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Background: Profound neuromuscular block (NMB) is important in surgeries where complete immobility is considered essential to improve tracheal intubation and surgical conditions. Rocuronium bromide is a commonly used NMB agent. This work describes a noninvasive approach for estimation of post-tetanic count (PTC) based on two pharmacokinetic (PK) models, the Saldien and the De Haes models. The aim was to investigate the rocuronium bromide PK-pharmacodynamic (PD) relationship in estimating the PTC effect during profound NMB., Methods: In this prospective, non-randomised, observational study, an induction bolus of rocuronium bromide was administered followed by continuous infusion for maintenance of a PTC of 1-2. measured every 3 min. Measurements were analysed as discrete categorical data and by applying the nonlinear mixed-effect modelling approach. Performance of the selected models was evaluated through simulation model-based diagnostics, further assessing the precision of the parameter estimates and the performance of the models at the individual level., Results: Data from 30 adult patients undergoing elective abdominal or neurosurgical procedures were included. Post-tetanic count response profiles during rocuronium bromide infusion were successfully characterised using the population PD analysis. The models showed a good performance for all PTC categories, albeit with a moderate over-prediction of PTC >6., Conclusions: Our findings indicate that using plasma concentrations of rocuronium bromide estimated with either of the two models, combined with a PD model, provides equal model performance when predicting PTC. These promising results may provide an important advance in guiding rocuronium bromide administration when profound NMB in routine clinical practice is desired., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

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.

Background: CW002 is an investigational nondepolarizing, neuromuscular blocking agent with a rapid onset and intermediate duration of action in animals. This is a single ascending dose, healthy subject study exploring tolerability, pharmacokinetics, and potency., Methods: Population pharmacokinetic and pharmacokinetic/pharmacodynamic models were developed using plasma drug concentration data from a previously published dose-response study in 28 healthy subjects receiving single doses of CW002 during sevoflurane anesthesia. Subjects included in the models were from five different dose cohorts (cohorts 3, 4, 5, 6, and 8 receiving 0.04, 0.06, 0.08, 0.10, and 0.14 mg/kg, respectively). Serial arterial plasma concentrations and muscle twitch heights were monitored., Results: A four-compartment model was fit to the concentration-time data, whereas a transit compartment with a sigmoid Emax model was fit to the pharmacokinetic/pharmacodynamic data. The population pharmacokinetics of CW002 was linear with very low interindividual variability in clearance (10.8%). Simulations were conducted to predict the onset and offset of effect at 2×, 3×, and 4× ED95. The time to 80% block was predicted to be 1.5, 0.8, and 0.7 min for 2×, 3×, and 4× ED95 doses, respectively. The simulated 25 to 75% recovery index was independent of dose., Conclusions: CW002 has predictable pharmacokinetics and is likely to have a rapid onset with an intermediate duration of action at 3× ED95. This model provides information to inform critical decisions (e.g., dose, study design) for continued development of CW002.

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 aim of the presented review is to highlight the clinical problem of postoperative residual curarization (PORC) following general anaesthesia in the elderly. Possible complications of PORC are described along with age-induced changes in pharmacokinetics of long and intermediate-acting neuromuscular blocking agents. This is intended to facilitate the selection and to promote appropriate intraoperative use of muscle relaxants in patients over the age of 65 years.

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: Burn patients develop resistance to non-depolarizing neuromuscular blocking agents (NDNMBAs) and require a significantly large dose to produce a desired clinical response. Pathophysiological changes related to burn injury may alter pharmacokinetics (PK) and pharmacodynamics of NDNMBAs. The purpose of this study was to compare vecuronium PK in burns vs non-burns., Methods: Twenty adults, aged 23-58 yr, with 27-81% total body surface area (TBSA) burn, were studied at 4-57 post-burn days and compared with age- and sex-matched, non-burn controls. Vecuronium 0.12 mg kg(-1) was given i.v. as a single bolus within 10 s. Blood samples (n=20) were collected over 12 h at predetermined time points. NONMEM was used to describe plasma drug concentration-time profiles for burns and non-burns., Results: A three-compartment model best described vecuronium concentration-time profiles. Burn patients showed enhanced distributional clearance at the terminal phase (0.12 vs 0.095 litre min(-1), P<0.0001), which yielded shorter elimination half-life for vecuronium (5.5 vs 6.6 h, P<0.001). BURN was the single most significant covariate that explained the altered vecuronium disposition in burns., Conclusions: The altered drug distribution between tissues may partially explain the known resistance to vecuronium in patients with major burns.

Background: The onset time for paralysis varies 3-fold among nondepolarizing muscle relaxants. Possible explanations include: (a) pharmacokinetic differences among drugs and (b) buffering of drug molecules by acetylcholine receptors as they diffuse into the neuromuscular junction. Although some pharmacokinetic models consider buffered diffusion, these models do not account for either the high density of receptors or synapse geometry. Here, I used computer simulations to calculate the kinetics of buffered diffusion. The goal was to determine the conditions under which buffered diffusion could account for differences in onset time among nondepolarizing muscle relaxants., Methods: Monte Carlo simulation was used along with a realistic 3-dimensional model of the rat neuromuscular junction. Simulations determined the time dependence of the number of drug-bound receptors. A 1000-fold range of drug potency was examined. In some simulations, the drug concentration outside the junction was changed instantaneously. In other simulations, the concentration changed according to predictions of pharmacokinetic models assuming time-dependent changes in plasma drug concentration. The rate constant for equilibration of drug between plasma and muscle, keo, was varied between 0.15 and 0.6 min(-1). Twitch amplitude was calculated from receptor occupancy assuming a high safety margin for neuromuscular transmission. Some simulations used a synaptic model with an increased nerve-muscle contact width., Results: Simulations with instantaneous changes in drug concentration at the synapse, indicated that the time to 50% twitch depression (onset time) was 0.1 to 30 seconds and was proportional to drug potency. This corresponds to iontophoretic application of drug to isolated neuromuscular junctions, but is too fast to explain onset times in humans. When pharmacokinetic models were used to calculate the drug concentration outside the synapse, buffered diffusion increased onset times of potent drugs (drugs for which the effective concentration at 50% twitch height is <600 nM). Simulations using keo = 0.6 min(-1) and a model with a 2- to 3-fold wider nerve-muscle contact width indicated that buffered diffusion could account for the differences in clinical onset times among the nondepolarizing muscle relaxants., Conclusion: Monte Carlo simulation provides a biophysically appropriate way to incorporate buffered diffusion into pharmacokinetic modeling. The simulations indicated that buffered diffusion could account for differences in onset time among drugs. However, a better understanding of the geometry of the human neuromuscular junction is needed before the magnitude of the effect of buffered diffusion can be quantified.

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.)

Developing a non-depolarizing neuromuscular blocking agent that, like succinylcholine, has a rapid onset and a short duration of effect remains a goal of ongoing research. While rocuronium fills a portion of this need, the large doses required for rapid intubation render it a much longer-acting neuromuscular blocking agent. Postoperative residual neuromuscular block (NMB) is an increasingly recognized complication of non-depolarizing neuromuscular blocking agents. This occurs because of dosing choices for neuromuscular blocking agents and anticholinesterases as well as insensitivity of typically used monitors of depth of NMB. While antagonism of NMB is necessary with partial recovery, it is unnecessary with more complete recovery. Even when monitoring with an accelerograph, reversal of NMB is complicated. In addition to the pharmacodynamics of the individual neuromuscular blocking agents, factors such as timing of anticholinesterase administration, dose of anticholinesterase, concomitant medications, electrolyte abnormalities, and hepatic or renal disease can influence the degree of reversal. Sugammadex works differently than anticholinesterases and, when administered in appropriate doses, can reverse even profound block induced with vecuronium or rocuronium. Two new fumarate neuromuscular blocking agents have a rapid onset of effect and can be reversed at any time by administration of cysteine, which could significantly reduce the risk of postoperative residual NMB.

Anaesthesiologists must be prepared to deal with pharmacokinetic and pharmacodynamic (PD) differences in morbidly obese individuals. As drug administration based on total body weight can result in overdose, weight-based dosing scalars must be considered. Conversely, administration of drugs based on ideal body weight can result in a sub-therapeutic dose. Changes in cardiac output and alterations in body composition affect the distribution of numerous anaesthetic drugs. With the exception of neuromuscular antagonists, lean body weight is the optimal dosing scalar for most drugs used in anaesthesia including opioids and anaesthetic induction agents. The increased incidence of obstructive sleep apnoea and fat deposition in the pharynx and chest wall places the morbidly obese at increased risk for adverse respiratory events secondary to anaesthetic agents, thus altering the PD properties of these drugs. Awareness of the pharmacology of the commonly used anaesthetic agents including induction agents, opioids, inhalation agents and neuromuscular blockers is necessary for safe and effective care of morbidly obese patients.

There have been great advancements in cardiac surgery over the last two decades; the widespread use of off-pump aortocoronary bypass surgery, minimally invasive cardiac surgery, and robotic surgery have also changed the face of cardiac anaesthesia. The concept of "Fast-track anaesthesia" demands the use of nondepolarising neuromuscular blocking drugs with short duration of action, combining the ability to provide (if necessary) sufficiently profound neuromuscular blockade during surgery and immediate re-establishment of normal neuromuscular transmission at the end of surgery. Postoperative residual muscle paralysis is one of the major hurdles for immediate or early extubation after cardiac surgery. Nondepolarising neuromuscular blocking drugs for cardiac surgery should therefore be easy to titrate, of rapid onset and short duration of action with a pathway of elimination independent from hepatic or renal dysfunction, and should equally not affect haemodynamic stability. The difference between repetitive bolus application and continuous infusion is outlined in this review, with the pharmacodynamic and pharmacokinetic characteristics of vecuronium, pancuronium, rocuronium, and cisatracurium. Kinemyography and acceleromyography are the most important currently used neuromuscular monitoring methods. Whereas monitoring at the adductor pollicis muscle is appropriate at the end of surgery, monitoring of the corrugator supercilii muscle better reflects neuromuscular blockade at more central, profound muscles, such as the diaphragm, larynx, or thoraco-abdominal muscles. In conclusion, cisatracurium or rocuronium is recommended for neuromuscular blockade in modern cardiac surgery.

Background: Among the factors influencing the onset of action of neuromuscular blocking agents (NMBA), the potency (EC50) and the rate of equilibration between blood and the effect compartment (k(e0)) have been highlighted. Although these descriptors are intrinsically influenced by the physicochemical characteristics of the drug, the impact of lipid solubility, molecular weight and protein binding on pharmacokinetic-pharmacodynamic (PK-PD) descriptors has not been established for most NMBA., Methods: The octanol/phosphate buffer distribution coefficients (logD) of various NMBA (vecuronium, rocuronium, mivacurium isomers (cis-cis, cis-trans and trans-trans), doxacurium, cisatracurium, atracurium, succinylcholine) were determined. The free fraction for each drug was measured using an ultrafiltration technique. PK-PD descriptors were obtained from selected clinical studies. Correlations between physicochemical parameters (including molecular weight) and PK-PD descriptors were assessed by linear or multiple linear regression., Results: A wide range of log D (-4.15 for succinylcholine to 0.75 for vecuronium) and free fraction (from 31% for vecuronium to 80% for succinylcholine) is observed for NMBA. Molecular weight combined with either lipid solubility (r2=0.70; P=0.001) or free fraction (r2=0.84; P<0.001) were highly correlated with potency, while for k(e0) a greater degree of correlation was obtained when both lipid solubility and free fraction (r2=0.74; P=0.002) were included., Conclusions: The basic characteristics of NMBAs, namely, molecular weight, lipid solubility and protein binding, are strongly associated with the kinetics of the drug response.

Background: A model of an antegrade, perfused, isolated rat peroneal nerve anterior tibial muscle was developed to study potentially important factors governing the time course of action of (nondepolarizing) neuromuscular blocking agents such as concentration, blood flow, and temperature. The model allows observation of the effects of selective changes in these factors., Methods: The authors isolated the anterior tibial muscle and cannulated the anterior tibial artery and vein, providing a way for single-pass perfusion with blood from a donor rat. A force transducer was connected to the tibialis anterior muscle and a stimulator was connected to the tibial nerve. The influence of intrinsic potency (EC90) and muscle blood flow rate on the time course of pancuronium and rocuronium was investigated., Results: The model remained stable for at least 4 h with respect to twitch height, muscle structure and function, and blood chemistry. Doubling the muscle-blood flow resulted in a significantly faster onset and offset for both pancuronium and rocuronium. Trebling the intrinsic potency (EC90) was not associated with significant changes in the time course of action of the relaxants., Conclusion: The authors developed and validated a model that allows us to study biophase kinetics of neuromuscular blocking agents in the anterior tibial muscle of the rat. In this model, muscle-blood flow rather than EC90 appears to predominantly determine the onset and offset time of nondepolarizing muscle relaxants.

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.

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.

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.

The degree of twitch depression induced by nondepolarizing neuromuscular blocking drugs is known to be dependent on the stimulation frequency employed. Train-of-four (TOF) stimulations with different frequencies (0.67, 1.33 and 2.0 Hz) were delivered to a sciatic nerve of a rat and series of four twitch heights of a tibialis anterior muscle were measured after d-tubocurarine (d-TC) administration. With a decrease of stimulus interval, twitch heights were intensely depressed. We hypothesized that the oservations are due to the changes of released amount of neuromuscular transmitter, acetylcholine, dependent on stimulus interval, and a pharmacokinetic/pharmacodynamic model based on the hypothesis was proposed. The model allowed simultaneous fitting of the twitch height depression after d-TC administration. It also could give a rationale to the fact that TOF stimulation at 2.0 Hz is a more sensitive monitoring method of neuromuscular function than single twitch stimulation (0.1-0.2 Hz).

The degree of train-of-four (TOF) fade, i.e., the reduction of the fourth to the first twitch height in a train, induced by d-tubocurarine (d-TC) and alpha-bungarotoxin (alpha-BX) was investigated. The fade induced by d-TC was pronounced in comparison with that by alpha-BX, and the difference was analyzed using a kinetic model. Based on the assumptions: (1) Acetylcholine (ACh) binds to the nicotinic receptor and evokes twitch response. (2) The amount of released ACh is dependent on stimulus interval. (3) d-TC interacts competitively with the receptor. (4) alpha-BX interacts irreversibly with the receptor. It was suggested that the fade by d-TC and alpha-BX can be explained by the difference of the receptor occupancy by ACh which was caused by different interaction mechanisms of the two muscle relaxants with receptors.

The pharmacokinetics, biodisposition, and neuromuscular blocking properties of 3-desacetylvecuronium were studied in 17 adult cats. Animals were divided into three groups: five cats with kidney failure induced by bilateral ligation of the renal pedicles, six cats with galactosamine-induced fulminant hepatitis, and six control cats. An intravenous bolus of 300 micrograms.kg-1 of 3-desacetylvecuronium was rapidly injected into the jugular vein. Arterial blood, urine, and bile samples were collected at regular intervals for 6 h in control cats and for 8 h in cats with kidney or liver failure. The liver was excised for analysis at the end of the experiment. In cats with renal failure, 3-desacetylvecuronium pharmacokinetic and pharmacodynamic variables did not differ from those in control cats. In cats with liver failure, plasma clearance was significantly less and mean residence time greater than in control cats (2.8 +/- 0.6 vs. 14.1 +/- 6.5 ml.kg-1.min-1 and 334 +/- 225 vs. 49 +/- 29 min, mean +/- SD, respectively). Volume of distribution at steady state in cats with liver failure and in control cats was not different. Also, in cats with liver failure, the duration of action and recovery index of 3-desacetylvecuronium was significantly greater than in control cats (168 +/- 62 vs. 82 +/- 32 min, and 39 +/- 19 vs. 10 +/- 4 min, respectively). Onset time of neuromuscular blockade was similar in all three groups. Total recovery of 3-desacetylvecuronium, for all three groups, in urine, bile, and liver was 90 +/- 11% (mean +/- SD). In control cats, 70 +/- 18% of 3-desacetylvecuronium was recovered in bile and liver and 19 +/- 14% in urine. No 3,17-bidesacetylvecuronium (a putative 3-desacetylvecuronium metabolite) was detected.(ABSTRACT TRUNCATED AT 250 WORDS)

The pharmacokinetics of pipecuronium 0.07 mg kg-1 and pancuronium 0.1 mg kg-1 were compared in 39 ASA class I or II patients. Plasma concentrations of these agents were measured for 6 h following administration, using a sensitive and specific capillary gas chromatographic assay. Concentration v. time data were analysed by non-linear regression and fitted to a two- or three-compartment model as appropriate. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. Pipecuronium had a larger steady-state volume of distribution (Vss) (309 (SD 103) ml kg-1) and greater plasma clearance (Cl) (2.4 (0.6) ml kg-1 min-1) than pancuronium (199 (54) ml kg-1 and 1.5 (0.4) ml kg-1 min-1, respectively). The volumes of the central compartment, distribution and elimination half-lives and mean residence times were similar for both agents and within the range expected for drugs of this type. The durations of action (injection to 25% recovery of twitch tension) of pipecuronium and pancuronium were similar: 98.0 (36.1) min and 117.2 (35.8) min, respectively. We conclude that the time courses of neuromuscular blockade following pipecuronium and pancuronium are similar, despite the differences in Vss and Cl.

The authors determined the pharmacokinetics and duration of action of a bolus dose of pipecuronium bromide (0.07 mg.kg-1) in 40 patients anesthetized with halothane and nitrous oxide. Twenty were patients with normal renal function, undergoing a variety of surgical procedures, and 20 were undergoing cadaver renal transplantation because of end-stage renal disease. Plasma concentrations of pipecuronium were measured for 6 h after administration using a sensitive and specific capillary gas chromatographic assay. Plasma concentration versus time data were analyzed by nonlinear regression and fit to a two-compartment or three-compartment model; in addition, the data were analyzed by a non-compartmental method based on statistical moments. Neuromuscular blockade was assessed by measuring the mechanical evoked response of the adductor pollicis muscle to train-of-four stimulation of the ulnar nerve. The pharmacokinetic parameters derived by compartmental modelling were (normal vs. renal failure, respectively): volume of distribution at steady state (309 +/- 103 vs. 442 +/- 158 ml.kg-1, mean +/- SD), plasma clearance, (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (140 +/- 63 vs. 329 +/- 198 min), and elimination half-life (137 +/- 68 vs. 263 +/- 168 min). The same parameters as derived by the non-compartmental method were (normal vs. renal failure, respectively): volume of distribution at steady state (307 +/- 80 vs. 426 +/- 119 ml.kg-1, mean +/- SD), plasma clearance (2.4 +/- 0.6 vs. 1.6 +/- 0.6 ml.kg-1.min-1), mean residence time (134 +/- 41 vs. 323 +/- 228 min), and elimination half-life (118 +/- 35 vs. 247 +/- 168 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic muscle disuse decreases the sensitivity of skeletal muscle to nondepolarizing relaxants, such as metocurine (MTC). In this study, the authors determined whether chronic conditioning would produce the opposite effect and increase the sensitivity of skeletal muscle to MTC. Five dogs were exercised by daily running over a period of 5 weeks. At the conclusion of this training period, a pharmacokinetic and pharmacodynamic study of the MTC dose-response relationship was performed. The same analysis was performed on four dogs housed in the same kennel who did not undergo conditioning. Neuromuscular blockade was measured and recorded bilaterally in both gastrocnemius muscles while the animal was anesthetized with nitrous oxide and pentobarbital, 30 ml.kg-1. Plasma concentrations of MTC were measured by radioimmunoassay. The MTC concentration estimated in the effect compartment which produced 50% paralysis was 0.114 +/- 0.008 micrograms.ml-1 (mean +/- SD) in exercised dogs and 0.189 +/- 0.038 micrograms.ml-1 in nonexercised dogs, which was significant at P less than 0.005). The MTC concentration versus response curves were parallel. This supports the authors' hypothesis that exercise increases sensitivity to the nondepolarizing muscle relaxant metocurine.

The pharmacokinetics of pipecuronium bromide have been studied in anesthetized beagle dogs with and without ligated renal pedicles. A gas chromatographic assay was used to measure the plasma, urine, bile concentrations, and liver content of pipecuronium, the later of which was obtained 8 h after injection. Following an iv bolus injection of 0.1 mg/kg, pipecuronium disappeared from the plasma exponentially with distribution half-lives of 3.9 +/- 1.1 min and 12.7 +/- 9.5 min (mean +/- SD), and elimination half-lives of 44.8 +/- 2.6 min and 196.7 +/- 102.0 min in animals with and without renal pedicle ligation, respectively. Except for the volume of central compartment, all other pharmacokinetic variables differed significantly between the two experimental groups. The elimination half-life was longer (196.7 +/- 102 (SD) vs. 44.8 +/- 2.6 min), plasma clearance slower (5.9 +/- 0.8 ml.kg-1.min-1 vs. 0.9 +/- 0.1 ml.kg-1.min-1) and mean residence time longer (221 +/- 73 vs. 51.1 +/- 1.8 min) in dogs with ligated renal pedicles. Eight hours after injection, the recovery of the parent form of pipecuronium approximated 77% of the administered dose in the urine, 4.5% in the bile, and 3.3% in the liver of normal animals. In animals with ligated renal pedicles 16% of the unchanged pipecuronium was excreted into the bile and 10% of the administered dose was recovered from the liver. Since the total recovery of unaltered pipecuronium approximated 85% of the administered dose in the intact animals, biotransformation seems to play an insignificant role in disposition of this new neuromuscular blocking drug.(ABSTRACT TRUNCATED AT 250 WORDS)