RESUMO
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.
Assuntos
Macaca fascicularis , Bloqueio Neuromuscular , Rocurônio , Animais , Masculino , Bloqueio Neuromuscular/métodos , Bloqueio Neuromuscular/veterinária , Rocurônio/farmacologia , Rocurônio/administração & dosagem , Fármacos Neuromusculares não Despolarizantes/administração & dosagem , Fármacos Neuromusculares não Despolarizantes/farmacologia , Atracúrio/farmacologia , Atracúrio/análogos & derivados , Atracúrio/administração & dosagem , Androstanóis/farmacologia , Androstanóis/administração & dosagem , Relação Dose-Resposta a Droga , Sugammadex/farmacologia , Sugammadex/administração & dosagem , Bloqueadores Neuromusculares/farmacologia , Bloqueadores Neuromusculares/administração & dosagemRESUMO
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.
Assuntos
Antídotos , Tetracaína , Animais , Tetracaína/farmacologia , Tetracaína/química , Camundongos , Antídotos/farmacologia , Antídotos/química , Amidas/química , Amidas/farmacologia , Masculino , Anestésicos Locais/farmacologia , Anestésicos Locais/química , Humanos , Bloqueadores Neuromusculares/química , Bloqueadores Neuromusculares/farmacologiaRESUMO
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.
Assuntos
Anestesia , Insuficiência Renal , Sugammadex , Humanos , Sugammadex/farmacologia , Anestesia/métodos , Anestesia/efeitos adversos , Rocurônio/farmacologia , Rocurônio/administração & dosagem , Bloqueadores Neuromusculares/efeitos adversos , Bloqueadores Neuromusculares/farmacologia , Animais , Succinilcolina/efeitos adversos , Neostigmina/farmacologia , Fármacos Neuromusculares não Despolarizantes/farmacologia , Rim/efeitos dos fármacosRESUMO
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.
Assuntos
Equilíbrio Ácido-Base , Humanos , Equilíbrio Ácido-Base/efeitos dos fármacos , Fármacos Neuromusculares Despolarizantes/farmacologia , Bloqueadores Neuromusculares/farmacologia , Anestésicos/farmacologia , Fármacos Neuromusculares não Despolarizantes/farmacologia , Succinilcolina/farmacologia , Rocurônio/farmacologiaRESUMO
BACKGROUND: The accuracy and precision of currently available, widely used acceleromyograph and electromyograph neuromuscular blockade monitors have not been well studied. In addition, the normalization of the train-of-four ratio from acceleromyography (train-of-four ratio [T4/T1] divided by the baseline train-of-four ratio) has not been validated in comparison to mechanomyography. METHODS: Enrolled patients had surgery under general anesthesia with a supraglottic airway and without any neuromuscular blocking drugs. Three acceleromyograph monitors, three electromyograph monitors, and a mechanomyograph built in the authors' laboratory were tested. Most patients had an electromyograph and the mechanomyograph on one arm and a third monitor on the contralateral arm. Train-of-four ratios were collected every 12 to 20 s for the duration of the anesthetic. At least 1,000 train-of-four ratios were recorded for each device. Gauge repeatability and reproducibility analysis was performed. RESULTS: Twenty-eight patients were enrolled. In total, 9,498 train-of-four ratio measurements were collected. Since no neuromuscular blocking drugs were used, the expected train-of-four ratio was 1.0. All of the acceleromyograph monitors produced overshoot in the train-of-four ratio (estimated means, 1.10 to 1.13) and substantial variability (gauge SDs, 0.07 to 0.18). Normalization of the train-of-four ratio measured by acceleromyography improved the estimated mean for each device (0.97 to 1.0), but the variability was not improved (gauge SDs, 0.06 to 0.17). The electromyograph and the mechanomyograph monitors produced minimal overshoot (estimated means, 0.99 to 1.01) and substantially less variation (gauge SDs, 0.01 to 0.02). For electromyography and mechanomyography, 0.3% of all train-of-four ratios were outside of the range 0.9 to 1.1. For acceleromyography, 27 to 51% of normalized train-of-four ratios were outside the range of 0.9 to 1.1. CONCLUSIONS: Three currently available acceleromyograph monitors produced overshoot and substantial variability that could be clinically significant. Normalization corrected the overshoot in the average results but did not reduce the wide variability. Three electromyograph monitors measured the train-of-four ratio with minimal overshoot and variability, similar to a mechanomyograph.
Assuntos
Eletromiografia , Miografia , Bloqueio Neuromuscular , Humanos , Masculino , Feminino , Eletromiografia/métodos , Eletromiografia/normas , Eletromiografia/instrumentação , Pessoa de Meia-Idade , Bloqueio Neuromuscular/métodos , Adulto , Miografia/métodos , Miografia/instrumentação , Miografia/normas , Reprodutibilidade dos Testes , Bloqueadores Neuromusculares/farmacologia , Idoso , Acelerometria/métodos , Acelerometria/instrumentação , Acelerometria/normas , Monitorização Intraoperatória/métodos , Monitorização Intraoperatória/instrumentação , Monitorização Intraoperatória/normas , Anestesia Geral/métodosRESUMO
Neuromuscular blocking agents (NMBAs) are widely used in anesthesia for intubation and surgical muscle relaxation. Novel atracurium and mivacurium derivatives were developed, with compounds 18c, 18d, and 29a showing mivacurium-like relaxation at 27.27 nmol/kg, and 15b, 15c, 15e, and 15h having a shorter duration at 272.7 nmol/kg. The structure-activity and configuration-activity relationships of these derivatives and 29a's binding to nicotinic acetylcholine receptors were analyzed through molecular docking. Rabbit trials showed 29a has a shorter duration compared to mivacurium. This suggests that linker properties, ammonium group substituents, and configuration are crucial for NMBA activity and duration, with compound 29a emerging as a potential ultra-short-acting NMBA.
Assuntos
Desenho de Fármacos , Isoquinolinas , Bloqueadores Neuromusculares , Bloqueadores Neuromusculares/farmacologia , Bloqueadores Neuromusculares/síntese química , Bloqueadores Neuromusculares/química , Relação Estrutura-Atividade , Animais , Isoquinolinas/química , Isoquinolinas/farmacologia , Isoquinolinas/síntese química , Coelhos , Receptores Nicotínicos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Dose-Resposta a Droga , Mivacúrio , Atracúrio/análogos & derivados , Atracúrio/farmacologia , Atracúrio/síntese química , Atracúrio/químicaRESUMO
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-Hâ§â§â§π interactions. The optimal size matching between the carboxylate AP5As and DMBr was â¼0.80. 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.
Assuntos
Bloqueadores Neuromusculares , Fármacos Neuromusculares não Despolarizantes , Organofosfonatos , gama-Ciclodextrinas , Animais , gama-Ciclodextrinas/farmacologia , Sugammadex , Bloqueadores Neuromusculares/farmacologia , BrometosRESUMO
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.
Assuntos
Bloqueio Neuromuscular , Bloqueadores Neuromusculares , Humanos , Bloqueadores Neuromusculares/farmacologia , Sugammadex , Bloqueio Neuromuscular/métodosAssuntos
Analgésicos Opioides , Bloqueadores Neuromusculares , Indução e Intubação de Sequência Rápida , Remifentanil , Aspiração Respiratória , Humanos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Anestésicos Intravenosos , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/métodos , Bloqueadores Neuromusculares/administração & dosagem , Bloqueadores Neuromusculares/farmacologia , Bloqueadores Neuromusculares/uso terapêutico , Indução e Intubação de Sequência Rápida/efeitos adversos , Indução e Intubação de Sequência Rápida/métodos , Remifentanil/administração & dosagem , Remifentanil/farmacologia , Remifentanil/uso terapêutico , Aspiração Respiratória/etiologia , Aspiração Respiratória/prevenção & controle , RiscoAssuntos
Analgésicos Opioides , Bloqueadores Neuromusculares , Indução e Intubação de Sequência Rápida , Remifentanil , Aspiração Respiratória , Humanos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Anestésicos Intravenosos , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/métodos , Bloqueadores Neuromusculares/administração & dosagem , Bloqueadores Neuromusculares/farmacologia , Bloqueadores Neuromusculares/uso terapêutico , Indução e Intubação de Sequência Rápida/efeitos adversos , Indução e Intubação de Sequência Rápida/métodos , Remifentanil/administração & dosagem , Remifentanil/farmacologia , Remifentanil/uso terapêutico , Aspiração Respiratória/etiologia , Aspiração Respiratória/prevenção & controle , RiscoAssuntos
Analgésicos Opioides , Bloqueadores Neuromusculares , Indução e Intubação de Sequência Rápida , Remifentanil , Aspiração Respiratória , Humanos , Anestésicos Intravenosos , Pressão Sanguínea/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/métodos , Bloqueadores Neuromusculares/administração & dosagem , Bloqueadores Neuromusculares/farmacologia , Bloqueadores Neuromusculares/uso terapêutico , Indução e Intubação de Sequência Rápida/efeitos adversos , Indução e Intubação de Sequência Rápida/métodos , Remifentanil/administração & dosagem , Remifentanil/farmacologia , Remifentanil/uso terapêutico , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/farmacologia , Analgésicos Opioides/uso terapêutico , Risco , Aspiração Respiratória/etiologia , Aspiração Respiratória/prevenção & controleRESUMO
INTRODUCTION: Tracheal intubation during anesthesia can be facilitated by the neuromuscular blocking agent cisatracurium. However, limited data exists about onset time, duration of action and effect on intubating conditions in elderly patients above 80 years of age. We hypothesized that elderly patients would present a longer onset time and duration of action compared to younger adults. METHODS: This prospective observational study included 31 young (18-40 years) and 29 elderly (≥ 80 years) patients. Patients were given fentanyl 2 µg/kg and propofol 1.5-2.5 mg/kg for induction of anesthesia and maintained with remifentanil and propofol. Monitoring of neuromuscular function was performed with acceleromyography. Primary outcome was onset time defined as time from injection of cisatracurium 0.15 mg/kg (based on ideal body weight) to a train-of-four (TOF) count of 0. Other outcomes included duration of action (time to TOF ratio ≥ 0.9), intubation conditions using the Fuchs-Buder scale and the Intubating Difficulty Scale (IDS), and occurrence of hoarseness and sore throat postoperatively. RESULTS: Elderly patients had significantly longer onset time compared with younger patients; 297 seconds (SD 120) vs. 199 seconds (SD 59) (difference: 98 seconds (95% CI: 49-147), P < 0.001)). Duration of action was also significantly longer in elderly patients compared with younger patients; 89 minutes (SD 17) vs. 77 minutes (SD 14) (difference: 12 minutes (95% CI: 2.5-20.5) P = 0.01)). No difference was found in the proportion of excellent intubating conditions (Fuchs-Buder); 19/29 (66%) vs 21/31 (68%) (P = 0.86) or IDS score (P = 0.74). A larger proportion of elderly patients reported hoarseness 24 hours postoperatively; 62% vs 34% P = 0.04. CONCLUSION: In elderly patients cisatracurium 0.15 mg/kg had significantly longer onset time and duration of action compared with younger patients. No difference was found in intubating conditions at a TOF count of 0. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04921735, date of registration 10 June 2021).
Assuntos
Bloqueadores Neuromusculares , Propofol , Humanos , Idoso , Rouquidão , Atracúrio/farmacologia , Bloqueadores Neuromusculares/farmacologia , Intubação IntratraquealRESUMO
OBJECTIVE: The optimal remifentanil concentration for improving intubation conditions when intubation is performed without neuromuscular blocking agents (NMBAs) but with ketamine as an induction agent remains unknown. Here, we aimed to identify the effective bolus doses of remifentanil required to achieve acceptable intubation conditions upon anesthesia induction with 1 or 2 mg/kg ketamine without NMBAs. PATIENTS AND METHODS: In this prospective, double-blinded, randomized up-down sequential allocation study, we enrolled pediatric patients aged 3-12 years undergoing general anesthesia for inguinal hernia surgery. The patients were randomly allocated to one of two groups to receive either ketamine 1.0 mg/kg (K1 group) or 2.0 mg/kg (K2 group) intravenously until seven success-failure pairs were achieved. The remifentanil dose for each patient was determined using the modified Dixon's up-and-down method with an initial dose of 2.5 µg/kg and a step size of 0.5 µg/kg. RESULTS: In total, 51 patients (22 in the K1 group and 29 in the K2 group) were enrolled. The effective dose (ED)50s of remifentanil for obtaining clinically acceptable intubation conditions under anesthesia induction with ketamine but without NMBAs was 3.2 µg/kg in the K1 group and 1.6 µg/kg in the K2 group. High-dose remifentanil with 1 mg/kg ketamine was associated with more severe chest wall rigidity and lower mean blood pressure and heart rate than was low-dose remifentanil with 2 mg/kg ketamine. CONCLUSIONS: The ED50 of remifentanil required for clinically acceptable intubation conditions with anesthesia induction using 1 mg/kg ketamine without NMBAs in pediatric patients was twice that when using 2 mg/kg ketamine. The combination of 2 mg/kg ketamine and remifentanil was better at preventing chest wall rigidity.
Assuntos
Ketamina , Bloqueadores Neuromusculares , Anestésicos Intravenosos , Criança , Frequência Cardíaca , Humanos , Intubação Intratraqueal , Ketamina/farmacologia , Bloqueadores Neuromusculares/farmacologia , Piperidinas/farmacologia , Estudos Prospectivos , Remifentanil/farmacologiaRESUMO
BACKGROUND: Previous studies reported a slow neuromuscular response with the currently recommended dose of cisatracurium in critically ill patients. Pharmacokinetic and pharmacodynamic studies of cisatracurium in critically ill patients are still limited. To our knowledge, this is the first study performed to better understand the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a loading dose of cisatracurium and to identify factors that affect PK and PD changes in critically ill patients. METHODS: A prospective PKs and PDs study was designed. Arterial blood samples of 10 critically ill patients with respiratory failure were collected after administering a loading dose of 0.2 mg/kg of cisatracurium. Plasma cisatracurium and laudanosine concentrations were determined using liquid chromatography-tandem mass spectrometry. The achievement of the desired pharmacodynamic response was evaluated by both 1) clinical assessment and 2) train-of-four monitoring. The PK/PD indices were analyzed for their correlation with patient'characteristics and other factors. RESULTS: The one-compartment model best described the plasma pharmacokinetic parameters of cisatracurium. The volume of distribution at steady state and total clearance were 0.11 ± 0.04 L/kg and 2.74 ± 0.87 ml/minute/kg, respectively. The mean time to train-of-four 0/4 was 6 ± 3.86 minutes. A time to the desired pharmacodynamic response of less than 5 minutes was found in 10% of the patients. A positive correlation was found between cisatracurium concentration and albumin levels and between pharmacokinetics data and patient factors [partial pressure of carbon dioxide and respiratory alkalosis]. CONCLUSION: The currently recommended loading dose of cisatracurium might not lead to the desired pharmacodynamic response in critically ill patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03337373. Registered on 9 November 2017.
Assuntos
Atracúrio/análogos & derivados , Cuidados Críticos/métodos , Bloqueadores Neuromusculares/farmacologia , Respiração Artificial/métodos , Insuficiência Respiratória/sangue , Insuficiência Respiratória/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Atracúrio/sangue , Atracúrio/farmacocinética , Atracúrio/farmacologia , Estado Terminal , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueadores Neuromusculares/sangue , Bloqueadores Neuromusculares/farmacocinética , Estudos ProspectivosAssuntos
Atracúrio/análogos & derivados , Eletromiografia/efeitos dos fármacos , Complicações Intraoperatórias/prevenção & controle , Monitorização Intraoperatória/métodos , Traumatismos do Nervo Laríngeo Recorrente/prevenção & controle , Glândula Tireoide/cirurgia , Adulto , Idoso , Atracúrio/administração & dosagem , Atracúrio/farmacologia , Relação Dose-Resposta a Droga , Eletromiografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Bloqueadores Neuromusculares/administração & dosagem , Bloqueadores Neuromusculares/farmacologiaRESUMO
BACKGROUND: Depressor anguli oris muscle hypertonicity in synkinetic facial paralysis patients may have an overpowering antagonistic effect on facial symmetry. Depressor anguli oris muscle block is a crucial diagnostic test before any treatment planning. Presented is the largest patient cohort analysis to date on static and dynamic facial symmetry changes after depressor anguli oris muscle block. METHODS: Unilateral synkinetic patients with depressor anguli oris muscle hypertonicity were included. Resting symmetry and smile modiolus angle, excursion, and exposure of teeth were measured on both synkinetic and healthy hemifaces before and after depressor anguli oris muscle block using Emotrics and FaceGram photographic analyses. RESULTS: Thirty-six patients were included. Before depressor anguli oris block, resting modiolus height was elevated on the synkinetic side (p = 0.047). During open-mouth smile, reduced modiolus angle (p < 0.0001), modiolus excursion (p < 0.0001), and exposure of teeth (p < 0.0001) were observed on the synkinetic hemiface. After depressor anguli oris block, resting modiolus height became symmetric (p = 0.64). During open-mouth smile, modiolus angle and exposure of teeth significantly increased (both p < 0.0001); excursion did not improve on the synkinetic side (p = 0.13) but unexpectedly improved in open-mouth smile on the healthy side (p = 0.0068). CONCLUSIONS: Depressor anguli oris muscle block improved resting symmetry and modiolus angle and exposure of teeth during smile, demonstrating the inhibitory mimetic role of a hypertonic depressor anguli oris muscle in synkinesis. It is a critical diagnostic and communication tool in the assessment and treatment planning of depressor anguli oris muscle hypertonicity, suggesting the potential effects of future depressor anguli oris myectomy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.
Assuntos
Assimetria Facial/tratamento farmacológico , Músculos Faciais/fisiopatologia , Paralisia Facial/fisiopatologia , Hipertonia Muscular/tratamento farmacológico , Bloqueio Neuromuscular/métodos , Sincinesia/etiologia , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Assimetria Facial/etiologia , Expressão Facial , Músculos Faciais/efeitos dos fármacos , Paralisia Facial/diagnóstico , Paralisia Facial/cirurgia , Feminino , Humanos , Injeções Intramusculares , Lidocaína/farmacologia , Lidocaína/uso terapêutico , Masculino , Pessoa de Meia-Idade , Hipertonia Muscular/etiologia , Bloqueadores Neuromusculares/farmacologia , Bloqueadores Neuromusculares/uso terapêutico , Cuidados Pré-Operatórios/métodos , Estudos Retrospectivos , Sorriso , Resultado do Tratamento , Adulto JovemRESUMO
Assessment of respiratory mechanics extends from basic research and animal modeling to clinical applications in humans. However, to employ the applications in human models, it is desirable and sometimes mandatory to study non-human animals first. To acquire further precise and controlled signals and parameters, the animals studied must be further distant from their spontaneous ventilation. The majority of respiratory mechanics studies use positive pressure ventilation to model the respiratory system. In this scenario, a few drug categories become relevant: anesthetics, muscle blockers, bronchoconstrictors, and bronchodilators. Hence, the main objective of this study is to briefly review and discuss each drug category, and the impact of a drug on the assessment of respiratory mechanics. Before and during the positive pressure ventilation, the experimental animal must be appropriately sedated and anesthetized. The sedation will lower the pain and distress of the studied animal and the plane of anesthesia will prevent the pain. With those drugs, a more controlled procedure is carried out; further, because many anesthetics depress the respiratory system activity, a minimum interference of the animal's respiration efforts are achieved. The latter phenomenon is related to muscle blockers, which aim to minimize respiratory artifacts that may interfere with forced oscillation techniques. Generally, the respiratory mechanics are studied under appropriate anesthesia and muscle blockage. The application of bronchoconstrictors is prevalent in respiratory mechanics studies. To verify the differences among studied groups, it is often necessary to challenge the respiratory system, for example, by pharmacologically inducing bronchoconstriction. However, the selected bronchoconstrictor, doses, and administration can affect the evaluation of respiratory mechanics. Although not prevalent, studies have applied bronchodilators to return (airway resistance) to the basal state after bronchoconstriction. The drug categories can influence the mathematical modeling of the respiratory system, systemic conditions, and respiratory mechanics outcomes.
Assuntos
Modelos Animais , Mecânica Respiratória/efeitos dos fármacos , Anestésicos/farmacologia , Animais , Broncoconstritores/farmacologia , Broncodilatadores/farmacologia , Bloqueadores Neuromusculares/farmacologiaRESUMO
Thiazolo- and thiadiazolo-[3,2-a][1,3]diazepines and their patented derivatives, tested with diverse CNS pharmacological activities, constitute an important class of compounds for new drug development. Therefore, research efforts were continued to design, synthesize, and evaluate compounds for their ultra-short, short-acting hypnotic, anticonvulsant, and neuromuscular blocking activities. The present review provides a summary of the work accomplished by these heterocycles and their biological evaluation.
Assuntos
Anticonvulsivantes/farmacologia , Azepinas/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Bloqueadores Neuromusculares/farmacologia , Receptores de GABA-A/metabolismo , Tiazóis/farmacologia , Animais , Anticonvulsivantes/química , Azepinas/química , Agonistas de Receptores de GABA-A/química , Humanos , Modelos Moleculares , Estrutura Molecular , Bloqueadores Neuromusculares/química , Tiazóis/químicaRESUMO
BACKGROUND: Neuromuscular-blocking agents (NMBAs) can cause both IgE-dependent and IgE-independent anaphylactic reactions, with activation of the mast cell receptor MRGPRX2 being important to the latter. Sugammadex, a reversal agent for certain aminosteroid NMBAs, has been proposed as an antidote for these anaphylactic events with conflicting outcomes. OBJECTIVE: We further characterize the involvement of MRGPRX2 in NMBA-induced mast cell activation and determine how this is influenced by sugammadex. We then apply these in vitro results to infer the possible utility of sugammadex in the acute management of non-IgE-dependent anaphylaxis. METHODS: The LAD2 human mast cell line and a MRGPRX2 knock-down derivative were used to validate the involvement of MRGPRX2 and to test the effect of sugammadex on mast cell activation by NMBAs and other MRGPRX2 agonists. RESULTS: All MRGPRX2 agonists tested were shown to induce MRGPRX2-dependent LAD2 mast cell calcium mobilization and cytokine release and all, apart from rocuronium, induced degranulation. Co-treatment of mast cells with sugammadex and some MRGPRX2 agonists significantly reduced cell activation, but if sugammadex was administered a few minutes following stimulation, degranulation was not attenuated. However, addition of sugammadex up to 180 min following LAD2 MRGPRX2 stimulation, significantly reduced CCL2 mRNA and protein induction. CONCLUSIONS AND CLINICAL RELEVANCE: We show that sugammadex, known to reverse muscle blockade by certain NMBAs, is also able to reduce MRGPRX2 activation by NMBAs and other, but not all, MRGPRX2 agonists. As sugammadex was ineffective in attenuating mast cell degranulation when added rapidly post MRGPRX2 activation, this suggests against the agent having efficacy in controlling acute symptoms of anaphylaxis to NMBAs caused by MRGPRX2 activation. Interestingly, however, sugammadex did impair MRGPRX2-induced CCL2 release, suggesting that it may have some benefit in perhaps dampening less well-defined adverse effects of MRGPRX2-dependent anaphylaxis associated with the more slowly elaborated mast cell mediators.
Assuntos
Anafilaxia/tratamento farmacológico , Quimiocina CCL2/efeitos dos fármacos , Mastócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/efeitos dos fármacos , Bloqueadores Neuromusculares/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores de Neuropeptídeos/efeitos dos fármacos , Sugammadex/farmacologia , Anafilaxia/induzido quimicamente , Antídotos/farmacologia , Atracúrio/efeitos adversos , Linhagem Celular , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Técnicas In Vitro , Mastócitos/imunologia , Mastócitos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Bloqueadores Neuromusculares/efeitos adversos , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Rocurônio/efeitos adversosRESUMO
STUDY OBJECTIVE: We aimed to determine whether jaw occlusive power decreases with the injection of neuromuscular blocking agents in masseter muscle - a method we named Sion's masseter muscle paralysis (SMP). METHODS: A randomized, placebo-controlled animal study was conducted in which researchers were blinded to group allocation. We used 12 male mongrel dogs aged 10-12 months and weighing 30-35 kg. Four groups were formed: a conventional dose (CD) group (0.004 mg/kg succinylcholine in 4 ml normal saline [NS]); a high dose (HD) group (0.04 mg/kg succinylcholine in 4 ml NS); a placebo group (4 ml NS); and no intervention group. To measure the jaw occlusive power, 1 kg weight was hung sequentially on a specifically designed device on the animal's lower jaw. At -4, -2, 0', +2, +4, +6, +8, +10, +20, and +30 min, we measured the jaw occlusive power, oxygen saturation (SpO2), and end-tidal carbon dioxide (ETCO2). RESULTS: After SMP, jaw occlusive power began to decline in CD and HD group. The arithmetical mean jaw occlusive power values at -4, -2, 0', +2, +4, +6, +8, and +10 min were 9.7, 9.7, 9.7, 8.7, 8.3, 7.3, 6.7, and 6.3 kgw in the CD group and 9.7, 9.3, 8.7, 8.0, 6.7, 5.0, 5.0, and 5.3 kgw in the HD group. No abnormalities in SpO2or ETCO2were detected. CONCLUSION: Jaw occlusive power was decreased after SMP with succinylcholine, without inducing respiratory complication.