxon signed rank-test with Yates correction for continuity was performed to analyze the overall alteration in the mechanical properties of erythrocytes. Statistical analysis showed that the three studied anesthetics changed the erythrocyte mechanical properties at different parts of the membrane. These results would imply an interaction of these anesthetics with the erythrocyte membrane. Finally, this could conduce to alterations in microcirculation.
Topics: Adult; Analgesics, Opioid; Anesthetics, Intravenous; Cytoskeleton; Elastic Modulus; Erythrocyte Deformability; Erythrocyte Membrane; Erythrocytes; Humans; Male; Neuromuscular Nondepolarizing Agents; Propofol; Remifentanil; Vecuronium Bromide; Viscosity; Young Adult
PubMed: 33421433
DOI: 10.1016/j.mvr.2021.104132 -
Chemical Research in Toxicology Feb 2021Drug-induced rhabdomyolysis (DIR) is a rare and potentially life-threatening muscle injury that is characterized by low incidence and high risk. To our best knowledge,...
Drug-induced rhabdomyolysis (DIR) is a rare and potentially life-threatening muscle injury that is characterized by low incidence and high risk. To our best knowledge, the performance of the current predictive models for the early detection of DIR is suboptimal because of the scarcity and dispersion of DIR cases. Therefore, on the basis of the curated drug information from the Drug-Induced Rhabdomyolysis Atlas (DIRA) database, we proposed a random forest (RF) model to predict the DIR severity of the marketed drugs. Compared with the state-of-art methods, our proposed model outperformed extreme gradient boosting, support vector machine, and logistic regression in distinguishing the Most-DIR concern drugs from the No-DIR concern drugs (Matthews correlation coefficient (MCC) and recall rate of our model were 0.46 and 0.81, respectively). Our model was subsequently applied to predicting the potentially serious DIR for 1402 drugs, which were reported to cause DIR by the postmarketing DIR surveillance data in the FDA Spontaneous Adverse Events Reporting System (FAERS). As a result, 62.7% (94) of drugs ranked in the top 150 drugs with the Most-DIR concerns in FAERS can be identified by our model. The top four drugs (odds ratio >30) including acepromazine, rapacuronium, oxyphenbutazone, and naringenin were correctly predicted by our model. In conclusion, the RF model can well predict the Most-DIR concern drug only based on the chemical structure information and can be a facilitated tool for early DIR detection.
Topics: Acepromazine; Databases, Chemical; Flavanones; Humans; Models, Molecular; Oxyphenbutazone; Quantitative Structure-Activity Relationship; Rhabdomyolysis; Vecuronium Bromide
PubMed: 33393765
DOI: 10.1021/acs.chemrestox.0c00347 -
Clinical and Translational Science Mar 2021This analysis of a published study (NCT03346070) evaluated the pharmacokinetics (PKs) of sugammadex dosed by actual body weight (ABW) or ideal body weight (IBW) for... (Randomized Controlled Trial)
Randomized Controlled Trial
This analysis of a published study (NCT03346070) evaluated the pharmacokinetics (PKs) of sugammadex dosed by actual body weight (ABW) or ideal body weight (IBW) for reversal of moderate or deep neuromuscular block (M-NMB or D-NMB) in adults with morbid obesity. Adults with body mass index ≥ 40 kg/m , ABW ≥ 100 kg, and American Society of Anesthesiologists (ASA) Class 3 were stratified by NMB agent (rocuronium or vecuronium) and randomized 1:1:1:1:1 to (i) M-NMB, sugammadex 2 mg/kg ABW; (ii) M-NMB, sugammadex 2 mg/kg IBW; (iii) M-NMB, neostigmine 5 mg + glycopyrrolate 1 mg; (iv) D-NMB, sugammadex 4 mg/kg ABW; and (v) D-NMB, sugammadex 4 mg/kg IBW. Plasma samples for sugammadex quantification were collected predose, 2, 5, 15, 60, and 120 minutes, and 4, 6 hours postdose. Natural log PK parameters were analyzed using linear fixed effect model with treatment, mode (ABW and IBW), and mode by treatment interaction as fixed terms. The sugammadex PK profile showed rapid distribution followed by monophasic decline consistent with a two-compartment model examined by dose and mode. Absolute sugammadex exposures were ~ 50% higher in the ABW vs. IBW group; dose-independent parameters (clearance and volume of distribution) and terminal half-life remained constant. Sugammadex PK parameter values increased in dose-dependent, linear manner following dosing by ABW or IBW, such that PK continues to be predictive across the clinical dose range. In conjunction with previously published results showing faster recovery with ABW vs. IBW dosing across NMB agent and depth of NMB, these PK findings continue to support dosing by ABW in patients with morbid obesity irrespective of depth of NMB.
Topics: Adult; Body Mass Index; Dose-Response Relationship, Drug; Drug Dosage Calculations; Female; Humans; Ideal Body Weight; Male; Middle Aged; Models, Biological; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Obesity, Morbid; Rocuronium; Sugammadex; Vecuronium Bromide
PubMed: 33278332
DOI: 10.1111/cts.12941