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.

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.

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).

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.

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.

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%.

The median effective dose (ED50) of cis-Atracurium for laryngeal mask airway insertion during general Anaesthesia for patients undergoing urinary surgery.

BACKGROUND: In clinical practice, the laryngeal mask airway is an easy-to-use supraglottic airway device. However, the cis-atracurium dosage for laryngeal mask insertion has not been standardised. We aimed to determine the optimal dose of cis-atracurium using a sequential method for successful laryngeal mask insertion. METHODS: The cohort study protocol is registered at clinicaltrial.gov (NCT-03668262). Twenty-three patients undergoing elective urinary surgery were sequentially administered cis-atracurium doses as follows: 150, 100, 70, 50, 30, and 20 µg·kg- 1. The main outcome involved the determination of the response to laryngeal mask airway insertion: ≥16 points and < 16 points indicated "satisfactory" and "unsatisfactory" responses, respectively. The median effective dose was estimated using the mean of the seven crossovers from "satisfactory" and "unsatisfactory" responses. The primary outcome involved the determination of the median effective dose (ED50) of cis-atracurium for laryngeal mask airway insertion. RESULTS: The median effective dose of cis-atracurium was 26.5 µg·kg- 1 (95% CI 23.6-29.8) using the sequential method. Heart rate was decreased in the 50 µg·kg- 1 group compared to that in the 30 µg·kg- 1 group at timepoints T7, T8, and T10 (P = 0.0482, P = 0.0460, and P = 0.0236, respectively), but no difference was observed in the 20 µg·kg- 1 group. Systolic blood pressure was decreased in the 50 µg·kg- 1 group compared to that in the 20 µg·kg- 1 group at timepoints T2, T3, and T4 (P = 0.0159, P = 0.0233, and P = 0.0428, respectively). The train-of-four value was significantly lower in the 50 µg·kg- 1 group than in the 30 µg·kg- 1 group at timepoint T3 (P = 0.0326). CONCLUSIONS: The ED50 of cis-atracurium was 26.5 µg·kg- 1 for laryngeal mask airway insertion. TRIAL REGISTRATION: Clinicaltrial.gov Registry, NCT03668262, Registered on 11 September 2018.

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.

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.

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.

Neuromuscular block monitoring after the administration of 1 mg/kg intravenous cis-atracurium in the anaesthetized pig.

Neuromuscular blocking agents should be included as part of a balanced anaesthetic protocol to improve anaesthetic management, although doses are not always established for each species. Cis-atracurium is a benzylisoquinolinium neuromuscular blocking agent with an intermediate duration of action devoid of significant adverse effects previously used in pigs with a wide dosage range. Cis-atracurium was administered at 1 mg/kg bolus to sixteen pigs to establish its time profile and effects. The pigs were premedicated intramuscularly with 4 mg/kg azaperone, 8 mg/kg ketamine and 0.2 mg/kg morphine IM and maintained with isoflurane in oxygen. After cis-atracurium administration, neuromuscular monitoring via acceleromyography was started until the recovery of the 90% of the train of four ratio. Complete decrease in the train of four ratio was accomplished in eleven pigs. Onset of action was 70 s, with a recovery of the fourth twitch at 26 min and a recovery of a train of four ratio greater than 90% in 60 min. In conclusion, 1 mg/kg intravenous cis-atracurium in the pig allowed for a rapid onset of action and a complete recovery after 60 min although high variability in the time profile is seen.

Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency Intubation: A Randomized Clinical Trial.

Importance: Propofol or a combination of a synthetic opioid and muscle relaxant are both recommended for premedication before neonatal intubation but have yet to be compared. Objective: To compare prolonged desaturation during neonatal nasotracheal intubation after premedication with atropine-propofol vs atropine-atracurium-sufentanil treatment. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial (2012-2016) in 6 NICUs in France that included 173 neonates requiring nonemergency intubation. The study was interrupted due to expired study kits and lack of funding. Interventions: Eighty-nine participants were randomly assigned to the atropine-propofol group and 82 to the atropine-atracurium-sufentanil group before nasotracheal intubation. Main Outcomes and Measures: The primary outcome was prolonged desaturation (Spo2 <80% lasting > 60 seconds), using intention-to-treat analysis using mixed models. Secondary outcomes assessed the characteristics of the procedure and its tolerance. Results: Of 173 neonates randomized (mean gestational age, 30.6 weeks; mean birth weight, 1502 g; 71 girls), 171 (99%) completed the trial. Of 89 infants, 53 (59.6%) in the atropine-propofol group vs 54 of 82 (65.9%) in the atropine-atracurium-sufentanil group achieved the primary outcome (adjusted RD, -6.4; 95% CI, -21.0 to 8.1; P = .38). The atropine-propofol group had a longer mean procedure duration than did the atropine-atracurium-sufentanil group (adjusted RD, 1.7 minutes; 95% CI, 0.1-3.3 minutes; P = .04); a less frequent excellent quality of sedation rate, 51.7% (45 of 87) vs 92.6% (75 of 81; P < .001); a shorter median time to respiratory recovery, 14 minutes (IQR, 8-34 minutes) vs 33 minutes (IQR, 15-56 minutes; P = .002), and shorter median time to limb movement recovery, 18 minutes (IQR, 10-43 minutes) vs 36 minutes (IQR, 19-65 minutes; P = .003). In the 60 minutes after inclusion, Spo2 was preserved significantly better in the atropine-propofol group (time × treatment interaction P = .02). Of the atropine-propofol group 20.6% had head ultrasound scans that showed worsening intracranial hemorrhaging (any or increased intraventricular hemorrhage) in the 7 days after randomization vs 17.6% in the atropine-atracurium-sufentanil group (adjusted RD, 1.2; 95% CI, -13.1 to 15.5, P = .87). Severe adverse events occurred in 11% of the atropine-propofol group and in 20% of the atropine-atracurium-sufentanil group. Conclusions and Relevance: Among neonates undergoing nonemergency nasotracheal intubation, the frequency of prolonged desaturation did not differ significantly between atropine used with propofol or atropine used with atracurium and sufentanil. However, the study may have been underpowered to detect a clinically important difference, and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01490580, EudraCT number: 2009-014885-25.

Altered pharmacodynamics and pharmacokinetics of cisatracurium in patients with severe mitral valve regurgitation during anaesthetic induction period.

AIM: The aim of the current study was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in patients with severe mitral valve regurgitation (MR) during the anaesthetic induction period. METHODS: Thirty patients in the clinical trial were divided into two groups: the MR group (n = 15) and the control group (n = 15). Arterial blood samples were obtained before (time 0) and at 1, 2, 4, 6, 8, 10, 15 and 20 min after intravenous injection of 0.15 mg kg-1 cisatracurium. The degree of neuromuscular block was measured by train of four (TOF) testing. The concentration of cisatracurium in the plasma was determined by high-performance liquid chromatography. A conventional two-compartment model and integrated PK/PD model were applied to PK and PD data analysis, respectively. RESULTS: The results of PK model fitting demonstrated that severe MR reduced the distribution rate of cisatracurium from the central to peripheral compartment, resulting in a higher concentration of the drug in the plasma. The time to the maximal neuromuscular blocking effect of cisatracurium was delayed in the MR group (2.08 min in the control group vs. 4.12 min in the MR group). The PK/PD model indicated that the distribution rate of cisatracurium from the blood to the effect compartment was decreased in the MR group. CONCLUSIONS: The present study suggested that the PK and PD of cisatracurium were significantly altered in patients with severe MR. The study has the potential to improve the safety of anaesthetic induction in patients with severe MR through accurate prediction of the PD responses of cisatracurium using the established PK/PD model.

Diabetes mellitus does not affect the neuromuscular blocking action of atracurium in dogs.

OBJECTIVE: To compare the duration of action of atracurium in diabetic and nondiabetic dogs. STUDY DESIGN: Prospective, blinded, clinical study. ANIMALS: A total of 26 diabetic and 29 nondiabetic dogs. METHODS: Following preanaesthetic medication and intravenous (IV) propofol induction, anaesthesia was maintained with isoflurane in oxygen. Atracurium 0.2 mg kg-1 IV was administered to provide neuromuscular blockade (NMB) and the responses (twitches; T) to train-of-four nerve stimulation were recorded by palpation and electromyography (EMG). Time to onset of NMB (from atracurium administration to loss of T4 by EMG), duration of NMB (to return of T1 by EMG) and also times to loss and return of T2-T4 were recorded. Heart rate (HR), mean arterial pressure, end-tidal isoflurane (Fe'Iso), end-tidal CO2 concentrations and oesophageal temperature were recorded at onset of NMB and when T1EMG returned. Groups were compared using t tests and Mann-Whitney U tests (p<0.05). RESULTS: Diabetic dogs were older (9.9±0.3 compared with 6.8±0.7 years, p=0.0003). Group parameters were similar at onset and offset of NMB apart from HR at offset, which was higher for diabetics compared to nondiabetics (114±4 compared with 100±3 beats minute-1, respectively, p=0.004), Fe'Iso was higher in the diabetic group at onset (1.3±0.03% compared with 1.2±0.04%, p=0.026) and offset (1.4±0.03% compared with 1.3±0.03%, p=0.007), and temperature was higher for diabetics at onset (37.5±0.1 °C compared with 37.0±0.2 °C, p=0.012) and offset (37.5±0.1 °C compared with 36.9±0.2 °C, p=0.004). The duration of action of atracurium(tactile) and atracurium(EMG) were similar for both groups. CONCLUSIONS AND CLINICAL RELEVANCE: The duration of action of atracurium was similar in diabetic and nondiabetic dogs as indicated by tactile and EMG monitoring.

[Effect of cisatracurium on entropy index of children undergoing sevoflurane anesthesia].

Objective: To investigate the effect of cisatracurium on entropy index of children undergoing sevoflurane anesthesia. Methods: Forty-five child patients (ASAⅠ-Ⅱ) who underwent cleft lip and palate repair surgery in Beijing Stomatological Hospital were selected from June to November in 2015. They aged from 8 to 24 months and were randomly divided into 3 groups, as well as maintained at different end-tidal sevoflurane concentrations (C(ET)Sev), respectively. The C(ET)Sev in Group Ⅰ was 2.5%, with a total number of 15 cases. The C(ET)Sev in Group Ⅱ was 3.0%, with a total number of 16 cases. The C(ET)Sev in Group Ⅲ was 3.5%, with a total number of 14 cases. After the child patients were sent into operating room, their ulnar nerves underwent train-of-four stimulation (TOF) inspection using Datex-Ohmeda anesthesia workstation. The four muscle twitches orderly occurring on abductor pollicis muscle were recorded as T(1,)T(2,)T(3) and T(4,)respectively. The level of state entropy (SE) and reactive entropy (RE) was monitored by the entropy index module. 6% of sevoflurane high-flow inhalation was used to induce children's sleep, and the oxygen flow was adjusted to 2 L/min. Also, the C(ET)Sev in 3 groups maintained at 2.5%, 3.0% and 3.5%, respectively, which lasted for more than 10 min. Then, they were administered with 0.15 mg/kg cisatracurium, and the level of SE and RE in 3 groups was recorded when they were before the drug delivery of cisatracurium (t(1)), 50% inhibition of T(1) (t(2)), 75% inhibition of T(1) (t(3)) and 100% inhibition of T(1) (t(4)), respectively. Results: At the time of t(1,)t(2,)t(3) and t(4,)the SE values in Group Ⅰ were (55±19), (53±20), (48±18) and (43±16), respectively, and the differences were statistically significant (F=3.881, P<0.05). The SE values in Group Ⅱ were (42±19), (41±21), (39±18), (31±13), and the differences were statistically significant (F=3.463, P<0.05). The SE values in Group Ⅲ were (34±11), (33±16), (33±14) and (32±13), respectively. The differences were not statistically significant (F=0.162, P>0.05). At the time of t(1,)t(2,)t(3) and t(4,)the RE values in Group Ⅰ were (54±13), (48±11), (34±13) and (30±13) respectively, and the differences were statistically significant (F=36.975, P<0.01). The RE values in Group Ⅱ were (43±13), (38±13), (33±12) and (28±11) respectively, the differences were statistically significant (F=12.438, P<0.01). The RE values in Group Ⅲ were (34±10), (33±11), (31±12) and (25±11) respectively, and the differences were statistically significant (F=6.019, P<0.01). The RE values of child patients in Group Ⅰ, Ⅱ and Ⅲ decreased after the drug delivery of cisatracurium. Conclusion: The muscle relaxants (cisatracurium) will decrease the entropy index of children undergoing sevoflurane anesthesia, but will not affect their SE values under deep anesthesia.

Neuromuscular Blocking Agent Cisatracurium Attenuates Lung Injury by Inhibition of Nicotinic Acetylcholine Receptor-α1.

BACKGROUND: Neuromuscular blocking agents (NMBAs) bind the nicotinic acetylcholine receptor α1 (nAChRα1) that also contributes to inflammatory signaling. Thus, the author hypothesized that the use of NMBA mitigates lung injury by improving ventilator synchrony and decreasing inflammatory responses. METHODS: Lung injury was induced by intratracheal instillation of hydrogen chloride in rats that were randomized to receive no NMBA with evidence of asynchronous ventilation (noNMBA/aSYNC, n = 10); no NMBA with synchronous ventilation (noNMBA/SYNC, n = 10); cisatracurium (CIS, n = 10); or pancuronium (PAN, n = 10). Mechanical ventilation was set at a tidal volume of 6 ml/kg and positive end-expiratory pressure 8 cm H2O for 3 h. Human lung epithelial, endothelial, and CD14⁺ cells were challenged with mechanical stretch, lipopolysaccharide, lung lavage fluids (bronchoalveolar lavage fluid), or plasma obtained from patients (n = 5) with acute respiratory distress syndrome, in the presence or absence of CIS or small-interfering RNA and small hairpin RNA to attenuate the cell expression of nAChRα1. RESULTS: The use of CIS and PAN improved respiratory compliance (7.2 ± 0.7 in noNMBA/aSYNC, 6.6 ± 0.5 in noNMBA/SYNC, 5.9 ± 0.3 in CIS, and 5.8 ± 0.4 cm H2O/l in PAN; P < 0.05), increased PaO2 (140 ± 54, 209 ± 46, 269 ± 31, and 269 ± 54 mmHg, respectively, P < 0.05), and decreased the plasma levels of tumor necrosis factor-α (509 ± 252 in noNMBA, 200 ± 74 in CIS, and 175 ± 84 pg/ml in PAN; P < 0.05) and interleukin-6 (5789 ± 79, 1608 ± 534, and 2290 ± 315 pg/ml, respectively; P < 0.05). The use of CIS and PAN or silencing the receptor nAChRα1 resulted in decreased cytokine release in the human cells in response to a variety of stimuli mentioned earlier. CONCLUSIONS: The use of NMBA is lung protective through its antiinflammatory properties by blocking the nAChRα1.