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.

Onset and duration of action of escalating doses of atracurium in anesthetized healthy goats.

OBJECTIVE: The aim of this study was to describe the onset and duration of action of escalating doses of atracurium in healthy, anesthetized goats. STUDY DESIGN: Randomized, blinded, triple crossover study. Animals A total of eight (five males and three females) healthy goats weighing 42.7-123.5 kg and aged from 11 months to 8 years. METHODS: Goats were anesthetized three times with propofol and anesthesia was maintained with isoflurane. One of three doses of atracurium was administered intravenously 30 minutes after induction: 0.25 mg kg-1 (AT25), 0.5 mg kg-1 (AT50) or 0.75 mg kg-1 (AT75). Acceleromyographic train-of-four ratio (TOFR) followed by train-of-four counts (TOFC) were recorded at 30 second intervals after atracurium administration to determine blockade onset (TOFC = 0). The TOFR followed by TOFC were recorded at 5 minute intervals until return to pre-atracurium baseline (TOFR = 1.0). Normally distributed data were analyzed with repeated measures anova and a Tukey multiple comparison test. Data not normally distributed were analyzed with a Friedman test and a Dunn's multiple comparison test. RESULTS: For AT50 and AT75, 100% of goats achieved TOFC = 0 after atracurium administration. For AT25, however, 87.5% of goats achieved TOFC = 0 after atracurium administration. The onset time was shorter for AT75 [1.5 (0.5-1.5) minutes; median (range)] than for AT25 [2 (1-4) minutes] (p = 0.048). The duration of action [from onset time to complete reversal (TOFR = 1.0)] was significantly shorter for AT25 (52 ± 12 minutes, mean ± SD) than for AT50 (77 ± 18 minutes) (p < 0.001) and AT75 (85 ± 16 minutes) (p < 0.001). There was no significant difference in duration between AT50 and AT75 (p = 0.238). CONCLUSIONS AND CLINICAL RELEVANCE: Doses of 0.5 and 0.75 mg kg-1 atracurium may produce complete neuromuscular blockade in healthy, anesthetized goats.

Optimal dose of neostigmine antagonizing cisatracurium-induced shallow neuromuscular block in elderly patients: a randomized control study.

BACKGROUND: Residual neuromuscular block after using neuromuscular blocking agents is a common and potentially harmful complication of general anesthesia. Neostigmine is a widely used antagonist, but its optimal dose for elderly patients is unclear. OBJECTIVES: To compare the optimal dosage and safety of neostigmine for reversing shallow residual block in elderly patients after cisatracurium-induced neuromuscular block. METHODS: A randomized controlled trial was conducted in 196 elderly patients undergoing non-cardiac surgery under general anesthesia with cisatracurium. Patients were assigned to receive either no neostigmine (control group) or neostigmine at 20 µg/kg, 40 µg/kg or 50 µg/kg when train-of-four (TOF) ratio reached 0.2 at the end of surgery. The primary outcome was the time to reach TOF ratio of 0.9 after administration. Secondary outcomes included TOF ratio at 10 min after administration, postoperative nausea and vomiting, postoperative cognitive impairment and post-anesthesia care unit (PACU) stay time. RESULTS: The time to reach TOF ratio of 0.9 in the 20 µg/kg, 40 µg/kg and 50 µg/kg groups was significantly shorter than the control group (H = 104.257, P < 0.01), and the time of 40 µg/kg group and 50 µg/kg group was significantly shorter than the 20 µg/kg group (P < 0.001). There was no significant difference between 40 µg/kg and 50 µg/kg groups (P = 0.249). The TOF ratio at 10 min after administration showed similar results. There were no significant differences among groups in postoperative nausea and vomiting, postoperative cognitive impairment or post-operation hospital stay. CONCLUSIONS: Timely use of neostigmine after general anesthesia in elderly patients can significantly shorten time of TOF value reaching 0.9, among which 40 µg/kg dosage may be a more optimized choice. TRIAL REGISTRATION: this study was registered on chictr.org.cn (ChiCTR2100054685, 24/12/2021).

Impact of intravenous dexamethasone on the initiation and recovery of atracurium in children: A double-blinded randomized controlled trial.

BACKGROUND: Chronic steroid intake has been associated with attenuation of neuromuscular block. Despite some promising animal and adult studies, the effect of a single dose of intravenous dexamethasone on neuromuscular blockers is not well established. Thus, the present study aimed to demonstrate the effect of dexamethasone given at the time of induction for the prevention of PONV on the action of neuromuscular blockers in children undergoing elective surgery. METHOD: After obtaining approval from the Institute Ethics Committee and written informed parental consent, 100 ASA I and II children aged 4-15 years undergoing elective surgery randomized to receive either: 0.15 mg/kg (maximum of 5 mg) of dexamethasone diluted to a total volume of 2 ml with 0.9% saline (n = 50) or 2 ml of 0.9% saline (n = 50) at the time of induction. The time interval between application of atracurium and maximum T1 depression, 25% twitch height recovery of T1, amid 25% and 75% twitch height recovery of T1, amid the 25% twitch height recovery of T1 and recovery of the neuromuscular block to a TOF ratio of 0.9, and in between the initiation of atracurium injection till the recovery of the neuromuscular block to a TOF ratio of 0.9 was defined as onset time, clinical duration, recovery index, recovery time, and total recovery period, respectively, and recorded. RESULTS: The onset time and recovery index time were lower (1.96 ± 0.39, 8.04 ± 2.14, respectively) with dexamethasone in comparison with saline (2.01 ± 0.51, 8.9 ± 3.4, respectively) but not statistically significant. The clinical duration, recovery time, and total recovery period were similar. CONCLUSION: Application of a single bolus dose (0.15 mg/kg) of dexamethasone during induction does not attenuate atracurium-induced neuromuscular blockade in children.

Duration of neuromuscular block is more variable and recovery time is shorter with rocuronium than cisatracurium in anesthetized dogs.

OBJECTIVE: To compare the variability in the duration of action of a single dose of rocuronium or cisatracurium, and duration of subsequent top-up doses in anesthetized dogs. ANIMALS: Thirty dogs requiring ophthalmic surgery with neuromuscular block. PROCEDURES: Neuromuscular function was monitored with train-of-four (TOF) and acceleromyography. Dogs received an initial dose of rocuronium 0.6 mg/kg, or cisatracurium 0.15 mg/kg IV, which produced complete neuromuscular block. Upon return of the first response (T1) of TOF, a third of the initial dose was repeated. The duration of the initial dose and its variability were compared between agents. Duration of subsequent top-up doses was assessed with mixed effect models. Spontaneous (from last return of T1) or neostigmine-enhanced (from administration to complete recovery) recovery times were measured for each agent. RESULTS: Duration of action of the initial dose was [median (range)] 25 (10-60) min with rocuronium and 35 (15-45) min with cisatracurium (p = .231). The variability of rocuronium was 3.25 times larger than cisatracurium (p = .034). Duration of top-up doses did not vary for either agent. Spontaneous recovery was shorter for rocuronium [15 (10-20) min] than cisatracurium [25 (15-45) min] (p = .02). Neostigmine-enhanced recovery times were 5 (5-25) for rocuronium and 10 (5-10) for cisatracurium (p = .491). CONCLUSIONS: Duration of action for a single dose is significantly more variable with rocuronium than cisatracurium. Time to spontaneous recovery was longer for cisatracurium, and cases of unexpectedly long recovery times were observed with both agents. Objective monitoring is recommended.

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.).

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 onset time, duration of action, and intubating conditions after cisatracurium 0.15 mg/kg in young and elderly patients.

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).

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.

[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.

MRGPRX2 activation in mast cells by neuromuscular blocking agents and other agonists: Modulation by sugammadex.

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.

Neurodevelopmental Outcomes after Premedication with Atropine/Propofol vs Atropine/Atracurium/Sufentanil for Neonatal Intubation: 2-Year Follow-Up of a Randomized Clinical Trial.

This study followed 173 newborn infants in the PREmedication Trial for Tracheal Intubation of the NEOnate multicenter, double-blind, randomized controlled trial of atropine-propofol vs atropine-atracurium-sufentanil for premedication before nonemergency intubation. At 2 years of corrected age, there was no significant difference between the groups in death or risk of neurodevelopmental delay assessed with the Ages and Stages Questionnaire. Trial registration Clinicaltrials.gov: NCT01490580.

Neuromuscular Blockade Monitoring in Acute Respiratory Distress Syndrome: Randomized Controlled Trial of Clinical Assessment Alone or With Peripheral Nerve Stimulation.

BACKGROUND: Whether train-of-four (TOF) monitoring is more effective than clinical monitoring to guide neuromuscular blockade (NMB) in patients with acute respiratory distress syndrome (ARDS) is unclear. We compared clinical monitoring alone or with TOF monitoring to guide atracurium dosage adjustment with respect to drug dose and respiratory parameters. METHODS: From 2015 to 2016, we conducted a randomized controlled trial comparing clinical assessments every 2 hours with or without corrugator supercilii TOF monitoring every 4 hours in patients who developed ARDS (Pao2/Fio2 <150 mm Hg) in a cardiothoracic intensive care unit. The primary outcome was the cumulative atracurium dose (mg/kg/h). Secondary outcomes included respiratory parameters during the neuromuscular blockade. RESULTS: A total of 38 patients in the clinical + TOF (C + TOF) group and 39 patients in the clinical (C) group were included in an intention-to-treat (ITT) analysis. The cumulative atracurium dose was higher in the C + TOF group (1.06 [0.75-1.30] vs 0.65 [0.60-0.89] mg/kg/h in the C group; P < .001) compared to C group, as well as the atracurium daily dose (C + TOF - C group mean difference = 0.256 mg/kg/h [95% confidence interval {CI}, 0.099-0.416], P = .026). Driving pressures during neuromuscular blocking agent (NMBA) administration did not differ between groups (P = .653). Intensive care unit (ICU) mortality was 22% in the C group and 27% in the C + TOF group (P = .786). Days on ventilation were 17 (8-26) in the C group and 16 (10-35) in the C + TOF group. CONCLUSIONS: In patients with ARDS, adding TOF to clinical monitoring of neuromuscular blockade did not change ICU mortality or days on mechanical ventilation (MV) but did increase atracurium consumption when compared to clinical assessment alone. TOF monitoring may not be needed in all patients who receive neuromuscular blockade for ARDS.

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).

Neuromuscular blockade with atracurium for ophthalmic surgery in horses-Effects on surgical and anesthetic characteristics and recovery quality.

OBJECTIVE: To study the surgical, anesthetic and recovery qualities of horses receiving either a neuromuscular blocking agent (atracurium) or intravenous lidocaine (treatment groups A and L, respectively). ANIMALS STUDIED: A total of thirty horses presented for ocular surgery were used in this study. PROCEDURE: Horses were randomly assigned to receive either atracurium (group A) or a lidocaine constant rate infusion (group L). Surgical quality was graded on a scale from 1 (excellent)-5 (poor). While anesthetized, the heart rate, oxygen saturation and mean arterial blood pressure, and end-expiratory carbon dioxide and desflurane concentration were monitored and recorded every 5 minutes. Recovery was scored on a scale from 10 (best)-115 (worst). RESULTS: Horses in treatment group A needed significantly less desflurane then horses in treatment group L (p = 0.04). Horses in treatment group A had a significantly better surgery score of 1 (1-2) (median and range) then horses in treatment group L (2.5; 1-5) (p = 0.02). The quality of recovery was significantly better in horses in treatment group A compared with treatment group L, and horses needed significantly less time to reach the standing position. CONCLUSIONS: Atracurium and lidocaine CRI are safe methods of anesthesia for equine patients undergoing ocular surgery. Horses receiving atracurium needed less desflurane and had better surgery and recovery scores than horses receiving a lidocaine constant rate infusion.

[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%.