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Cells Jan 2023Cardiac arrest (CA) and return of spontaneous circulation (ROSC), a global ischemia and reperfusion event, lead to neuronal damage and/or death in the spinal cord as...
Therapeutic Hypothermia after Cardiac Arrest Attenuates Hindlimb Paralysis and Damage of Spinal Motor Neurons and Astrocytes through Modulating Nrf2/HO-1 Signaling Pathway in Rats.
Cardiac arrest (CA) and return of spontaneous circulation (ROSC), a global ischemia and reperfusion event, lead to neuronal damage and/or death in the spinal cord as well as the brain. Hypothermic therapy is reported to protect neurons from damage and improve hindlimb paralysis after resuscitation in a rat model of CA induced by asphyxia. In this study, we investigated roles of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in the lumbar spinal cord protected by therapeutic hypothermia in a rat model of asphyxial CA. Male Sprague-Dawley rats were subjected to seven minutes of asphyxial CA (induced by injection of 2 mg/kg vecuronium bromide) and hypothermia (four hours of cooling, 33 ± 0.5 °C). Survival rate, hindlimb motor function, histopathology, western blotting, and immunohistochemistry were examined at 12, 24, and 48 h after CA/ROSC. The rats of the CA/ROSC and hypothermia-treated groups had an increased survival rate and showed an attenuated hindlimb paralysis and a mild damage/death of motor neurons located in the anterior horn of the lumbar spinal cord compared with those of the CA/ROSC and normothermia-treated groups. In the CA/ROSC and hypothermia-treated groups, expressions of cytoplasmic and nuclear Nrf2 and HO-1 were significantly higher in the anterior horn compared with those of the CA/ROSC and normothermia-treated groups, showing that cytoplasmic and nuclear Nrf2 was expressed in both motor neurons and astrocytes. Moreover, in the CA/ROSC and hypothermia-treated group, interleukin-1β (IL-1β, a pro-inflammatory cytokine) expressed in the motor neurons was significantly reduced, and astrocyte damage was apparently attenuated compared with those found in the CA/ROSC and normothermia group. Taken together, our results indicate that hypothermic therapy after CA/ROSC attenuates CA-induced hindlimb paralysis by protecting motor neurons in the lumbar spinal cord via activating the Nrf2/HO-1 signaling pathway and attenuating pro-inflammation and astrocyte damage (reactive astrogliosis).
Topics: Animals; Male; Rats; Astrocytes; Heart Arrest; Heme Oxygenase-1; Hindlimb; Hypothermia; Hypothermia, Induced; Motor Neurons; NF-E2-Related Factor 2; Paralysis; Rats, Sprague-Dawley; Signal Transduction
PubMed: 36766758
DOI: 10.3390/cells12030414 -
BMC Cardiovascular Disorders Dec 2022Cardiac arrest (CA) is caused by a nonshockable rhythm with a low success rate of return of spontaneous circulation (ROSC) and a poor prognosis. This study intended to...
OBJECTIVE
Cardiac arrest (CA) is caused by a nonshockable rhythm with a low success rate of return of spontaneous circulation (ROSC) and a poor prognosis. This study intended to establish a nonshockable rhythm CA model caused by asphyxia.
MATERIALS AND METHODS
Healthy adult male Wistar rats were injected with vecuronium bromide to induce CA. After the CA duration reached the target time point, cardiopulmonary resuscitation was performed. The survival status and neurological and cardiac function were evaluated after ROSC. Brain histopathology, including hematoxylin staining, Nissl staining and Terminal dUTP nick-end labeling (TUNEL) staining, was performed to evaluate the surviving cells and apoptotic cells. Apoptosis-related proteins after ROSC for 72 h were analyzed by western blot.
RESULTS
CA was successfully induced in all animals. The time for the three groups of animals to PEA was 320 ± 22 s in the CA-8 group, 322 ± 28 s in the CA-12 group and 320 ± 18 s in the CA-15 group. The time to asystole was 436 ± 54 s in the CA-8 group, 438 ± 62 s in the CA-12 group and 433 ± 56 s in the CA-15 group. The NDS of rats in the CA group was significantly decreased after ROSC for 24 h. The NDS in the CA-15 group was 5-16 points, while it was 58-67 points and 15-43 points in the CA-8 and CA-12 groups, respectively. The cardiac function of animals in the CA group was impaired after ROSC, and the ejection fraction, fractional shortening, stroke volume and cardiac output, were all significantly decreased. Brain histopathology showed that the number of surviving neurons was decreased, and the number of apoptotic cells was increased in CA group, the longer the CA duration, the more apoptotic cells increased. The expression of the proapoptotic protein Bax and the apoptotic executive protein caspase3 in the hippocampus of CA rats was significantly increased, while the expression of the antiapoptotic protein Bcl-2 was significantly reduced.
CONCLUSIONS
The use of vecuronium can successfully induce CA caused by nonshockable rhythm in rats, which will help to further study the pathophysiological changes after CA by nonshockable rhythm.
Topics: Rats; Male; Animals; Asphyxia; Rats, Wistar; Heart Arrest; Cardiopulmonary Resuscitation; Brain
PubMed: 36581829
DOI: 10.1186/s12872-022-02996-w -
Antioxidants (Basel, Switzerland) Dec 2022Research reports using animal models of ischemic insults have demonstrated that oxcarbazepine (a carbamazepine analog: one of the anticonvulsant compounds) extends...
Therapeutic Administration of Oxcarbazepine Saves Cerebellar Purkinje Cells from Ischemia and Reperfusion Injury Induced by Cardiac Arrest through Attenuation of Oxidative Stress.
Research reports using animal models of ischemic insults have demonstrated that oxcarbazepine (a carbamazepine analog: one of the anticonvulsant compounds) extends neuroprotective effects against cerebral or forebrain injury induced by ischemia and reperfusion. However, research on protective effects against ischemia and reperfusion cerebellar injury induced by cardiac arrest (CA) and the return of spontaneous circulation has been poor. Rats were assigned to four groups as follows: (Groups 1 and 2) sham asphyxial CA and vehicle- or oxcarbazepine-treated, and (Groups 3 and 4) CA and vehicle- or oxcarbazepine-treated. Vehicle (0.3% dimethyl sulfoxide/saline) or oxcarbazepine (200 mg/kg) was administered intravenously ten minutes after the return of spontaneous circulation. In this study, CA was induced by asphyxia using vecuronium bromide (2 mg/kg). We conducted immunohistochemistry for calbindin D-28kDa and Fluoro-Jade B histofluorescence to examine Purkinje cell death induced by CA. In addition, immunohistochemistry for 4-hydroxy-2-nonenal (4HNE) was carried out to investigate CA-induced oxidative stress, and immunohistochemistry for Cu, Zn-superoxide dismutase (SOD1) and Mn-superoxide dismutase (SOD2) was performed to examine changes in endogenous antioxidant enzymes. Oxcarbazepine treatment after CA significantly increased the survival rate and improved neurological deficit when compared with vehicle-treated rats with CA (survival rates ≥ 63.6 versus 6.5%), showing that oxcarbazepine treatment dramatically protected cerebellar Purkinje cells from ischemia and reperfusion injury induced by CA. The salvation of the Purkinje cells from ischemic injury by oxcarbazepine treatment paralleled a dramatic reduction in 4HNE (an end-product of lipid peroxidation) and increased or maintained the endogenous antioxidant enzymes (SOD1 and SOD2). In brief, this study shows that therapeutic treatment with oxcarbazepine after CA apparently saved cerebellar neurons (Purkinje cells) from CA-induced neuronal death by attenuating oxidative stress and suggests that oxcarbazepine can be utilized as a therapeutic medicine for ischemia and reperfusion brain (cerebellar) injury induced by CA.
PubMed: 36552657
DOI: 10.3390/antiox11122450 -
Anesthesiology Feb 2023The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented....
BACKGROUND
The clinical actions of sugammadex have been well studied, but the detailed molecular mechanism of the drug encapsulation process has not been systematically documented. The hypothesis was that sugammadex would attract rocuronium and vecuronium via interaction with the sugammadex side-chain "tentacles," as previously suggested.
METHODS
Computational molecular dynamics simulations were done to investigate docking of sugammadex with rocuronium and vecuronium. To validate these methods, strength of binding was assessed between sugammadex and a heterogeneous group of nine other drugs, the binding affinities of which have been experimentally determined. These observations hinted that high concentrations of unbound sugammadex could bind to propofol, potentially altering its pharmacokinetic profile. This was tested experimentally in in vitro cortical slices.
RESULTS
Sugammadex encapsulation of rocuronium involved a sequential progression down a series of metastable states. After initially binding beside the sugammadex molecule (mean ± SD center-of-mass distance = 1.17 ± 0.13 nm), rocuronium then moved to the opposite side to that hypothesized, where it optimally aligned with the 16 hydroxyl groups (distance, 0.82 ± 0.04 nm) before entering the sugammadex cavity to achieve energetically stable encapsulation by approximately 120 ns (distance, 0.35 ± 0.12 nm). Vecuronium formed fewer hydrogen bonds with sugammadex than did rocuronium; hence, it was less avidly bound. For the other molecules, the computational results showed good agreement with the available experimental data, showing a clear bilogarithmic relation between the relative binding free energy and the association constant (R2 = 0.98). Weaker binding was manifest by periodic unbinding. The brain slice results confirmed the presence of a weak propofol-sugammadex interaction.
CONCLUSIONS
Computational simulations demonstrate the dynamics of neuromuscular blocking drug encapsulation by sugammadex occurring from the opposite direction to that hypothesized and also how high concentrations of unbound sugammadex can potentially weakly bind to other drugs given during general anesthesia.
Topics: Sugammadex; Vecuronium Bromide; Rocuronium; gamma-Cyclodextrins; Neuromuscular Nondepolarizing Agents; Androstanols; Propofol; Dose-Response Relationship, Drug; Neuromuscular Blockade
PubMed: 36512718
DOI: 10.1097/ALN.0000000000004442 -
Medicine Nov 2022Sevoflurane and desflurane are commonly used inhalation anesthetics in clinical practice. This study compared the synergistic effects of sevoflurane and desflurane on... (Randomized Controlled Trial)
Randomized Controlled Trial
Sevoflurane and desflurane are commonly used inhalation anesthetics in clinical practice. This study compared the synergistic effects of sevoflurane and desflurane on the muscarinic agent vecuronium in laparoscopic colon cancer surgery. The aim of this study was to compare sevoflurane and desflurane in a synergistic effect on the muscle relaxant vecuronium in laparoscopic colon cancer surgery. Sixty patients undergoing elective laparoscopic radical resection of colon cancer were randomly divided into sevoflurane (n = 30) and desflurane (n = 30) groups. After anesthesia and successful tracheal intubation, patients in both groups were maintained with combined remifentanil. Muscle relaxant effects were monitored in both groups using a muscle relaxant monitor (train of stimuli-Watch), the onset time, T1 and T2 recovery time, and muscle relaxant dosage of vecuronium were observed. Hemodynamic changes were observed in both groups, and the dosage of vasoactive drugs was recorded. The quality of recovery of the patients was evaluated using the Mini-Mental State Examination (MMSE) and the discharge from the Aldrete score criteria. There was no significant difference in the onset time of vecuronium between the two groups (P > .05). The desflurane group's T1 and T2 recovery times were later than that of the sevoflurane group. The dosage of vecuronium was statistically significantly less than that in the sevoflurane group (P < .05); the extubation time in the desflurane group was statistically significantly longer than that in the sevoflurane group (P < .05). There were no significant differences in preoperative and intraoperative mean arterial pressure, heart rate, ephedrine and atropine dosage, MMSE score, and Aldrete score between the 2 groups (P > .05). Compared with sevoflurane, desflurane has a stronger synergistic effect on the muscle relaxant of vecuronium without increasing the incidence of cardiovascular adverse reactions and affecting patient recovery.
Topics: Humans; Sevoflurane; Desflurane; Vecuronium Bromide; Isoflurane; Methyl Ethers; Anesthesia Recovery Period; Laparoscopy; Colonic Neoplasms; Muscles
PubMed: 36397349
DOI: 10.1097/MD.0000000000031569 -
Spectrochimica Acta. Part A, Molecular... Feb 2023Near-infrared (NIR) spectroscopy is a non-destructive, efficient and convenient detection technology, with the emergence of portable NIR spectrometers, NIR mobile...
Near-infrared (NIR) spectroscopy is a non-destructive, efficient and convenient detection technology, with the emergence of portable NIR spectrometers, NIR mobile applications (APPs) come into being. The popularity of intelligent mobile phones provides an impetus to the research and development of NIR APPs, however, the primary functions such as operating the NIR spectrometers and collecting data cannot satisfy NIR users in the field of data processing. Herein, we propose an APP processing NIR data locally at the mobile terminal, by the comprehensive utilization of Principal Component Analysis (PCA) and Cuckoo Search algorithm optimized Support Vector Classifier with radial basis function (RBFSVC) kernel (CS-RBFSVC). 738 NIR samples of four drugs (Cydiodine Buccal Tablets, Sulfasalazine Enteric-coated Tablets, Dexamethasone Acetate Tablets, Vecuronium Bromide for Injection) were used as the validation objects to train and test the data classification model. Firstly, the original data were subjected to dimensional reduction through PCA for the purpose of compressing calculation amount. Secondly, the CS-RBFSVC model was utilized to classify the types of drugs and their manufacturers, moreover, the improved accuracy and efficiency by introducing Cuckoo Search (CS) algorithm into RBFSVC were proven in comparison with the conventional grid optimized RBFSVC (Grid-RBFSVC) and Linear Support Vector Classifier (Linear-SVC). Last but not least, an APP based on the proposed PCA and CS-RBFSVC model is developed and demonstrated to be able to classify the type of drugs with an accuracy of 100%, the accuracies of classifying the drugs' manufacturers were 100%, 100%, 98.3% and 90.7%, respectively. Conclusively, the proposed PCA and CS-RBFSVC based model can provide a low-consumption, high accuracy and quick strategy for NIR data classification and overcome the limitations of internal storage and operating speed at phone terminals, in conjunction with the portable NIR spectrometer, it is believed to push forward NIR technology into the instant detection and on-site inspection.
Topics: Principal Component Analysis; Spectroscopy, Near-Infrared; Algorithms; Tablets
PubMed: 36370633
DOI: 10.1016/j.saa.2022.122080 -
The Journal of Allergy and Clinical... Feb 2023Skin testing (ST) concentrations of neuromuscular blocking agents (NMBAs), NMBA-reversal agents, and the sugammadex-rocuronium inclusion complex (S-R-Cx) vary widely...
BACKGROUND
Skin testing (ST) concentrations of neuromuscular blocking agents (NMBAs), NMBA-reversal agents, and the sugammadex-rocuronium inclusion complex (S-R-Cx) vary widely among reports.
OBJECTIVE
To determine maximal ST nonirritant concentrations (NICs) of NMBAs (cisatracurium, rocuronium, succinylcholine, and vecuronium), NMBA-reversal agents (neostigmine and sugammadex), and S-R-Cx in NMBA-tolerant and NMBA-naïve participants.
METHODS
A single-center, prospective study between October 2019 and November 2021 of adult participants with or without a planned surgical procedure. The reference standard was tolerance of medication tested during a procedure (NMBA-tolerant group) before ST. Participants received skin prick testing (SPT) and intradermal test (IDT) injections at 5-7 increasing concentrations of 1 or more medications. All medications were reconstituted according to package insert instructions and diluted with 0.9% saline. A concentration was considered irritant when more than 5% of participants had a positive test per ST positivity criteria (wheal ≥3 mm than initial wheal and associated erythema of the same size or greater than wheal). We also compared our results with current guidelines.
RESULTS
A total of 187 participants (78% NMBA-tolerant) underwent 7812 skin tests. All undiluted SPT concentrations were nonirritant. We found the following maximal IDT NICs (mg/mL): cisatracurium (0.02), rocuronium (0.05), succinylcholine (0.8), vecuronium (0.01), neostigmine (0.2), sugammadex (50), and S-R-Cx (sugammadex 7.14 + rocuronium 2).
CONCLUSION
Our results suggest that SPT may be performed with undiluted stock concentrations. We confirm maximal IDT NICs for cisatracurium and rocuronium. We also propose that currently recommended maximal IDT NICs of succinylcholine, neostigmine, sugammadex, and S-R-Cx could be increased, whereas the maximal IDT NIC of vecuronium could be decreased compared with current guidelines and prior reports.
Topics: Adult; Humans; Sugammadex; Rocuronium; Vecuronium Bromide; Neuromuscular Nondepolarizing Agents; Neostigmine; gamma-Cyclodextrins; Succinylcholine; Prospective Studies; Androstanols; Neuromuscular Blockade; Neuromuscular Blocking Agents
PubMed: 36108924
DOI: 10.1016/j.jaip.2022.08.049 -
American Journal of Health-system... Jan 2023There is a lack of information on the compatibility of remimazolam with opioid analgesics, muscle relaxants, and other sedatives. This study aimed to evaluate the...
PURPOSE
There is a lack of information on the compatibility of remimazolam with opioid analgesics, muscle relaxants, and other sedatives. This study aimed to evaluate the physical compatibility of remimazolam with these drug classes.
METHODS
Remimazolam was combined with 1 or 2 target drugs (remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam). Ten physical compatibility tests were conducted, including four 3-drug compatibility tests. Remimazolam was dissolved in 0.9% sodium chloride injection to a final concentration of 5 mg/mL. Other medications were diluted in 0.9% sodium chloride injection to obtain clinically relevant concentrations. Compatibility tests were conducted with 3 test solutions, wherein remimazolam and the target drugs were compounded at equal volume ratios (1:1 or 1:1:1). Visual appearance was assessed and testing of Tyndall effect, turbidity, and pH was performed immediately after mixing and then again 1 hour and 4 hours after mixing. Appearance and turbidity were evaluated by comparison with the control solution of each target drug diluted with 0.9% sodium chloride injection to the same concentration as the test solution.
RESULTS
All drugs tested were determined to be compatible with remimazolam. The drug combination with the highest change of turbidity was remimazolam and vecuronium (a mean increase of 0.16 NTU relative to the remimazolam control solution), 4 hours after mixing. The combination with the highest pH was remimazolam, fentanyl, and vecuronium (mean [SD], 3.76 [0.01]), 4 hours after mixing. The combination of remimazolam and fentanyl showed a larger change in pH at 4 hours after mixing (a mean increase of 2.6%) than immediately after mixing.
CONCLUSION
Remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam are physically compatible with remimazolam during simulated Y-site administration.
Topics: Humans; Analgesics, Opioid; Drug Incompatibility; Remifentanil; Sodium Chloride; Anti-Bacterial Agents; Infusions, Intravenous; Hypnotics and Sedatives; Midazolam; Vecuronium Bromide; Rocuronium; Dexmedetomidine; Fentanyl; Muscles
PubMed: 36094564
DOI: 10.1093/ajhp/zxac262 -
The Journal of International Medical... Aug 2022To conduct a meta-analysis to compare different dosing scalars of sugammadex in a morbidly obese population for reversal of neuromuscular blockade (NMB). (Meta-Analysis)
Meta-Analysis
Appropriate dosing of sugammadex for reversal of rocuronium-/vecuronium-induced muscle relaxation in morbidly obese patients: a meta-analysis of randomized controlled trials.
OBJECTIVE
To conduct a meta-analysis to compare different dosing scalars of sugammadex in a morbidly obese population for reversal of neuromuscular blockade (NMB).
METHODS
PubMed®, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar were searched for relevant randomized controlled trials (RCTs) comparing lower-dose sugammadex using ideal body weight (IBW) or corrected body weight (CBW) as dosing scalars with standard-dose sugammadex based on total body weight (TBW) among morbidly obese people after NMB. Mean difference with SD was used to estimate the results.
RESULTS
The analysis included five RCT with a total of 444 morbidly obese patients. The reversal time was significantly longer in patients receiving sugammadex with dosing scalar based on IBW than in patients receiving sugammadex with dosing scalar based on TBW (mean difference 55.77 s, 95% confidence interval [CI] 32.01, 79.53 s), but it was not significantly different between patients receiving sugammadex with dosing scalars based on CBW versus TBW (mean difference 2.28 s, 95% CI -10.34, 14.89 s).
CONCLUSION
Compared with standard-dose sugammadex based on TBW, lower-dose sugammadex based on IBW had 56 s longer reversal time whereas lower-dose sugammadex based on CBW had a comparable reversal time.
Topics: Androstanols; Body Weight; Humans; Muscle Relaxation; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Obesity; Randomized Controlled Trials as Topic; Rocuronium; Sugammadex; Vecuronium Bromide; gamma-Cyclodextrins
PubMed: 35983671
DOI: 10.1177/03000605221116760 -
Drugs & Aging Oct 2022Residual neuromuscular paralysis, the presence of clinically significant weakness after administration of pharmacologic neuromuscular blockade reversal, is associated...
Residual neuromuscular paralysis, the presence of clinically significant weakness after administration of pharmacologic neuromuscular blockade reversal, is associated with postoperative pulmonary complications and is more common in older patients. In contemporary anesthesia practice, reversal of neuromuscular blockade is accomplished with neostigmine or sugammadex. Neostigmine, an acetylcholinesterase inhibitor, increases the concentration of acetylcholine at the neuromuscular junction, providing competitive antagonism of neuromuscular blocking drug and facilitating muscle contraction. Sugammadex, a modified gamma-cyclodextrin, antagonizes neuromuscular blockade by encapsulating rocuronium and vecuronium in a one-to-one ratio for renal clearance, a pharmacokinetic property that led to the recommendation that sugammadex not be administered to those with end-stage renal disease. While data are limited, reports suggest sugammadex is efficacious and well tolerated in individuals with reduced renal function. Sugammadex provides a more rapid and complete reversal of neuromuscular blockade than neostigmine. There is also accumulating evidence that sugammadex may provide a protective effect against the development of postoperative pulmonary complications, nausea, and vomiting, and that it may have beneficial effects on the rate of bowel and bladder recovery after surgery. Accordingly, sugammadex administration is beneficial for most older patients undergoing surgery.
Topics: Acetylcholine; Acetylcholinesterase; Aged; Cholinesterase Inhibitors; Humans; Neostigmine; Neuromuscular Blockade; Neuromuscular Nondepolarizing Agents; Postoperative Complications; Rocuronium; Sugammadex; Vecuronium Bromide; gamma-Cyclodextrins
PubMed: 35934764
DOI: 10.1007/s40266-022-00969-4