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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., (© 2022. The Author(s).)

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 VCO 2 (EE in kcal/day = VCO 2  × 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.

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 (K 12  = 0.19 ± 0.02 and K 21  = 0.11 ± 0.01 in the AR group vs. K 12= 0.26 ± 0.01 and K 21  = 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.

Objective: To investigate the pharmacokinetics and pharmacodynamics of cisatracurium in patients undergoing surgery under acute normovolemic hemodilution (ANH) and acute hypervolemic hemodilution (AHH)., Methods: Ninety patients with orthopedic surgery were divided into ANH, AHH and control groups, which received hemodilution by hydroxyethyl starch 130/0.4 transfusion, Voluven transfusion and regular transfusion and infusion during surgery, respectively. Each group was divided into 3 sub-groups, administrated with cisatracurium at dosage of 0.1, 0.2 and 0.3mg/kg respectively. The changes in plasma protein, pH and electrolytes from the hemodilution beginning to surgery finish were monitored. Before and after cisatracurium administration, the phamocodynamic indicators of muscle relaxant were observed, and the plasma drug concentration was measured., Results: After hemodilution or regular transfusion, all three groups experienced a distinct drop in total plasma protein, albumin and pH. Compared with control group, the plasma concentrations of both K + and Ca 2+ in ANH and AHH groups significantly dropped (P<0.05), and those in each group after administration of cisatracurium also dropped, compared with before (P<0.05). After administration with cisatracurium, the onset time of muscle relaxation in AHH group was extended notably, compared with AHH and control groups (P<0.05), with no distinct difference of residual pharmacodynamics parameters (P>0.05). In the same hemodilution or regular infusion, with increase of drug dosage, the onset time of muscle relaxation was shortened, and the period of no response to train-of-four stimulation, muscle relaxation blockade duration and action time of muscle relaxation blockade in body were extended (P<0.05)., Conclusion: When using cisatracurium under AHH, the dosage should be increased appropriately, while it need not be adjusted under ANH., (Copyright © 2017 Elsevier Inc. All rights reserved.)

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., (© 2016 The British Pharmacological Society.)

The neuromuscular blocking agent cisatracurium is frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery. We aimed to determine the pharmacokinetics (PK)/pharmacodynamics (PD) of cisatracurium in patients with congenital heart defects (CHDs), such as ventricular septal defects and atrial septal defects, and to assess the effects of CHDs on the PK/PD profiles of cisatracurium. A modified two-compartment model with drug clearance from both compartments was best fitted to the PK data to determine the PK parameters. The model suggested that septal defects significantly lowered the rate of cisatracurium distribution from the central to peripheral compartment. The intercompartment rate constants k12 and k21 were significantly reduced (35%-60%, P < 0.05) in patients with ventricular septal defects and in patients with atrial septal defects compared with control patients. Consistently, septal defects caused a marked increase (160%-175%, P < 0.001) in the distribution half-life. Furthermore, significantly delayed pharmacodynamic responses to cisatracurium were observed in patients with septal defects. The onset time (i.e., the time to maximal neuromuscular block) was prolonged from 2.2 minutes to 5.0 minutes. PK/PD modeling suggested that reduced concentrations of cisatracurium in the effect compartment due to poorer distribution were the main cause of lagged pharmacodynamic responses. In conclusion, cisatracurium PK/PD were significantly altered in patients with septal defects. Our study should be of use in clinical practice for the administration of cisatracurium to patients with CHDs., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Pancuronium is a long-duration neuromuscular blocking drug (NMBD) that has been used in anesthetized rabbits at 0.1 mg/kg. However, there are limited data regarding the time course for recovery from this dose either spontaneously or with pharmacologic reversal. Here we defined the potency, onset, and recovery characteristics for the intermediate-duration NMBD cisatracurium and CW002 (a novel cysteine-inactivated molecule) in the rabbit, and test the hypothesis that these drugs may be alternatives to 0.1 mg/kg pancuronium for survival procedures. New Zealand white rabbits anesthetized with isoflurane were studied in a cross-over design. Potencies of cisatracurium and CW002 were defined as the effective dose for 95% depression of evoked muscle twitch (ED95). Responses to 3×ED95 were used to define onset (time to maximal effect), recovery index (RI; time from 25% to 75% recovery of twitch), and duration (time to complete recovery). Responses to all drugs were determined with and without reversal by neostigmine-glycopyrrolate or L-cysteine. CW002 was 4-fold more potent than was cisatracurium, but their onset, RI, and duration were similar. Pancuronium had similar onset and RI but longer duration, compared with cisatracurium and CW002. Reversal shortened the recovery index and duration for all 3 drugs. At 3×ED95, cisatracurium and CW002 had the same onset as did standard-dose pancuronium, but durations were shorter and more predictable. In addition, CW002 can be reversed without the potential side effects of cholinergic manipulation. We conclude that cisatracurium and CW002 are viable alternatives to pancuronium for survival studies in rabbits.

Background: Acute normovolemic hemodilution (ANH) is an efficacious blood conservation strategy for avoiding or reducing allogeneic blood transfusion. In a previous publication, on a different cohort of patients, we demonstrated that cisatracurium's potency and duration of action were not influenced by ANH, but we could not establish which role, if any, pharmacokinetics played., Methods: Forty patients were randomly allocated to the ANH or control groups. Patients received cisatracurium single 100 µg kg-1 bolus dose, serial arterial blood samples were collected and assayed for pharmacokinetic analysis., Results: Central and steady state apparent volumes of distribution (V1, Vdss) and slope factor (γ) were larger, effect-compartment concentration at 50% neuromuscular block was lower in the ANH (90.8±41.6 mL kg-1, 159.1±39.2 mL kg-1, 6.0±0.9 and 136.4±29.1 ng·mL-1) compared with the control group (65.5±26.1 mL kg-1, 134.8±31.8 mL kg-1, 5.5±0.8 and 158.5±26.0 ng·mL-1) respectively. Elimination half-life (t1/2 β) and mean residence time (MRT) were longer in the ANH (37.2±20.9, 23.5±13.2 min) than the control group (26.8±9.8, 16.9±6.2 min), albeit not statistically significant (P=0.051, P=0.051). There were no significant differences in distribution half-life (t1/2 α), effect-compartment equilibration rate-constant (keo), central and total clearances (Clc, Cl) between the ANH (2.4±1.2 min, 0.070±0.013 min-1, 6.1±1.9 mL kg-1 min-1 and 7.7±2.3 mL kg-1 min-1) and control group (1.9±1.2 min, 0.063±0.008 min-1, 7.0±1.8 mL kg-1 min-1 and 8.5±2.1 mL kg-1 min-1) respectively., Conclusion: ANH altered some pharmacokinetic parameters such as significantly larger volumes of distribution. Other parameters such as elimination half-life were considerably longer albeit not statistically significant.

This study was designed to compare the variability of the onset and offset of the effect of two neuromuscular blocking drugs with different elimination pathways in adult and elderly patients during total intravenous anesthesia (TIVA). After Ethics Committee approval and patients' informed consent, the drugs were compared in 40 adult and 40 elderly patients scheduled for elective surgery under TIVA with tracheal intubation who were randomized to receive a single bolus dose of 0.15 mg/kg cisatracurium or 0.9 mg/kg rocuronium. The time of onset of maximum depression, duration of action, and recovery index time were measured and recorded for each patient and variability is reported as means ± standard deviation. Time of onset was significantly shorter for rocuronium than cisatracurium for the adult and elderly groups (P = 0.000), but the variability of cisatracurium was significantly greater compared with rocuronium for the same age groups (93.25 vs 37.01 s in the adult group and 64.56 vs 33.75 s in the elderly group; P = 0.000). The duration of the effect in the elderly group receiving rocuronium was significantly longer than in the elderly group receiving cisatracurium, and the variability of the duration was significantly greater in the rocuronium group than in the cisatracurium group. Mean time of recovery was significantly longer for the elderly group receiving rocuronium than for the elderly group receiving cisatracurium (P = 0.022), and variability was also greater (P = 0.002). Both drugs favored good intubating conditions. In conclusion, cisatracurium showed less variability in these parameters than rocuronium, especially in the elderly, a fact that may be of particular clinical interest.

Aim: To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in critically ill patients with severe sepsis., Methods: Blood samples were collected before and over 8 h after a single bolus dose of cisatracurium 0.1 mg kg(-1) . Neuromuscular block was assessed by accelerometric peripheral nerve stimulation (TOF Watch). Plasma concentration and neuromuscular block data were fitted using population analysis., Results: Steady-state volume of distribution was determined to be 111 ± 71 ml kg(-1) and plasma clearance was 5.2 ± 1.8 ml min(-1) kg(-1) in these patients with greater inter-patient variability compared with other populations. The time to maximum block (8.3 ± 2.9 min) and delay time of transferring from central to effect compartment (17.2 min) was much longer, while the maximum block (95.0 ± 6.3%) was less compared with those in other patient populations. The effect compartment concentration resulting in 50% of maximum effect (128 ± 58 ng ml(-1)) was larger than previously described., Conclusions: This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. Use of a larger dose may overcome this reduced delayed response., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Cisatracurium undergoes primarily temperature and pH-dependent Hofmann elimination in humans. This study was conducted to describe the pharmacokinetics of cisatracurium in anesthetized dogs and determine whether its in vitro degradation rate in plasma is predictive of its in vivo elimination rate, as this is the case in humans. Nine dogs were anesthetized with pentobarbital and administered different bolus doses of cisatracurium in a randomized cross-over design. Arterial blood was collected at frequent intervals after each bolus injection. In vitro degradation rate (k(in vitro)) of cisatracurium was determined in each dog blank plasma. Plasma concentrations were determined by HPLC. Pharmacokinetic analyses were performed using two compartmental models assuming central or both central and peripheral elimination. Mean in vivo terminal elimination rate of cisatracurium (16.4 +/- 2.7 min) was twofold faster than mean in vitro degradation rate (32.9 +/- 3.7 min) in our dogs. Organ clearance was 6.12 +/- 1.69 mL/min.kg and accounted for 56 +/- 12% of the total body clearance. Apparent volume of distribution, an exit site-dependent parameter, averaged 212 or 184 mL/kg whether or not peripheral elimination was accounted for in the model. The in vitro rate of degradation in plasma is not of predictive value for the in vivo elimination rate of cisatracurium in anesthetized dogs. Organ clearance plays a more important role in the elimination of cisatracurium in dogs than in humans. Increased biliary excretion and/or presence of renal secretion are potential mechanisms that need to be explored.

The paper presents a new method for target control infusion (TCI) for neuromuscular blockade (NMB) level control of patients subject to general anaesthesia. The method combines an inversion of the pharmacokinetic/pharmacodynamic (PK/PD) model with a hybrid parameter estimation method that uses on-line data from the initial bolus response to estimate the model parameters. Although atracurium is considered as relaxant, the newly proposed method may be applied to other drugs for which the PK/PD model is available. Simulation results on a bank of 100 patient models are presented to demonstrate the achievable performance.

Objective: To evaluate and compare the efficacy, infusion rate and recovery profile of vecuronium and cisatracurium continuous infusion in critically ill children requiring mechanical ventilation., Design and Setting: Prospective, randomised, double-blind, single-centre study in critically ill children in a paediatric intensive care unit in a tertiary children's hospital., Methods: Thirty-seven children from 3 months to 16 years old (median 4.1 year) were randomised to receive either drug; those already receiving more than 6 h of neuromuscular blocking drugs were excluded. The Train-of-Four (TOF) Watch maintained neuromuscular blockade to at least one twitch in the TOF response. Recovery time was measured from cessation of infusion until spontaneous TOF ratio recovery of 70%., Results: The cisatracurium infusion rate in nineteen children averaged 3.9+/-1.3 microg kg(-1) min(-1) with a median duration of 63 h (IQR 23-88). The vecuronium infusion rate in 18 children averaged mean 2.6+/-1.3 microg kg(-1) min(-1) with a median duration of 40 h (IQR 27-72). Median time to recovery was significantly shorter with cisatracurium (52 min, 35-73) than with vecuronium (123 min, 80-480). Prolonged recovery of neuromuscular function (>24 h) occurred in one child (6%) on vecuronium., Conclusions: Recovery of neuromuscular function after discontinuation of neuromuscular blocking drug infusion in children is significantly faster with cisatracurium than vecuronium. Neuromuscular monitoring was not sufficient to eliminate prolonged recovery in children on vecuronium infusions.

A 41-year-old woman with end-stage renal insufficiency in peritoneal dialysis for 3 years received a kidney transplant under anesthesia with remifentanil, propofol, and cisatracurium. She had a history of hypertension and was being treated with enalapril, metoprolol and erythropoietin. After anesthetic induction, blood pressure fell significantly and surgery was performed in a context of hemodynamic stability. The postoperative course was good, with a functional graft and adequate diuresis from the start. Anesthetics with minimal residual effects and as little renal toxicity as possible are ideal for use in kidney transplantation. The drugs used in this case had pharmacokinetic and pharmacodynamic properties that make them particularly appropriate for such patients.

Study Objective: To examine the dose requirements and recovery profile of an infusion of cisatracurium during liver transplantation., Design: Open-label, descriptive study., Setting: University hospital., Patients: 6 ASA physical status III and IV patients with end-stage liver disease, undergoing liver transplantation., Interventions: Neuromuscular transmission was monitored electromyographically. After recovery of T1/T0 to 10%, cisatracurium was infused at an initial rate of 1.5 microg/kg/min. The infusion rate was adjusted to maintain T1/T0 at 10%. At the end of surgery, spontaneous recovery from the neuromuscular block was awaited., Measurements and Main Results: The infusion rate of cisatracurium was 1.6 +/- 0.4 microg/kg/min. Before the anhepatic phase, this rate was 1.5 +/- 0.4 microg/kg/min; during the anhepatic phase it was 1.7 +/- 0.5 microg/kg/min; and after reperfusion it was 1.9 +/- 0.4 microg/kg/min. There was a significant difference between the cisatracurium infusion rates before and after the anhepatic phase (p < 0.05). Following termination of the infusion, the time to 25% recovery of T1/T0 was 19.2 +/- 6.1 minutes, the recovery index (25% to 75%) was 28.8 +/- 7.0 minutes, and the time for the train-of-four (TOF) ratio to reach 0.7 was 50.2 +/- 7.1 minutes. The time for the TOF ratio to reach 0.9 was 61.4 +/- 6.6 minutes. There was no difference in body temperature or pH during the consecutive stages of transplantation., Conclusions: The infusion dose requirement for cisatracurium during liver transplantation tended to be higher than previously reported in healthy patients; recovery appeared prolonged. In continuous infusion of cisatracurium during liver transplantation, the tendency toward higher dose requirements, the protracted duration of infusion, the non-Hofmann elimination and/or other pharmacokinetic changes during transplantation might influence recovery from the neuromuscular block. Potential temperature or pH change during surgery seemed irrelevant in explaining the delayed recovery.

Unlabelled: Continuous neuromuscular blockade is often necessary in patients being treated for acute respiratory distress syndrome (ARDS) to optimize oxygenation. In this study, neuromuscular blockade (no response to two responses at the train-of-four stimulation at the orbicularis oculi muscle) was achieved in six patients with ARDS by a continuous infusion of cisatracurium. The plasma concentration of cisatracurium during the infusion averaged 1.00 (0.25-1.45) microg/mL, expressed as median (range). The clearance and half-life were 6.5 (3.3-7.6) mL. min(-1). kg(-1) and 25 (16-48) min, respectively. The laudanosine plasma concentrations were 0.70 (0.12-1.20) microg/mL. The pharmacokinetic variables of cisatracurium are similar to those of patients without organ failure undergoing elective surgery. Plasma laudanosine levels always remained well less that those associated with seizure activity in animal models. Long-term infusion of cisatracurium was not associated with any side effects. Cisatracurium is a suitable muscle relaxant when deep and continuous levels of muscle relaxation are required in patients treated for ARDS., Implications: We studied the pharmacokinetics of cisatracurium in six patients treated for respiratory distress syndrome by continuous muscle relaxation. A deep degree of neuromuscular blockade corresponding to abolition of two responses at the orbicularis oculi to train-of-four stimulation was obtained in all patients. The pharmacokinetic variables observed in these severely ill patients were similar to those of anesthetized patients. No accumulation of laudanosine was seen. Cisatracurium appears to be suitable when continuous muscle relaxation is required in critically ill patients.

Objective: Study of the recovery of neuromuscular block after continuous infusion of cisatracurium in patients with renal dysfunction., Study Design: Prospective case-control study., Patients: Forty adult patients scheduled for urological surgery were assigned to two groups according to the creatinine clearance (CC) as a measure of the renal function: group IR (CC < 60 mL.min-1) or group NR (CC > or = 60 mL.min-1)., Methods: After premedication with hydroxyzine, anaesthesia was induced with propofol, sufentanil and cisatracurium (0.15 mg.kg-1), and maintained using isoflurane, sufentanil and a continuous infusion of cisatracurium (0.12 mg.kg-1.h-1) adjusted for maintained a post-tetanic count < or = 5. Neuromuscular transmission was monitored at the adductor pollicis using accelerography (TOF Gard). Onset and recovery times in both groups were compared using Student's t test., Results: Infusion time and total dose of cisatracurium were comparable in both groups. Onset times were 3.9 +/- 0.8 min and 3.5 +/- 0.6 min in groups IR and NR respectively. After the infusion, the time to train-of-four ratio of 0.8 were not different in both groups: 77 +/- 18 min (group IR) and 73 +/- 13 min (group NR). However, the spontaneous recovery intervals 25%-75% were delayed in group IR (20 +/- 9 min vs 14 +/- 5 min p < 0.05)., Conclusion: There are minor differences in the pharmacodynamics of cisatracurium between patients with normal or impaired renal function. Nevertheless, a marked interindividual variability in the recovery parameters was observed in patients with renal dysfunction.

Objectives: To assess the effect of four anesthetic techniques on recovery after a single dose of 0.2 mg/kg of cisatracurium., Patients and Method: After giving informed consent, 96 patients of both sexes, ASA I-III, were enrolled. Anesthesia was induced with fentanyl, propofol O2-N2O (FiO2 40%) after which the patients were randomly assigned to four groups according to maintenance technique: propofol by infusion, sevoflurane, desflurane or isoflurane at 1.3 MAC. Neuromuscular block was monitored (electromyographic recording of the pollicis adductor). Variables recorded were time of maximum block, duration of action of 1% and 25%, and recovery indices at T0-TR75 andT25%-T75%. ANOVA was performed ( = 0.05 and beta = 0.1)., Results: The groups were homogeneous. Time until recovery of 25% of baseline amplitude of the first response to a train of four (TOF) (T1) was longer in the desflurane group (68.4 +/- 11.1 min) than in the propofol group (60.2 +/- 9.4 min; p < 0.05). Time until recovery of 75% of the TOF-ratio was longer in the sevoflurane (96.8 +/- 13.1 min), desflurane (101.5 +/- 14.4 min) and isoflurane (94.1 +/- 13.9 min) groups than in the propofol group (83.7 +/- 1.3 min) (p < 0.0001). Times until recovery of T1 up to 1% were not statistically different: 45.8 +/- 10.7 (propofol), 50.6 +/- 11.0 (sevoflurane), 51.3 +/- 11.5 (desflurane) and 46.5 +/- 11.2 min (isoflurane). The 25% - 75% recovery index was also similar at 19.0 +/- 9.3 (propofol), 20.0 +/- 5.1 (sevoflurane), 25.7 +/- 12.4 (desflurane) and 20.9 +/- 7.9 (isoflurane)., Conclusions: The inhaled anesthetics studied prolong the duration of clinical effect of cisatracurium more than does propofol.

Background: The comparative clinical pharmacology of cisatracurium and rocuronium and their combinations has not been reported. In this study, the authors compared the relative potency and the clinical profile and characterized the interaction of both drugs., Methods: Two hundred twenty adults classified as American Society of Anesthesiologists physical status I and anesthetized with propofol-fentanyl-nitrous oxide were studied. In part 1, the neuromuscular-blocking effects of cisatracurium and rocuronium were assessed after administration of bolus doses of 20-50 microg/kg and 100-300 microg/kg, respectively. In part 2, we compared the time course of 1xED50, 1, 1.5, and 2xED95 doses of both drugs (where ED50 and ED95 are, respectively, the doses producing 50% and 95% depression of the first twitch height [T1]). In part 3, equieffective combinations of both drugs were studied to characterize their interaction., Results: The calculated ED50 values and their 95% confidence intervals were 111 (107-115) and 26.2 (25.8-26.5) microg/kg [corrected] for rocuronium and cisatracurium, respectively. Compared with equipotent doses of cisatracurium, rocuronium had a faster onset, and a faster spontaneous T1 and train-of-four recovery times that were significant except at maximum recovery with the 2xED95 dose. The interaction between rocuronium and cisatracurium was synergistic, and the time profile of the combination group was different from that of the single-dose groups., Conclusions: Cisatracurium is four to five times more potent than rocuronium. Rocuronium had a faster onset of action, a shorter clinical duration, and a faster spontaneous recovery rate compared with equipotent doses of cisatracurium.

Unlabelled: Fourteen patients, ASA physical status I or II, were recruited to assess the pharmacokinetic-pharmacodynamic relationship of cisatracurium under nitrous oxide/sufentanil/propofol anesthesia. The electromyographic response of the abductor digiti minimi muscle was recorded on train-of-four stimulation of the ulnar nerve. A 0.1-mg/kg dose of cisatracurium was given as an infusion over 5 min. Arterial plasma concentrations of cisatracurium and its major metabolites were measured by using high-performance liquid chromatography. A nontraditional two-compartment pharmacokinetic model with elimination from central and peripheral compartments was used. The elimination rate constant from the peripheral compartment was fixed to the in vitro rate of degradation of cisatracurium in human plasma (0.0237 min(-1)). The mean terminal half-life of cisatracurium was 23.9+/-3.3 min, and its total clearance averaged 3.7+/-0.8 mL x min(-1) x kg(-1). Using this model, the volume of distribution at steady state was significantly increased compared with that obtained when central elimination only was assumed (0.118+/-0.027 vs 0.089+/-0.017 L/kg). The effect-plasma equilibration rate constant was 0.054+/-0.013 min(-1). The 50% effective concentration (153+/-33 ng/mL) was 56% higher than that reported in patients anesthetized with volatile anesthetics, which suggests that, compared with inhaled anesthetics, a cisatracurium neuromuscular block is less enhanced by propofol., Implications: The drug concentration-effect relationship of the muscle relaxant cisatracurium has been characterized under balanced and isoflurane anesthesia. Because propofol is now widely used as an IV anesthetic, it is important to characterize the biological fate and the concentration-effect relationship of cisatracurium under propofol anesthesia as well.

The dose proportionality of cisatracurium pharmacokinetics was assessed using a population approach by incorporating the collection of sparse blood samples from patients in clinical trials. Plasma concentration-time data from 131 patients with limited concentration-time data and 38 patients with full sampling were pooled and analyzed using nonlinear mixed-effects modeling (NONMEM). Dose proportionality was assessed using dichotomous parameterization and a linear model. The population pharmacokinetic approach revealed that the pharmacokinetics of cisatracurium are independent of dose between 0.1 mg/kg and 0.4 mg/kg, as was expected based on the importance of Hofmann elimination, a chemical process dependent on pH and temperature.

Cisatracurium (51W89) is one of the ten stereoisomers of atracurium, accounting for about 15% of the racemate. The ED95 of cisatracurium was determined to be about 50 micrograms/kg (cation, molecular weight 929), while the ED95 of atracurium (besylate salt, molecular weight 1245) was 250 micrograms/kg. Thus, on a molar basis in adult patients, cisatracurium is about 3.5 times as potent as the racemic atracurium mixture. We compared atracurium with cisatracurium in healthy adult patients and found an almost identical pharmacodynamic profile. In children, an ED95 of about 40 micrograms/kg was determined, while a 1-min-longer onset of cisatracurium was found in geriatric than in young adult patients. The presence of chronic renal failure did not prolong the duration of action of cisatracurium. The recovery of neuromuscular transmission from a cisatracurium infusion of up to 145 h was investigated in intensive care unit patients. Their time from the end of infusion to a train-of-four ratio > 0.7 (68 +/- 18 min) was on average only some 70% longer than after an infusion of cisatracurium for 2 h in normal surgical patients. In another study, no signs of histamine release nor any clinically relevant cardiovascular effects of cisatracurium were found in doses up to eight times ED95.

Cisatracurium besilate (besylate) is a nondepolarising neuromuscular blocking agent with an intermediate duration of action. It is the R-cis, R'-cis isomer of atracurium besilate and is approximately 3-fold more potent than the mixture of isomers that constitute the parent drug. The ED95 for cisatracurium besilate (dose required to produce 95% suppression of twitch response to nerve stimulation) in adults is 0.05 mg/kg during N2O/O2 opioid anaesthesia. As for atracurium besilate, the primary route of elimination of cisatracurium besilate is by spontaneous degradation. Cisatracurium besilate is not associated with dose-related histamine release (at bolus doses of < or = 8 x ED95) and, consistent with this, has demonstrated cardiovascular stability in both healthy patients (< or = 8 x ED95) and those with coronary artery disease (< or = 6 x ED95). In clinical trials, cisatracurium besilate has been used successfully to facilitate intubation (at 2 to 4 x ED95) and as a muscle relaxant during surgery and in intensive care. Compared with vecuronium, cisatracurium besilate was associated with a significantly faster recovery after continuous infusion in patients in intensive care. Relative to atracurium besilate, cisatracurium besilate has a lower propensity to cause histamine release is more potent but has a slightly longer onset time at equipotent doses. It also offers a more predictable recovery profile than vecuronium after prolonged use in patients in intensive care. Thus, comparative data provide some indication of the potential of cisatracurium besilate as an intermediate-duration neuromuscular blocking agent but further comparisons with other like agents are required to define precisely its relative merits.

Rocuronium and cisatracurium are the two most recent muscle relaxant additions to our pharmacopocia. These two drugs are significant advances and are likely to have an increasingly important role in clinical anaesthesia in the future.

Purpose: The population PK/PD approach was prospectively used to determine the PK/PD of cisatracurium in various subgroups of healthy surgical patients., Methods: Plasma concentration (Cp) and neuromuscular block data from 241 patients in 8 prospectively-designed Phase I-III trials were pooled and analyzed using NONMEM. The analyses included limited Cp-time data randomly collected from 186 patients in efficacy/safety studies and full Cp-time data from 55 patients in pharmacokinetic studies. The effects of covariates on the PK/PD parameters of cisatracurium were evaluated. The time course of neuromuscular block was predicted for various patient subgroups., Results: The population PK/PD model for cisatracurium revealed that anesthesia type, gender, age, creatinine clearance, and presence of obesity were associated with statistically significant (p < 0.01) effects on the PK/PD parameters of cisatracurium. These covariates were not associated with any clinically significant changes in the predicted recovery profile of cisatracurium. Slight differences in onset were predicted in patients with renal impairment and patients receiving inhalation anesthesia. Based on the validation procedure, the model appears to be accurate and precise., Conclusions: The prospective incorporation of a population PK/PD strategy into the clinical development of cisatracurium generated information which influenced product labeling and reduced the number of studies needed during development.

Cisatracurium, one of 10 isomers of atracurium, undergoes pH and temperature-dependent Hofmann elimination in plasma and tissues. The clearance of cisatracurium due to Hofmann elimination and organ elimination was estimated by applying a nontraditional two-compartment pharmacokinetic model with elimination occurring from both compartments to plasma cisatracurium concentration-time data from 31 healthy adult surgical patients with normal renal and hepatic function. The elimination rate constant from the central compartment, intercompartmental rate constants, and the volume of the central compartment were obtained from the model fit. The elimination rate constant from the peripheral compartment could not be independently estimated in vivo and was therefore fixed to the rate of degradation of cisatracurium in human plasma (pH 7.4 and 37 degrees C) and held constant in the model. Total body clearance, Hofmann clearance, organ clearance, and the volume of distribution at steady-state were derived from the model parameter estimates. Renal clearance was calculated from cisatracurium urinary excretion data from 12 of the 31 patients. Clearance values (mean +/- SD) were 5.20 +/- 0.86, 4.00 +/- 1.04, 1.20 +/- 0.71, and 0.85 +/- 0.32 mL.min-1.kg-1 for total body clearance, Hofmann clearance, organ clearance, and renal clearance, respectively. Hofmann clearance accounted for 77% of total body clearance. Organ clearance was 23% of total body clearance. Renal clearance, a component of organ clearance, was 16% of total body clearance. The organ-independent nature of the elimination of cisatracurium was characterized by a relationship between steady-state volume of distribution and total body clearance. The half-life is an independent variable and is not dependent on the total body clearance nor the steady-state volume of distribution. Hofmann elimination is the predominant pathway for cisatracurium elimination in humans.