Design, synthesis, and biological evaluation of new bis-benzylisoquinoline-based analogues as potential neuromuscular blocking agents.

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.

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.

Assessing the clinical advantage of opioid-reduced anesthesia in thoracoscopic sympathectomy: a prospective randomized controlled trial.

BACKGROUND: Opioid-reduced multimodal analgesia has been used clinically for many years to decrease the perioperative complications associated with opioid drugs. We aimed to assess the clinical effects of opioid-reduced anesthesia during thoracoscopic sympathectomy. METHODS: Surgical patients (n = 151) with palmar hyperhidrosis were randomly divided into control (Group C, 73 patients) and test (Group T, 78 patients) groups. All patients were administered general anesthesia using a laryngeal mask. In Group C, patients received propofol, fentanyl, and cisatracurium for anesthesia induction, and maintenance was achieved with propofol and remifentanil, along with mechanical ventilation during the operation. In Group T, anesthesia was induced with propofol, dezocine, and dexmedetomidine (DEX) and maintained with propofol, DEX, and an intercostal nerve block, along with spontaneous breathing throughout the operation. Perioperative complications related to opioid use include hypotension, bradycardia, hypertension, tachycardia, hypoxemia, nausea, vomiting, urine retention, itching, and dizziness were observed. To assess the impact of these complications, we recorded and compared vital signs, blood gas indices, visual analogue scale (VAS) scores, adverse events, and patient satisfaction between the two groups. RESULTS: Perioperative complications related to opioid use were similar between groups. There were no significant differences in the type of perioperative sedation, analgesia index, respiratory and circulatory indicators, blood gas analysis, postoperative VAS scores, adverse reactions, propofol dosage, postoperative recovery time, and patient satisfaction. CONCLUSIONS: In minimally invasive surgeries such as thoracoscopic sympathectomy, opioid-reduced anesthesia was found to be safe and effective; however, this method did not demonstrate clinical advantages. TRIAL REGISTRATION: Chinese Clinical Trial Register: ChiCTR2100055005, on December 30, 2021.

Early Neuromuscular Blockade in the Acute Respiratory Distress Syndrome.

BACKGROUND: The benefits of early continuous neuromuscular blockade in patients with acute respiratory distress syndrome (ARDS) who are receiving mechanical ventilation remain unclear. METHODS: We randomly assigned patients with moderate-to-severe ARDS (defined by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of <150 mm Hg with a positive end-expiratory pressure [PEEP] of ≥8 cm of water) to a 48-hour continuous infusion of cisatracurium with concomitant deep sedation (intervention group) or to a usual-care approach without routine neuromuscular blockade and with lighter sedation targets (control group). The same mechanical-ventilation strategies were used in both groups, including a strategy involving a high PEEP. The primary end point was in-hospital death from any cause at 90 days. RESULTS: The trial was stopped at the second interim analysis for futility. We enrolled 1006 patients early after the onset of moderate-to-severe ARDS (median, 7.6 hours after onset). During the first 48 hours after randomization, 488 of the 501 patients (97.4%) in the intervention group started a continuous infusion of cisatracurium (median duration of infusion, 47.8 hours; median dose, 1807 mg), and 86 of the 505 patients (17.0%) in the control group received a neuromuscular blocking agent (median dose, 38 mg). At 90 days, 213 patients (42.5%) in the intervention group and 216 (42.8%) in the control group had died before hospital discharge (between-group difference, -0.3 percentage points; 95% confidence interval, -6.4 to 5.9; P = 0.93). While in the hospital, patients in the intervention group were less physically active and had more adverse cardiovascular events than patients in the control group. There were no consistent between-group differences in end points assessed at 3, 6, and 12 months. CONCLUSIONS: Among patients with moderate-to-severe ARDS who were treated with a strategy involving a high PEEP, there was no significant difference in mortality at 90 days between patients who received an early and continuous cisatracurium infusion and those who were treated with a usual-care approach with lighter sedation targets. (Funded by the National Heart, Lung, and Blood Institute; ROSE ClinicalTrials.gov number, NCT02509078.).

Combined opioid free and loco-regional anaesthesia enhances the quality of recovery in sleeve gastrectomy done under ERAS protocol: a randomized controlled trial.

BACKGROUND: It is debatable whether opioid-free anaesthesia (OFA) is better suited than multimodal analgesia (MMA) to achieve the goals of enhanced recovery after surgery (ERAS) in patients undergoing laparoscopic sleeve gastrectomy. METHODS: In all patients, anaesthesia was conducted with an i.v. induction with propofol (2 mg. kg-1), myorelaxation with cisatracurium (0.15 mg.kg-1), in addition to an ultrasound-guided bilateral oblique subcostal transverse abdominis plane block. In addition, patients in the OFA group (n = 51) received i.v. dexmedetomidine 0.1 µg.kg-1 and ketamine (0.5 mg. kg-1) at induction, then dexmedetomidine 0.5 µg. kg-1.h-1, ketamine 0.5 mg.kg-1.h-1, and lidocaine 1 mg. kg-1.h-1 for maintenance, while patients in the MMA group (n = 52) had only i.v. fentanyl (1 µg. kg-1) at induction. The primary outcome was the quality of recovery assessed by QoR-40, at the 6th and the 24th postoperative hour. Secondary outcomes were postoperative opioid consumption, time to ambulate, time to tolerate oral fluid, and time to readiness for discharge. RESULTS: At the 6th hour, the QoR-40 was higher in the OFA than in the MMA group (respective median [IQR] values: 180 [173-195] vs. 185 [173-191], p < 0.0001), but no longer difference was found at the 24th hour (median values = 191 in both groups). OFA also significantly reduced postoperative pain and morphine consumption (20 mg [1-21] vs. 10 mg [1-11], p = 0.005), as well as time to oral fluid tolerance (238 [151-346] vs. 175 min [98-275], p = 0.022), and readiness for discharge (505 [439-626] vs. 444 min [356-529], p = 0.001), but did not influence time to ambulate. CONCLUSION: While regional anaesthesia achieved most of the intraoperative analgesia, avoiding intraoperative opioids with the help of this OFA protocol was able to improve several sensible parameters of postoperative functional recovery, thus improving our knowledge on the OFA effects. CLINICAL TRIAL NUMBER: Registration number NCT04285255.

Pharmacokinetics and pharmacodynamics studies of a loading dose of cisatracurium in critically ill patients with respiratory failure.

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.

[Comparison of the anesthetic effects of mivacurium and cisatracurium besylate in laser laryngeal microsurgery].

Objective: To compare the anesthetic effects of mivacurium and cisatracurium besylate in laser laryngeal microsurgery, and to provide clinical evidence and reference for further optimization of muscle relaxation application. Methods: From October 2021 to January 2022, fifty-six patients of Beijing Tongren Hospital, Capital Medical University, scheduled for laser laryngeal microsurgery with general anesthesia, were enrolled. These patients, aged 18-65 years old, 25 males and 31 females, were divided into two groups (n=28) by random number table method. Cisatracurium besylate group (group C): cisatracurium besylate was injected at 0.1 mg/kg. Normal saline was continuously infused during operation. Mivacurium group (group M):Mivacurium was injected at 0.25 mg/kg and continuously infused at 0.3 mg·kg-1·h-1 during operation.The intubation time, the extubation time, recovery index, Cooper's score, Cormack-Lehane grade, surgical condition grade, postoperative residual neuromuscular block and allergic related adverse events were compared between the two groups. Results: The intubation time and the extubation time of group M were (3.7±1.1) and (16.2±5.0) min, which were statistically significant shorter than those of group C (4.9±0.7) and (26.4±8.6) min (all P<0.05). The recovery indexes of the patients in group M and group C were (4.5±3.4) and (6.2±5.0) min. The Cooper's scores of the two groups were both 9(9, 9). The Cormack-Lehane grades of the two groups were all grade Ⅰ. The number of cases with good/excellent surgical condition grades in group M and group C were 5/23 and 0/28. There were no significant differences in recovery index, Cooper's score, Cormack-Lehane grades and surgical condition grades between the two groups (all P>0.05). The TOF ratio of group M in the post anesthesia care unit (PACU) was (95.7±2.6) %, which was significantly higher than (92.9±3.9) % of group C(P=0.015). There were no significant differences in MAP and HR between the two groups at different time points (all P>0.05). The incidence of skin flushing in group M and group C was 10.7% (3/28) and 0, and the difference was not statistically significant (P=0.074). There were no cases of severe hypotension, significantly elevated airway pressure or airway spasm in both groups. Conclusion: In laser laryngeal microsurgery, compared with cisatracurium besylate, mivacurium has shorter intubation time and extubation time, stable hemodynamics, no significant increase in allergic related adverse events. mivacurium is safe and effective.

Lidocaine combined with magnesium sulfate preserved hemodynamic stability during general anesthesia without prolonging neuromuscular blockade: a randomized, double-blind, controlled trial.

BACKGROUND: Lidocaine and magnesium sulfate have become increasingly utilized in general anesthesia. The present study evaluated the effects of these drugs, isolated or combined, on hemodynamic parameters as well as on the cisatracurium-induced neuromuscular blockade (NMB). METHODS: At a university hospital, 64 patients, ASA physical status I and II, undergoing elective surgery with similar pain stimuli were randomly assigned to four groups. Patients received a bolus of lidocaine and magnesium sulfate before the tracheal intubation and a continuous infusion during the operation as follows: 3 mg.kg- 1 and 3 mg.kg- 1.h- 1 (lidocaine - L group), 40 mg.kg- 1 and 20 mg.kg- 1.h- 1 (magnesium - M group), equal doses of both drugs (magnesium plus lidocaine - ML group), and an equivalent volume of isotonic solution (control - C group). Hemodynamic parameters and neuromuscular blockade features were continuously monitored until spontaneous recovery of the train of four (TOF) ratio (TOFR > 0.9). RESULTS: The magnesium sulfate significantly prolonged all NMB recovery features, without changing the speed of onset of cisatracurium. The addition of lidocaine to Magnesium Sulfate did not influence the cisatracurium neuromuscular blockade. A similar finding was observed when this drug was used alone, with a significantly smaller fluctuation of mean arterial pressure (MAP) and heart rate (HR) measures during anesthesia induction and maintenance. Interestingly, the percentage of patients who achieved a TOFR of 90% without reaching T1-95% was higher in the M and ML groups. Than in the C and L groups. There were no adverse events reported in this study. CONCLUSION: Intravenous lidocaine plays a significant role in the hemodynamic stability of patients under general anesthesia without exerting any additional impact on the NMB, even combined with magnesium sulfate. Aside from prolonging all NMB recovery characteristics without altering the onset speed, magnesium sulfate enhances the TOF recovery rate without T1 recovery. Our findings may aid clinical decisions involving the use of these drugs by encouraging their association in multimodal anesthesia or other therapeutic purposes. TRIAL REGISTRATION: NCT02483611 (registration date: 06-29-2015).

[Effect of Cisatracurium to Intensify Diaphragmatic Atrophy in Mechanically Ventilated Rats].

OBJECTIVE: To investigate the role of cisatracurium in diaphragm atrophy in mechanically ventilated (MV) rats and its possible mechanism. METHODS: 30 adult male Sprague-Dawley (SD) rats were randomly assigned to 5 groups: Rats in the control (CON) group ( n=6) were fasted for 30 h without any other intervention; rats in the MV group ( n=6) were fasted for 6 h, and then mechanically ventilated for 24 h while receiving continuous infusion of sodium pentobarbital and 0.9% NaCl; rats in the MV+cisatracurium (MVC) group ( n=6) were fasted for 6 h, and then mechanically ventilated for 24 h while receiving continuous infusion of sodium pentobarbital and cisatracurium; rats in the MV+chloroquine (QMV) group ( n=6) and rats in the MV+cisatracurium+chloroquine (QMVC) group ( n=6) received intraperitoneal injection of chloroquine (30 mg/kg), an autophagy inhibitor, at 24 h and 30 min prior to MV in addition to the treatments given to the MV group and the MVC group, respectively. The rats in each group were sacrificed 30 hours later, and costal diaphragm muscle specimens were collected. The cross-sectional area (CSA) of the diaphragm fibers was observed through HE staining, and the colocalizations of TOM20 and LC3 were assessed by immunofluorescence staining. The expression levels of PINK1, Parkin, P62 and LC3, the mitophagy-related proteins, and the expression levels of MAFbx and MURF-1, muscular-atrophy-related proteins, were evaluated by Western blot. RESULTS: Respective comparisons of the MV group with the CON group and the MVC group with the MV group showed that the CSA decreased ( P<0.05), the expression of MURF-1, MAFbx, PINK1, Parkin and LC3Ⅱ/Ⅰproteins increased ( P<0.05), the number of co-expressed mitochondria of TOM20 and LC3 and the expression of LC3 increased and the expression of P62 protein decreased ( P<0.05) in the MV and MVC groups. Respective comparisons of the QMV group with the MV group and the QMVC group with the MVC group showed that the CSA increased ( P<0.05), the expression of MURF-1, MAFbx, PINK1, Parkin and LC3Ⅱ/Ⅰ proteins increased ( P<0.05), the number of co-expressed mitochondria of TOM20 and LC3 and the expression of LC3 decreased and the expression of P62 protein decreased ( P<0.05) in the QMV and QMVC group. CONCLUSION: Mechanical ventilation for 24 h caused diaphragm atrophy in SD rats. Cisatracurium may aggravate diaphragm atrophy in mechanically ventilated rats through the autophagy-lysosome (AL) pathway, a process that may be related to the PINK1/Parkin-mediated mitophagy, and chloroquine may reduce diaphragmatic atrophy induced by cisatracurium by blocking the AL pathway.

Cisatracurium stimulates testosterone synthesis in rat and mouse Leydig cells via nicotinic acetylcholine receptor.

As a cis-acting non-depolarizing neuromuscular blocker through a nicotinic acetylcholine receptor (nAChR), cisatracurium (CAC) is widely used in anaesthesia and intensive care units. nAChR may be present on Leydig cells to mediate the action of CAC. Here, by Western blotting, immunohistochemistry and immunofluorescence, we identified that CHRNA4 (a subunit of nAChR) exists only on rat adult Leydig cells. We studied the effect of CAC on the synthesis of testosterone in rat adult Leydig cells and mouse MLTC-1 tumour cells. Rat Leydig cells and MLTC-1 cells were treated with CAC (5, 10 and 50 µmol/L) or nAChR agonists (50 µmol/L nicotine or 50 µmol/L lobeline) for 12 hours, respectively. We found that CAC significantly increased testosterone output in rat Leydig cells and mouse MLTC-1 cells at 5 µmol/L and higher concentrations. However, nicotine and lobeline inhibited testosterone synthesis. CAC increased intracellular cAMP levels, and nicotine and lobeline reversed this change in rat Leydig cells. CAC may increase testosterone synthesis in rat Leydig cells and mouse MLTC-1 cells by up-regulating the expression of Lhcgr and Star. Up-regulation of Scarb1 and Hsd3b1 expression by CAC was also observed in rat Leydig cells. In addition to cAMP signal transduction, CAC can induce ERK1/2 phosphorylation in rat Leydig cells. In conclusion, CAC binds to nAChR on Leydig cells, and activates cAMP and ERK1/2 phosphorylation, thereby up-regulating the expression of key genes and proteins in the steroidogenic cascade, resulting in increased testosterone synthesis in Leydig cells.

The effect of cisatracurium infusion on the energy expenditure of critically ill patients: an observational cohort study.

BACKGROUND: Both overfeeding and underfeeding of intensive care unit (ICU) patients are associated with worse outcomes. A reliable estimation of the energy expenditure (EE) of ICU patients may help to avoid these phenomena. Several factors that influence EE have been studied previously. However, the effect of neuromuscular blocking agents on EE, which conceptually would lower EE, has not been extensively investigated. METHODS: We studied a cohort of adult critically ill patients requiring invasive mechanical ventilation and treatment with continuous infusion of cisatracurium for at least 12 h. The study aimed to quantify the effect of cisatracurium infusion on EE (primary endpoint). EE was estimated based on ventilator-derived VCO2 (EE in kcal/day = VCO2 × 8.19). A subgroup analysis of septic and non-septic patients was performed. Furthermore, the effects of body temperature and sepsis on EE were evaluated. A secondary endpoint was hypercaloric feeding (> 110% of EE) after cisatracurium infusion. RESULTS: In total, 122 patients were included. Mean EE before cisatracurium infusion was 1974 kcal/day and 1888 kcal/day after cisatracurium infusion. Multivariable analysis showed a significantly lower EE after cisatracurium infusion (MD - 132.0 kcal (95% CI - 212.0 to - 52.0; p = 0.001) in all patients. This difference was statistically significant in both sepsis and non-sepsis patients (p = 0.036 and p = 0.011). Non-sepsis patients had lower EE than sepsis patients (MD - 120.6 kcal; 95% CI - 200.5 to - 40.8, p = 0.003). Body temperature and EE were positively correlated (Spearman's rho = 0.486, p < 0.001). Hypercaloric feeding was observed in 7 patients. CONCLUSIONS: Our data suggest that continuous infusion of cisatracurium in mechanically ventilated ICU patients is associated with a significant reduction in EE, although the magnitude of the effect is small. Sepsis and higher body temperature are associated with increased EE. Cisatracurium infusion is associated with overfeeding in only a minority of patients and therefore, in most patients, no reductions in caloric prescription are necessary.

Cisatracurium inhibits the proliferation, migration and invasion of breast cancer cells by regulating the expression of miR-3174.

Breast cancer is a type of cancer that begins in the breast tissue. Being a woman is the most important factor in the risk of breast cancer. Although men also get the cancer, women are much more likely to get it. This experiment was founded to investigate the effect and mechanism of Cisatracurium on breast cancer cell proliferation, migration and invasion. Breast cancer cells MDA-MB-231 were cultured in vitro. MDA-MB-231 cells were treated with cisatracurium of different concentrations for 48 h. CCK-8method detected cell proliferation, Transwell detected cell migration and invasion, Western Blot method detected the expression levels of CyclinD1, p21, MMP-2andMMP-9protein in cells, RT-qPCR) detected the expression level of miR-3174in cells. After miR-3174 inhibitor was transfected into MDA-MB-231 in order to down-regulate the expression of miR-3174, the same methods as above were used to observe the effect of the down-regulating miR-3174 expression on MDA-MB-231 cell proliferation, migration and invasion as well as the expression levels of CyclinD1, p21, MMP -2 andMMP-9 protein. After different concentrations of Cisatracurium acted on MDA-MB-231 cells, the cell inhibition rate and p21 protein expression were significantly increased (p<0.05), the number of cell migration and invasion and the expression levels of CyclinD1, MMP-2 and MMP-9 were significantly reduced (p<0.05), and the expression of miR-3174 in cells was significantly reduced (p<0.05). After down-regulating the expression of miR-3174, the cell inhibition rate and p21 protein expression were significantly increased (p<0.05), the number of cell migration and invasion and the expression levels of CyclinD1, MMP-2 and MMP-9 were significantly reduced (p<0.05). Up-regulating miR-3174 expression could reverse the effect of Cisatracurium on the proliferation, migration and invasion of MDA-MB-231 cells. Cisatracurium can inhibit the proliferation, migration and invasion of breast cancer MDA-MB-231 cells, and its mechanism is related to the down-regulation of miR-3174 expression in cells.

Incidence of residual neuromuscular blockade in children below 3 years after a single bolus of cisatracurium 0.1 mg/kg: A quality assurance study.

BACKGROUND: The aim of this quality assurance study was to determine the proportion of patients with residual block (train-of-four (TOF) ratio <0.9) upon conclusion of surgery after a bolus of cisatracurium 0.1 mg/kg. It was considered good quality if less than 10% of the study population had residual block upon conclusion of surgery. METHODS: A total of 40 patients ≤3 years of age scheduled for cleft lip and palate repair were consecutively enrolled. They received general anaesthesia with either sevoflurane and fentanyl (n = 20) or propofol and remifentanil (n = 20). TOF stimulation using acceleromyography was applied on the tibial nerve. Cisatracurium 0.1 mg/kg was administered to facilitate tracheal intubation. RESULTS: Three patients (8%; 95% CI: 1.7-21) had a TOF ratio <0.9 at conclusion of surgery, all three receiving sevoflurane. In the sevoflurane group, this corresponded to 16% (95% CI: 3.3-40) of the patients. Mean duration of action of cisatracurium 0.1 mg/kg was 119 minutes (SD 40) with sevoflurane and 73 minutes (SD 29) during total intravenous anaesthesia (P < .001). Onset time of cisatracurium 0.1 mg/kg was 166 seconds (SD 37) with sevoflurane and 199 seconds (SD 60) during total intravenous anaesthesia. CONCLUSION: We found that 8% of the children had residual neuromuscular blockade (TOF ratio <0.9) after administration of a single bolus of cisatracurium 0.1 mg/kg but we cannot exclude that the true proportion is around 20%.

Drug Challenge Tests With General Anesthetics: Predictive Value of Skin Tests.

BACKGROUND: The study of perioperative drug reactions remains a major challenge for both diagnosis and therapy. The lack of a standard assessment of allergy to general anesthetics and of data establishing the true value of skin tests for most drugs used in induction and maintenance of anesthesia, as well as the lack of commercially available reagents for in vitro tests, renders the study of these reactions problematic. The aims of this study were to provide a diagnostic protocol for drug challenge testing with general anesthetics, to establish an etiological diagnosis that is as specific as possible, and to determine the predictive value of skin tests. METHODS: Twenty-nine patients with perioperative drug reactions were included in the study from November 2008 to December 2018. RESULTS: We confirmed the high negative predictive value of the tests (96%-100%) in the case of propofol, rocuronium, and fentanyl. To our knowledge, this is the first study to describe drug challenge testing with general anesthetics and, therefore, to establish the true negative predictive value of skin tests, which leads to a definitive diagnosis and safer surgery. CONCLUSIONS: After assessing risks and benefits and considering the importance of this group of drugs, we conclude that drug challenge testing with general anesthetics is necessary. We propose a protocol for perioperative drug reactions that enables us to make a highly accurate etiological diagnosis with minimum risk for the patient.

Abnormal cisatracurium pharmacodynamics and pharmacokinetics among patients with severe aortic regurgitation during anesthetic induction.

BACKGROUND: This study was designed to examine whether severe aortic regurgitation will affect the pharmacodynamics (PD) and pharmacokinetics (PK) of cisatracurium during anesthetic induction. METHODS: A total of 32 patients were divided into two groups: the AR group (n = 16) and the control group (n = 16). Arterial blood samples were drawn before and at 1, 2, 4, 6, 8, 10, 16 and 20 min after intravenous injection of 0.15 mg/kg cisatracurium. TOF tests were applied to determine the onset time of maximal muscle relaxation. The concentration of cisatracurium in plasma was determined by high-performance liquid chromatography. RESULTS: The onset time to maximal neuromuscular block was prolonged from 2.07 ± 0.08 min to 4.03 ± 0.14 min, which indicated that the PD responses to cisatracurium were significantly delayed in the AR group (P < 0.05) compared to the control group. A conventional two-compartment PK model showed a higher plasma concentration of cisatracurium among the AR group with markedly reduced intercompartment transfer rate (K12 = 0.19 ± 0.02 and K21 = 0.11 ± 0.01 in the AR group vs. K12=0.26 ± 0.01 and K21 = 0.19 ± 0.01 in the control group, P < 0.01) compared to the control group. CONCLUSION: Backward blood flow during diastole in severe AR impaired distribution of cisatracurium from the central compartment to the peripheral compartment, which accounted for the lagged PD responses. Findings in this study underlie the importance of muscular blockade monitoring among patients with severe aortic regurgitation during anesthetic induction. REGISTRATION: Name of the registry: Abnormal Cisatracurium Pharmacodynamics and Pharmacokinetics among Patients with Severe Aortic Regurgitation during Anesthetic Induction. TRIAL REGISTRATION NUMBER: ChiCTR1800019654. Date of registration: November 20th 2018.

Supine versus semi-Fowler's positions for tracheal extubation in abdominal surgery-a randomized clinical trial.

BACKGROUND: Tracheal extubation is commonly performed in the supine position. However, in patients undergoing abdominal surgery, the supine position increases abdominal wall tension, especially during coughing and deep breathing, which may aggravate pain and lead to abdominal wound dehiscence. The semi-Fowler's position may reduce abdominal wall tension, but its safety and comfort in tracheal extubation have not been reported. We aimed to evaluate the safety and comfort of different extubation positions in patients undergoing abdominal surgery. METHODS: We enrolled 141 patients with an American Society of Anesthesiologists grade of I-III who underwent abdominal surgery. All patients were anesthetized with propofol, fentanyl, cisatracurium, and sevoflurane. After surgery, all patients were transferred to the post-anesthesia care unit (PACU). Patients were then randomly put into the semi-Fowler's (n = 70) or supine (n = 71) position while 100% oxygen was administered. The endotracheal tube was removed after the patients opened their eyes and regained consciousness. Vital signs, coughing, and pain and comfort scores before and/or after extubation were recorded until the patients left the PACU. RESULTS: In comparison with the supine position, the semi-Fowler's position significantly decreased the wound pain scores at all intervals after extubation (3.51 ± 2.50 vs. 4.58 ± 2.26, 2.23 ± 1.68 vs. 3.11 ± 2.00, 1.81 ± 1.32 vs. 2.59 ± 1.88, P = 0.009, 0.005 and 0.005, respectively), reduced severe coughing (8[11.43%] vs. 21[29.58%], P = 0.008) and bucking after extubation (3[4.29%] vs. 18[25.35%], P < 0.001), and improved the comfort scores 5 min after extubation (6.11 ± 2.30 vs. 5.17 ± 1.78, P = 0.007) and when leaving from post-anesthesia care unit (7.17 ± 2.27 vs. 6.44 ± 1.79, P = 0.034). The incidences of vomiting, emergence agitation, and respiratory complications were of no significant difference. CONCLUSION: Tracheal extubation in the semi-Fowler's position is associated with less coughing, sputum suction, and pain, and more comfort, without specific adverse effects when compared to the conventional supine position. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR1900025566 . Registered on 1st September 2019.

First derivative synchronous spectrofluorimetric method for the simultaneous determination of propofol and cisatracurium besylate in biological fluids.

Propofol and cisatracurium besylate have been simultaneously determined using a highly sensitive first derivative synchronous spectrofluorometric method. The method is based on measuring first derivative synchronous spectrofluorimetric amplitude at Δλ = 40 nm with a scanning rate of 600 nm/min. The different experimental parameters affecting the fluorescence intensity of the two drugs were carefully studied and optimized. The amplitude-concentration plots were rectilinear over the range 40.0-400.0 ng/mL and 20.0-280.0 ng/mL for propofol and cisatracurium, respectively with lower detection limits of 4.0 and 2.35 ng/mL and quantification limits of 12.1 and 7.1 ng/mL for propofol and cisatracurium, respectively. The proposed method was successfully applied for the determination of the two compounds in synthetic mixtures and in commercial ampoules. The high sensitivity attained using the proposed method allowed the simultaneous determination of both drugs in spiked plasma samples. The mean % recoveries in spiked human plasma (n = 3) were 96.53 ± 0.90 and 96.20 ± 1.64 for each of propofol and cisatracurium, respectively. The method was validated in compliance with International Council of Harmonization (ICH) Guidelines.

Comparison of the neuromuscular blocking effects of cisatracurium during isoflurane or propofol anesthesia in dogs.

OBJECTIVE: To compare the neuromuscular blocking effects of cisatracurium during isoflurane versus propofol anesthesia in dogs. STUDY DESIGN: Prospective, randomized study. ANIMALS: A total of 20 healthy, client-owned dogs (16 females, four males) weighing 12.5-22 kg and aged 1-8 years. METHODS: Dogs undergoing elective surgery were randomized in equal numbers to an isoflurane (ISO) or propofol (PPF) group. Other drugs used during anesthesia were equal between groups. Single-twitch (ST) stimulation was used to monitor neuromuscular response. After recording the baseline ST (T0), cumulative doses of cisatracurium (0.05 mg kg-1) were administered intravenously until ST/T0 ≤5%. Effective doses 50 (ED50) and 95 (ED95) of cisatracurium in each group were calculated from group dose-response curves. Recovery of ST (TR) was defined as spontaneous recovery of ST to 80-120% of T0 remaining stable for 2 minutes. The ST after each dose of cisatracurium, duration 25% (time after the last dose until 25% recovery of TR), recovery index (time to recovery from 25% to 75% of TR) and duration to TR (time after the last dose until recovery of TR) were recorded. RESULTS: Incremental doses of cisatracurium, median (range), were 2 (1-3) in ISO and 4 (2-5) in PPF to achieve ≥95% depression of ST/T0 (p < 0.01). ED50 and ED95 were 20 µg kg-1 and 117 µg kg-1 in ISO and 128 µg kg-1 and 167 µg kg-1 in PPF, respectively. The duration 25%, recovery index and duration to TR, median (range), were longer in ISO [22.6 (10.3-24.3), 5.3 (3.0-7.8) and 36.1 (20.1-49.7) minutes, respectively] than in PPF [10.2 (6.8-16.5), 3.0 (2.0-3.8) and 17.7 (14.2-28.7) minutes, respectively] (p < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Cisatracurium-induced neuromuscular blockade was significantly enhanced and prolonged by isoflurane compared with propofol.

The Effects of Postoperative Residual Neuromuscular Blockade on Hospital Costs and Intensive Care Unit Admission: A Population-Based Cohort Study.

BACKGROUND: Postoperative residual neuromuscular blockade continues to be a frequent occurrence with a reported incidence rate of up to 64%. However, the effect of postoperative residual neuromuscular blockade on health care utilization remains unclear. We conducted a retrospective cohort study to investigate the effects of postoperative residual neuromuscular blockade on hospital costs (primary outcome), intensive care unit admission rate, and hospital length of stay (secondary outcomes). METHODS: We performed a prespecified secondary analysis of data obtained in 2233 adult patients undergoing surgery under general anesthesia. Postoperative residual neuromuscular blockade was defined as a train-of-four ratio <0.9 in the postanesthesia care unit (PACU). Our confounder model adjusted for a variety of patient, surgical, and anesthesia-related factors. We fitted truncated negative binomial regression models for hospital cost and hospital length of stay analyses and a logistic regression model for our intensive care unit admission analysis. RESULTS: Overall, 457 (20.5%) patients in our cohort had residual neuromuscular blockade on admission to the PACU. Postoperative residual neuromuscular blockade was not independently associated with increased hospital costs (adjusted incidence rate ratio, 1.04, CI, 0.98-1.11; P = .22). There were significantly higher odds of intensive care unit admission in those with postoperative residual neuromuscular blockade compared to those without (adjusted odds ratio, 3.03, CI, 1.33-6.87; P < .01). Further, we found a trend toward increased hospital length of stay in patients with postoperative residual neuromuscular blockade (adjusted incidence rate ratio, 1.09; P = .06). Sensitivity analysis using the same model in the day of surgery admissions and ambulatory surgery confirmed our findings. CONCLUSIONS: Postoperative residual neuromuscular blockade at PACU admission was not significantly associated with increased hospital costs, but was associated with higher rates of intensive care unit admission. These findings support the view that clinicians should continue to work to reduce the rate of postoperative residual neuromuscular blockade.

Minimum Alveolar Concentration of Sevoflurane with Cisatracurium for Endotracheal Intubation in Neonates.

BACKGROUND Sevoflurane inhalation induction is widely used in pediatric anesthesia, but the minimum alveolar concentration for endotracheal intubation (MACEI) when combined with neuromuscular blockade in neonates has been largely unexplored. This study assessed the MACEI of sevoflurane combined with cisatracurium in neonates. MATERIAL AND METHODS Anesthesia induction was commenced by inhaling 4% sevoflurane with 2 l/min of 100% oxygen via mask. Neonates were administered cisatracurium 0.2 mg/kg followed by adjustment of inspired sevoflurane to target end-tidal concentration based on intubation condition of the preceding subject. When the steady-state end-tidal sevoflurane concentration target was maintained for at least 15 min, endotracheal intubation by direct laryngoscope was performed. The intubation condition was considered failed if either heart rate (HR) after intubation increased by 20% or mean arterial blood pressure (MAP) by 30% or more than that before intubation. Otherwise, the intubation condition was regarded as successful. Dixon's up-and-down method was used with 0.2% as the step size to determine the target end-tidal sevoflurane concentration. RESULTS The MACEI of sevoflurane combined with cisatracurium in neonates was 2.76±0.24%. Using probit analysis, the 50% effective end-tidal sevoflurane concentration (ED50) for successful condition of endotracheal intubation was 2.61% (95%CI 2.07-2.88%) and the 95% effective end-tidal sevoflurane concentration (ED95) was 3.28% (95%CI 2.95-7.19%). Hypotension and bradycardia occurred in 2 neonates during induction. CONCLUSIONS Sevoflurane combined with cisatracurium is feasible and effective for intubation in neonates, and the MACEI of sevoflurane in this subpopulation is 2.76±0.24%. However, cardiovascular adverse effects should be taken into consideration.