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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).)

Objective: To investigate in vitro the effect of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time (PT) prolongations with various anticoagulants as well as the neutralizing effect of rocuronium and vecuronium on sugammadex effects on APTT and PT., Materials and Methods: We investigated in vitro the effect of sugammadex on APTT and/or PT in plasma of patients on a vitamin K antagonist and with elevated international normalized ratios (INRs), in plasma of healthy subjects spiked with either a low or high concentration of enoxaparin, fondaparinux, rivaroxaban, and dabigatran, and in perioperatively collected patient plasma. In addition, we explored whether the effects of sugammadex persisted in the presence of rocuronium or vecuronium, or whether they were counteracted by these compounds., Results: Sugammadex concentration-dependently increased APTT and PT(INR) in all anticoagulant conditions, mainly in a proportional manner, with no differences between perioperatively collected patient and control plasma. Rocuronium and vecuronium both neutralized the effects of sugammadex on APTT and PT., Conclusion: Sugammadex has a transient effect on coagulation and is unlikely to increase bleeding risk, this possibility cannot be excluded for scenarios not clinically studied.

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.

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.)

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.

Muscle relaxation facilitates tracheal intubation and improves surgical conditions during anaesthesia. However, unexpected prolonged muscle relaxation may occur. This article describes important causes of prolonged muscle relaxation and gives suggestions for its prevention. Drug interactions, incomplete reversal, co-morbidity, inaccurate neuromuscular monitoring and critical illness may prolong the effect of muscle relaxants. The anaesthetist must titrate the muscle relaxants using objective neuromuscular monitoring and proper reversal of the blockade when needed.

Objective: To study an expediency and efficacy of application of different reverses drugs (naloxone, flumazenil, neostigmine, galantamine, sugammadex) either their separate or combined using., Methods: We studied 119 patients underwent endoluminal endoscopic procedures and surgeries on trachea-bronchial tree and intestines under sedation or general anaesthesia., Results: The article deals with conceptual approaches to the reversal of residual effects of opioids, benzodiazepine sedation and neuromuscular block (the so-called agonist-antagonist technique)., Conclusions: A reversion of neuromuscular block without using of antagonists' combination does not provide complete recovery of psychomotor and cognitive functions for rapid socialization of patients after anaesthesia.

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.

Aim: The aim of the present study was to determine (1) whether successful intraoperative electromyography monitoring for lateral spread response (LSR) is possible with partial neuromuscular blockade (NMB) in subjects undergoing microvascular decompression (MVD) for hemifacial spasm and (2) the adequate level of NMB to achieve that goal., Material and Methods: A total of 61 patients in whom LSR was monitored during MVD were enrolled in the study. Patients were randomly allocated to two groups: group TOF in which the NMB target was maintenance of two train-of-four (TOF) counts and group T1 in which the NMB target was maintenance of a T1/Tc ratio of 50 % (T1: first twitch height of TOF and Tc: control twitch height). The adductor pollicis brevis muscle was used to monitor TOF responses. The frequency of successful LSR monitoring, defined as successful baseline establishment and maintenance of LSR until surgical decompression, was compared between the two groups., Results: Of the 61 patients 2 were excluded from the study so that 30 patients in group TOF and 29 patients in group T1 were analyzed. The success rate of LSR monitoring was clinically acceptable and significantly higher in group T1 than in group TOF, i.e. n = 15 (50.0 %) in group TOF versus n = 24 (82.8 %) in group T1 (P = 0.008), corresponding to a 32.8 % higher success rate in group T1 than group TOF (95 % CI: 13.9-51.7 %). Mean vecuronium infusion dose was smaller and mean TOF count was higher in group T1 than group TOF with a TOF count = 2 (1) in group TOF versus 3 (1) in group T1 (P = 0.003). Mean sevoflurane and remifentanil infusion doses were not different between groups. There was no incidence of spontaneous movement during microscopy in either group., Conclusion: Maintenance of partial NMB with a target T1/Tc ratio of 50 % resulted in a clinically acceptable success rate of LSR monitoring and surgical condition during MVD. Maintenance of partial NMB with a target T1/Tc ratio of 50 % rather than TOF count of two during LSR monitoring for MVD can therefore be recommended.

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.

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.

Neuromuscular blockade is a pharmacological adjunct for anesthesia and for surgical interventions. Neuromuscular blockers can facilitate ease of instrumentation and reduce complications associated with intubation. An undesirable sequela of these agents is residual neuromuscular blockade. Residual neuromuscular blockade is linked to aspiration, diminished response to hypoxia, and obstruction of the upper airway that may occur soon after extubation. If an operation is particularly complex or requires a long anesthesia time, residual neuromuscular blockade can contribute to longer stays in the intensive care unit and more hours of mechanical ventilation. Given the risks of this medication class, it is essential to have an understanding of the mechanism of action of, assessment of, and factors affecting blockade and to be able to identify factors that affect pharmacokinetics.

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.)

Pharmacologic reversal of neuromuscular blockade is a topic not very well acknowledged and controversially discussed. Reasons for this are numerous and include missing perception of the potential complications of residual neuromuscular paralysis including an increased morbidity and mortality, as well as low efficacy and numerous unwanted side effects of the available antagonists. Duration of action of muscle relaxants cannot be pharmacologically predicted. Objective neuromuscular monitoring is the only way to detect residual paralysis. This review article would like to discuss in its first part some of the myths which revolve around the use of muscle relaxants, then highlight the problems regarding the use of acetylcholine esterase inhibitors and, in the third part, discuss the steroidal muscle relaxant encapsulator sugammadex.

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.

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.

Curare was clinically used in a patient with acute appendicitis by Griffith and Johnson in January 1942. From the day on, the development of new muscle relaxants went on in the world. Since pancuronium was synthesized by Savage in 1964, it was widely used in clinical cases because it provided sufficient muscle relaxation during operation. At present, pancuronium, vecuronium and rocuronium are routinely used in the world. In the future, we expect development of new muscle relaxants with rapid onset, intermediate duration of action, rapid recovery and without side effects.

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.

Background: An estimated 24% to 70% of individuals have prolonged paralysis or severe weakness after receiving neuromuscular blocking agents (NMBAs) when therapy is terminated., Objectives: The purposes of this study were to (1) evaluate the relationship between recovery of neuromuscular transmission (NMT) and functional muscle activity after NMBA administration; (2) evaluate the relationship between delayed recovery of NMT or muscle activity and functional performance; and (3) determine the predictors of delayed recovery of NMT, muscle activity, and functional performance., Methods: This was a multisite study using a prospective, nonexperimental, descriptive design with convenience sampling techniques. Instruments used included a five-point muscle score, Actigraph, and peripheral nerve stimulator., Results: Key findings were as follows: (1) NMT returned promptly, whereas muscle activity remained severely depressed; (2) only two subjects (5%) recovered functional performance within 24 hours; (3) degree of muscle weakness immediately after neuromuscular blockade was associated with prolonged time to extubation and mobility; and (4) predictors of delayed recovery included cumulative dose of aminosteroid NMBAs, age, and renal function., Conclusion: Prolonged recovery of muscle activity and extreme weakness may occur despite brisk recovery of NMT after neuromuscular blockade.

Author has reviewed the literature and his own work related to the chemistry, pharmacology, and clinical aspects of new muscle relaxants. Emphasis has been placed on the basic science concepts and technologies (e.g. structure-activity relationships, nicotinic receptor pharmacology, and investigation of side effects) behind the development of rapidly and short acting nondepolarizing muscle relaxants., ((c) 2005 Wiley Periodicals, Inc.)

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.

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.

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.

The train-of-four (TOF) stimulation pattern consists of 4 stimuli (T1, T2, T3, and T4) at 2 Hz, and is used in daily anesthesiological practice to determine the degree of relaxation caused by muscle relaxants. At a surgical levels of relaxation the degree of relaxation can be estimated by counting the number of "measurable" or "visible" muscular reactions to the 4 stimuli in the TOF stimulation pattern (TOF count). During recovery relaxation can be estimated by calculating the TOF ratio (T4/T1). Bartkowski and Epstein described a pharmacokinetic-pharmacodynamic (PK-PD) model to predict TOF ratio by modifying and extending the PK-PD model as described by Sheiner to use a hypothetical distributed effect compartment described by a median equilibration rate constant and a dispersion parameter. We extended the Bartkowski and Epstein PK-PD model to simulate all four TOF twitches by including EC50 terms for T2 and T3. We fit this model to data from the pig and compared the results to fitted models using separate PD models for each TOF twitch (extended Sheiner model). The extended Bartkowski and Epstein model fit the twitch height data from all four TOF twitches better than the extended Sheiner model and has fewer parameters.

The physiological changes that occur with increasing age can have significant effects on the pharmacokinetics of neuromuscular-blocking drugs. Changes in cardiac output can affect drug distribution and therefore the speed of onset of neuromuscular block. A decrease in muscle mass and increase in body fat with age can also affect their distribution. The deterioration in renal and hepatic function associated with aging affects the clearance and elimination of many neuromuscular-blocking drugs. The effects of these physiological changes on the pharmacokinetics of neuromuscular-blocking agents may not become apparent clinically in healthy individuals until the age of at least 75 years. There is very little evidence to suggest any alteration in the sensitivity of the neuromuscular junction to neuromuscular-blocking drugs with increasing age. Neuromuscular-blocking drugs that undergo a significant degree of organ-dependent elimination, such as pancuronium bromide, vecuronium bromide, rocuronium bromide and doxacurium chloride, may have a significantly prolonged duration of action in elderly patients. These drugs can be used safely in elderly patients if the anaesthetist is aware of their altered pharmacokinetics in this patient group. Appropriate changes must be made to drug dosage and dose intervals. As the pharmacokinetic changes can be unpredictable, monitoring of neuromuscular block is strongly advised when using these drugs in such patients. The risk of residual block occurring postoperatively after the use of pancuronium bromide increases with age. The duration of action of mivacurium chloride may also be prolonged in the elderly; this change has not been demonstrated to be a result of an alteration in plasma cholinesterase activity. In contrast, there is no evidence of an alteration in the action of suxamethonium chloride (succinylcholine chloride) with increasing age. Atracurium besilate and cisatracurium besilate undergo predominantly organ-independent elimination. Onset of block with these two drugs may be prolonged in the elderly, but their clinical duration of action does not alter significantly with age, making them particularly suitable for use in this patient group. Although atracurium besilate may cause histamine release, there is little evidence of it producing haemodynamic changes in the elderly. Its (1R,1R')-isomer, cisatracurium besilate, has very little direct or indirect cardiovascular effect and is, therefore, the most suitable nondepolarising agent to use in elderly patients.

The first use of neuromuscular blocking agents (muscle relaxants) in clinical practice (1942) revolutionised the practice of anaesthesia and started the modern era of surgery. Since 1942 introduction of tubocurarine (18) neuromuscular blocking agents have been used routinely to provide skeletal muscle relaxation during surgical procedures allowing access to body cavities without hindrance from voluntary or reflex muscle movement. After the introduction of tubocurarine and the depolarizing suxamethonium chloride (4) (1949) several nondepolarizing steroidal and nonsteroidal neuromuscular blocking agents with different onset time and duration of effect were introduced e.g. gallamine triethiodide (1) (1949), methocurine (2) (1949), alcuronium chloride (3) (1963), pancuronium bromide (9) (1968), vecuronium bromide (11) (1982), pipecuronium bromide (10) (1982), atracurium besylate (5) (1982), doxacurium chloride (6) (1991), mivacurium chloride (8) (1992), rocuronium bromide (12) (1994) cisatracurium besylate (7) (1996), and rapacuronium bromide (13) (2000). SZ 1677 (14) a steroid type nondepolarizing neuromuscular blocking agent under development (preclinical phase). This review article deals with a comprehensive survey of the progress in chemical, pharmacological and, in some respects, of clinical studies of neuromuscular blocking agents used in the clinical practice and under development, including the synthesis, structure elucidation, pharmacological actions, structure activity relationships studies of steroidal and nonsteroidal derivatives.

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.

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.

There are differences between pediatric patients and adults in the responses to neuromuscular blockers. The results of new studies of neuromuscular blockers in pediatric patients are generally consistent with earlier studies in the type of age-related differences documented. Surprising new results are the side effects, including anaphylaxis, that have been observed, and studied directly, in pediatric patients. Continued evaluation of these drugs in pediatric patients will provide better information regarding the variability of the effects of neuromuscular blockers in healthy and diseased infants and children.

A sensitive and specific liquid chromatography/mass spectrometry (LC/MS) method has been developed and validated for the quantification of the modified gamma-cyclodextrin Org 25969 and Rocuronium bromide (Roc or Org 9426) in the plasma and urine of guinea pigs. The assay was linear and reproducible over the range 25-10000 ng/mL for both compounds. The lowest limit of quantification (LLOQ) for both compounds in urine was 25 ng/mL. In plasma, the LLOQ was 25 ng/mL for Org 9426 and 50 ng/mL for Org 25969. The inter- and intra-day variation was lower than 20%. The physicochemical properties of both compounds imposed different modes of extraction from plasma. The modified gamma-cyclodextrin was extracted by trifluoroacetic acid (TFA) precipitation while Rocuronium was extracted by acetonitrile precipitation. Both compounds were quantified in urine by direct injection onto the column. The LC/MS analyses of Org 25969 and Org 9426 were performed using two different assay conditions. It was not possible to quantify the complex of cyclodextrin and Roc as it dissociated on the LC column. The use of LC/MS conferred great advantage to the quantification of both Org 25969 and Org 9426, as they were not chromogenic enough to afford the sensitivity and specificity required for the assay., (Copyright 2002 John Wiley & Sons, Ltd.)

The historical development, pharmacology, pharmacodynamics, pharmacokinetics, clinical applications, pharmacologic basis for selection, adverse effects, and cost of neuromuscular blockers (NMBs) are discussed. The first NMB to be used was tubocurarine. During neurotransmission, acetylcholine is synthesized, stored in vesicles at the neuromuscular junction, released into the synapse, and bound to nicotinic receptors in the muscle end plate. For muscle contraction to occur, the impulse generated in a neuron's cell body must create an action potential that is chemically transmitted across the synapse. The postsynaptic nicotinic receptor at the neuromuscular junction is the major site of action of depolarizing and nondepolarizing NMBs. All NMBs have the potential for cross-reactivity at other nicotinic and muscarinic sites. Drug interactions most commonly occur between NMBs and inhalation anesthetics, certain antimicrobials, calcium-channel blockers, and anticholinesterases. When selecting an NMB, an agent's onset and duration of action must be considered. NMBs can be used on a short-term or long-term basis. Apart from cost, the choice of an NMB is made on the basis of its adverse-reaction profile, pharmacokinetics, and indications for use. Monitoring tools, their use, the rationale for their use, and the interpretation of the results they provide are unique. The patterns of peripheral nerve stimulation vary and elicit different characteristics of nondepolarizing neuromuscular blockade. The effectiveness of reversal agents is proportional to the degree of blockade. The mechanism of action of anticholinesterases involves inhibition of acetylcholinesterase. The expensive NMBs should be conserved for use in surgery, while the cheaper, long-acting [corrected] agents should be used in the intensive care unit. An understanding of the pharmacology, pharmacodynamics, and pharmacokinetics of NMBs will help health care providers gain expertise in the selection and use of these agents.

The use of NMB agents for more than 24 to 48 hours in critically ill patients is associated with many potential complications. Neuromuscular-blocking drugs should be used only when their use is essential for optimal patient care. The indications for neuromuscular blockade must be defined clearly, and patients should be evaluated during treatment for the need for continued muscle relaxation. The smallest doses of NMB agents that will accomplish clinical goals should be used. This dosage can be determined through clinical evaluations and peripheral nerve monitoring. It is essential that all patients treated with NMB drugs receive appropriate sedation and analgesia. Myopathies, neuropathies, and alterations of the neuromuscular junction can occur in the ICU setting, and nondepolarizing muscle relaxants seem to be involved in the development of these disorders. Clinicians should be aware of risk factors that may predispose certain patients to neuromuscular complications, including sepsis and the use of high-dose steroids. Neuromuscular-blocking agents should be avoided in these patients if possible. Although not proved, early recognition and treatment of iatrogenic neuromuscular complications may improve patient outcome.

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.

A rapid, sensitive and selective method has been developed for the quantification of plasma concentrations of neuromuscular blocking drug, rocuronium, using gas chromatography with mass spectrometric detection. 3-Desacetylvecuronium served as the internal standard. The method involved iodide ion pair formation and a single-step liquid-liquid extraction with dicholoromethane. This method also permits simultaneous determination of its putative metabolite, 17-desacetylrocuronium, although the high detection limit for the metabolite limits the practical application of this method in pharmacokinetic study of the metabolite. The extraction efficiency was approximately 75% for rocuronium and approximately 50% for 17-desacetylrocuronium. The limit of quantification was 26 ng/ml for rocuronium and 870 ng/ml for its metabolite. The assay was used successfully in a patient undergoing liver transplantation and receiving rocuronium as a constant rate infusion and in a patient undergoing general elective surgery receiving the drug as an intravenous bolus. This assay is a time-saving alternative to published gas or liquid chromatographic methods for assaying rocuronium.

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.

Many drugs interact with neuromuscular blocking drugs and often enhance the induced block; this is of clinical importance for volatile anaesthetics, antimicrobials, magnesium and some more specific drugs. Difficulty in reversing the block occurs with calcium-channel blockers and polymyxin. Phenytoin, carbamazepine and other anticonvulsants may cause resistance to neuromuscular blocking drugs. Moreover, clinically important interactions are found between individual neuromuscular blockers. Giving succinylcholine after a non-depolarizing neuromuscular blocking drug prolongs the onset of succinylcholine; when non-depolarizing drugs are administered after succinylcholine their effects are prolonged. The succinylcholine block is prolonged when the drug is administered during recovery from pancuronium or following neostigmine reversal. Drugs or diseases that decrease the activity of plasma cholinesterase may prolong a succinylcholine-induced block. Finally, liver dysfunction, renal failure, disturbances of acid-base balance, change in temperature and neurological diseases all have an effect on the profile of the neuromuscular blocking drugs; the response to an induced block may be altered in patients under intensive care and those with cancer. Although knowledge of the most important theoretical interactions of neuromuscular blocking drugs is favourable, the anaesthetist should be aware that pharmacological interactions can lead to an unpredictable induced neuromuscular block in many cases in daily clinical practice. Therefore anaesthetists should become familiar with the use of neuromuscular transmission monitoring in order to manage the block correctly.