Pharmacokinetics and pharmacodynamics studies of a loading dose of cisatracurium in critically ill patients with respiratory failure.

BACKGROUND: Previous studies reported a slow neuromuscular response with the currently recommended dose of cisatracurium in critically ill patients. Pharmacokinetic and pharmacodynamic studies of cisatracurium in critically ill patients are still limited. To our knowledge, this is the first study performed to better understand the pharmacokinetics (PKs) and pharmacodynamics (PDs) of a loading dose of cisatracurium and to identify factors that affect PK and PD changes in critically ill patients. METHODS: A prospective PKs and PDs study was designed. Arterial blood samples of 10 critically ill patients with respiratory failure were collected after administering a loading dose of 0.2 mg/kg of cisatracurium. Plasma cisatracurium and laudanosine concentrations were determined using liquid chromatography-tandem mass spectrometry. The achievement of the desired pharmacodynamic response was evaluated by both 1) clinical assessment and 2) train-of-four monitoring. The PK/PD indices were analyzed for their correlation with patient'characteristics and other factors. RESULTS: The one-compartment model best described the plasma pharmacokinetic parameters of cisatracurium. The volume of distribution at steady state and total clearance were 0.11 ± 0.04 L/kg and 2.74 ± 0.87 ml/minute/kg, respectively. The mean time to train-of-four 0/4 was 6 ± 3.86 minutes. A time to the desired pharmacodynamic response of less than 5 minutes was found in 10% of the patients. A positive correlation was found between cisatracurium concentration and albumin levels and between pharmacokinetics data and patient factors [partial pressure of carbon dioxide and respiratory alkalosis]. CONCLUSION: The currently recommended loading dose of cisatracurium might not lead to the desired pharmacodynamic response in critically ill patients with respiratory failure. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03337373. Registered on 9 November 2017.

The effect of cisatracurium infusion on the energy expenditure of critically ill patients: an observational cohort study.

BACKGROUND: Both overfeeding and underfeeding of intensive care unit (ICU) patients are associated with worse outcomes. A reliable estimation of the energy expenditure (EE) of ICU patients may help to avoid these phenomena. Several factors that influence EE have been studied previously. However, the effect of neuromuscular blocking agents on EE, which conceptually would lower EE, has not been extensively investigated. METHODS: We studied a cohort of adult critically ill patients requiring invasive mechanical ventilation and treatment with continuous infusion of cisatracurium for at least 12 h. The study aimed to quantify the effect of cisatracurium infusion on EE (primary endpoint). EE was estimated based on ventilator-derived VCO2 (EE in kcal/day = VCO2 × 8.19). A subgroup analysis of septic and non-septic patients was performed. Furthermore, the effects of body temperature and sepsis on EE were evaluated. A secondary endpoint was hypercaloric feeding (> 110% of EE) after cisatracurium infusion. RESULTS: In total, 122 patients were included. Mean EE before cisatracurium infusion was 1974 kcal/day and 1888 kcal/day after cisatracurium infusion. Multivariable analysis showed a significantly lower EE after cisatracurium infusion (MD - 132.0 kcal (95% CI - 212.0 to - 52.0; p = 0.001) in all patients. This difference was statistically significant in both sepsis and non-sepsis patients (p = 0.036 and p = 0.011). Non-sepsis patients had lower EE than sepsis patients (MD - 120.6 kcal; 95% CI - 200.5 to - 40.8, p = 0.003). Body temperature and EE were positively correlated (Spearman's rho = 0.486, p < 0.001). Hypercaloric feeding was observed in 7 patients. CONCLUSIONS: Our data suggest that continuous infusion of cisatracurium in mechanically ventilated ICU patients is associated with a significant reduction in EE, although the magnitude of the effect is small. Sepsis and higher body temperature are associated with increased EE. Cisatracurium infusion is associated with overfeeding in only a minority of patients and therefore, in most patients, no reductions in caloric prescription are necessary.

Abnormal cisatracurium pharmacodynamics and pharmacokinetics among patients with severe aortic regurgitation during anesthetic induction.

BACKGROUND: This study was designed to examine whether severe aortic regurgitation will affect the pharmacodynamics (PD) and pharmacokinetics (PK) of cisatracurium during anesthetic induction. METHODS: A total of 32 patients were divided into two groups: the AR group (n = 16) and the control group (n = 16). Arterial blood samples were drawn before and at 1, 2, 4, 6, 8, 10, 16 and 20 min after intravenous injection of 0.15 mg/kg cisatracurium. TOF tests were applied to determine the onset time of maximal muscle relaxation. The concentration of cisatracurium in plasma was determined by high-performance liquid chromatography. RESULTS: The onset time to maximal neuromuscular block was prolonged from 2.07 ± 0.08 min to 4.03 ± 0.14 min, which indicated that the PD responses to cisatracurium were significantly delayed in the AR group (P < 0.05) compared to the control group. A conventional two-compartment PK model showed a higher plasma concentration of cisatracurium among the AR group with markedly reduced intercompartment transfer rate (K12 = 0.19 ± 0.02 and K21 = 0.11 ± 0.01 in the AR group vs. K12=0.26 ± 0.01 and K21 = 0.19 ± 0.01 in the control group, P < 0.01) compared to the control group. CONCLUSION: Backward blood flow during diastole in severe AR impaired distribution of cisatracurium from the central compartment to the peripheral compartment, which accounted for the lagged PD responses. Findings in this study underlie the importance of muscular blockade monitoring among patients with severe aortic regurgitation during anesthetic induction. REGISTRATION: Name of the registry: Abnormal Cisatracurium Pharmacodynamics and Pharmacokinetics among Patients with Severe Aortic Regurgitation during Anesthetic Induction. TRIAL REGISTRATION NUMBER: ChiCTR1800019654. Date of registration: November 20th 2018.

Effect of age on cis-atracurium besylate pharmacokinetics following a single 1 mg kg-1 intravenous bolus in young pigs.

OBJECTIVE: To determine the cis-atracurium pharmacokinetic data and laudanosine production of a single 1 mg kg-1 cis-atracurium dose in the pig and to compare the pharmacokinetics between two groups of different ages. STUDY DESIGN: Prospective experimental study. ANIMALS: Sixteen female pigs in two groups. Group A included eight animals aged 2.0-2.5 months and weighed 26.6 ± 3.6 kg. Group B included eight animals aged 4.0-5.0 months and weighed 57.4 ± 8.3 kg. METHODS: The pigs were anaesthetized and monitored throughout the procedure. Arterial blood samples collected at 0, 0.5, 1, 2, 5, 10, 20, 30, 45, 60, 90, 120 and 180 minutes after cis-atracurium injection were cooled and centrifuged. Plasma was acidified and stored at -20 °C for subsequent cis-atracurium and laudanosine analyses. RESULTS: Anaesthetic parameters were within normal ranges throughout the procedure. Plasma cis-atracurium and laudanosine concentrations were measured for the 16 pigs. Elimination rate constant, elimination half-life, area under the curve, mean residence time, distribution volume and total clearance were calculated for each pig. Statistical differences (p < 0.05) in the elimination rate constant, elimination half-life, mean residence time and distribution volume values were observed between the two groups. Elimination half-life, mean residence time and distribution volume values were higher and elimination rate constant lower in younger pigs than in older pigs. No plasma laudanosine concentrations were detected in any pig. CONCLUSION AND CLINICAL RELEVANCE: Longer duration of plasma cis-atracurium concentrations were observed in younger pigs. Distribution volume was also higher in younger pigs. Conversely, total clearance and area under the curve were similar between the two age groups. No laudanosine production was detected, suggesting a different cis-atracurium metabolism in the pig compared with other species.

Real-time potentiometric sensor; an innovative tool for monitoring hydrolysis of chemo/bio-degradable drugs in pharmaceutical sciences.

In recent years, the whole field of ion-selective electrodes(ISEs) in pharmaceutical sciences has expanded far beyond its original roots. The diverse range of opportunities offered by ISEs was broadly used in a number of pharmaceutical applications, with topics presented ranging from bioanalysis of drugs and metabolites, to protein binding studies, green analytical chemistry, impurity profiling, and drug dissolution in biorelevant media. Inspired from these advances and with the aim of extending the functional capabilities of ISEs, the primary focus of the present paper is the utilization of ISE as a tool in personalized medicine. Given the opportunity to explore biological events in real-time (such as drug metabolism) could be central to personalized medicine. (ATR) is a chemo-degradable and bio-degradable pharmaceutically active drug. Laudanosine (LDS) is the major degradation product and metabolite of ATR and is potentially toxic and reported to possess epileptogenic activity which increases the risk of convulsive effects. In this work, ATR have been subjected to both chemical and biological hydrolysis, and the course of the reactions is monitored by means of a ISE. In this study, we have designed an efficient real-time tracking strategy which substantially resolve the challenges of the ATR chemical and biological degradation kinetics. By utilizing a potentiometric sensor, tracking of ATR chemical and biological degradation kinetics can be performed in a very short time with excellent accuracy. The LOD was calculated to be 0.23 µmol L-1, the potential drift was investigated over a period of 60 min and the value was 0.25 mV h-1. Real serum samples for measurement the rate of in vitro metabolism of ATR was performed. Furthermore, a full description of the fabricated screen-printed sensor was presented.

Pharmacokinetics and pharmacodynamics of cisatracurium in patients undergoing surgery with two hemodilution methods.

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 Ca2+ 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.

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

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

[Pharmacokinetics of a cisatracurium dose according to fat-free mass for anesthesia induction in morbidly obese patients].

OBJECTIVE: To compare the pharmacokinetics of cisatracurium between normal weight patients and morbidly obese patients. METHODS: Twelve obese ASA I-II patients (BMI≥35 kg/m2) undergoing laparoscopic Roux-en-Y gastric bypass and 12 normal weight ASA I-II patients (BMI of 18.5-24 kg/m2) undergoing laparoscopic surgery were enrolled. The obese patients were given a cisatracurium dose of 0.15 mg/kg according to the fat-free mass (FFM), and the non-obese patients received a dose of 0.15 mg/kg according to the total body weight. Plasma concentrations of cisatracurium was monitored in the patients with high-performance liquid chromatography (HPLC) before anesthetic induction and at 1, 2, 4, 6, 8, 10, 12, 15, and 20 min after cisatracurium administration and the pharmacokinetic parameters were computed. SBP, DBP, HR, MAP, SpO2 and PetCO2 were recorded before anesthetic induction (T0) and at 1 min (T1), 2 min (T2), 4 min (T3) after cisatracurium administration. RESULTS: Compared with those measured at T0, SBP, DBP and MAP in the 2 groups were significantly decreased at the time points of T1-3 (P<0.05). Compared with the non-obese patients, the obese patients showed significantly increased Hct level (P<0.05). The total clearance, apparent volume of distribution, and distribution and elimination half-life of the drug were similar between the 2 groups (P>0.05). The plasma concentration of cisatracurium at T1-2 was significantly decreased in the obese patients compared with that in the non-obese patients (P<0.05). CONCLUSION: Cisatracurium doses according to fat-free mass is clinically reasonable for inducing anesthesia in morbidly obese patients, but due to a prolonged muscle relax onset time, the timing of tracheal intubation should be delayed by 1-2 min.

Altered Cisatracurium Pharmacokinetics and Pharmacodynamics in Patients with Congenital Heart Defects.

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.

Use of cisatracurium in critical care: a review of the literature.

Cisatracurium is currently one of the most commonly used neuromuscular blocking agent (NMBA) in intensive care units. Cisatracurium was developed primarily for anaesthetic purposes in order to attempt to resolve some of the problems associated with earlier NMBAs, such as histamine release and laudanosine accumulation. Cisatracurium, the the R-cis-R-cis isomer of atracurium, is up to 5 times more potent than atracurium and so is administered in smaller quantities and produces a lesser degree of laudanosine accumulation in the plasma. In both adult and paediatric settings cisatracurium has favourable pharmacological characteristics compared to vecuronium, a steroid based NMBA often used in critical care. Recent randomised clinical trials suggested that the use of cisatracurium is associated with better outcome in acute respiratory distress syndrome (ARDS). Its use has been associated with better outcomes in therapeutic hypothermia and in traumatic brain injury. Although it has many favorable pharmacological properties, it is more expensive than comparable agents and some safety concerns persist regarding adverse events associated with the drug. The aim of the present study was to perform the first comprehensive review to date of all literature relating to the use of cisatracurium in critically ill patients.

Comparative pharmacodynamics of pancuronium, cisatracurium, and CW002 in rabbits.

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.

High-performance liquid chromatography assay with programmed flow elution for cisatracurium in human plasma: application to pharmacokinetics in infants and children.

A high-performance liquid chromatography (HPLC) assay with fluorescence detection (FLD) for quantification of cisatracurium in human plasma was developed and fully validated. Liquid-liquid extraction was employed for sample preparation. The separation was carried out on a C18 column with ternary mobile phase composed of 30mmolL(-1) phosphate buffer (pH 3.0), acetonitrile and methanol (60:35:5, v/v/v). Verapamil was used as the internal standard. The isocratic elution with programmed flow rate was employed by setting at 0.8mLmin(-1) from 0 to 3.5min, 0.5mLmin(-1) from 3.5 to 6min, and 1.0mLmin(-1) from 6 to 10min. The fluorescence detection was performed at 236nm for excitation and 324nm for emission. The assay was linear from 50 to 2800ngmL(-1), with a detection limit of 12ngmL(-1). The correlation coefficient (r) for linear regression was 0.9997. The intra-day coefficients of variation (CVs) were less than 2.0%, and the inter-day CVs were less than 4.0%. The mean recoveries were in the range of 92.1-100.4%. The total HPLC run time was less than 10min. The developed HPLC method was fast, simple, sensitive, accurate and suitable for studying the pharmacokinetics of cisatracurium in infants and children after intravenous administration.

Influence of acute normovolemic hemodilution on the pharmacokinetics of Cisatracurium Besylate.

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 ß) 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.

Comparison of the variability of the onset and recovery from neuromuscular blockade with cisatracurium versus rocuronium in elderly patients under total intravenous anesthesia

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.

Comparison of the variability of the onset and recovery from neuromuscular blockade with cisatracurium versus rocuronium in elderly patients under total intravenous anesthesia.

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.

The pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients with severe sepsis.

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.

[Comparison of atracurium, cisatracurium and vecuronium during anaesthesia for laparoscopic surgery]. / Ocena porównawcza atrakurium, cisatrakurium i wekuronium podczas znieczulenia ogólnego do operacji laparoskopowych.

BACKGROUND: The aim of the study was to compare the intubating conditions, onset time, and duration of action of atracurium, cisatracurium, and vecuronium, when used for muscle relaxation in laparoscopic surgery with carbon dioxide inflation. In trying to find an "ideal" relaxant we compared the relative potency of these drugs, and also measured pH, PaCO2 and skin temperature. METHODS: Ninety-five ASA I and II patients were randomly allocated to three groups, to receive atracurium (I), cisatracurium (II), or vecuronium (III), during propofol/fentanyl anaesthesia. Neuromuscular transmission was monitored using accelerography (TOF GUARD). Patients were intubated after the injection of 0.5 mg kg-1 atracurium (I), 0.1 mg kg(-1) cisatracurium (II), or 0.1 mg kg(-1) vecuronium (III). Muscle relaxation was maintained with incremental doses of 0.1 0.2 mg kg(-1) and 0.03 mg kg(-1) of the relaxants respectively, given after a second response to TOF stimulation was noted. Recovery time was defined as the time from a maximal block (TOF=0) to spontaneous recovery of TOF 75%. RESULTS: Conditions for performing tracheal intubation were noted to be excellent in groups I and III, and good in group II. The mean recovery time was significantly shorter in groups II and III, than in group I. No significant correlations were found between the duration of neuromuscular blockade and pH, PaCO2 or palm skin temperature. CONCLUSIONS: Vecuronium, besides providing excellent conditions for tracheal intubation, had the fastest onset time and optimal duration of action. We found the drug to be the most suitable for laparoscopic surgery.

Cisatracurium pharmacokinetics and pharmacodynamics during hypothermic cardiopulmonary bypass in infants and children.

BACKGROUND: Hypothermia potentiates neuromuscular blockade in adults during cardiopulmonary bypass (CPB) but the pediatric literature is sparse. Temperature-dependent Hoffman degradation of cisatracurium may allow reduction in infusion rate (IR) during hypothermia. The effect of hypothermic CPB on the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium has not been described in children. METHODS AND MATERIALS: Using neuromuscular monitoring with a Datex Relaxograph, cisatracurium IR was adjusted to obtain a pseudo-steady state during each phase of surgery (pre-CPB, CPB, post-CPB). Paired samples were taken at each phase. Cisatracurium plasma concentrations (Cpss) were determined by HPLC. Core and skin temperatures were recorded. RESULTS: Data from ten infants were analyzed: Group 1: mean 33.6°C; Group 2: mean 21.9°C. To maintain T1% between 5% and 10% in Group 2, the IR was decreased by a mean of 89% (P < 0.001). IR was not significantly different in Group 1. Post-CPB IR approximated pre-CPB rates in both groups. During CPB, Cpss fell by 27% in Group 1 and by 50% in Group 2 (P = 0.039). Post-CPB Cpss was not significantly different to pre-CPB in either group. Clearance did not change significantly in Group 1 but fell significantly in Group 2 during CPB (P = 0.002). Clearance post-CPB was unchanged from pre-CPB. CONCLUSIONS: Cisatracurium IR may be decreased by around 60% during CPB with moderate hypothermia but can be maintained at baseline during mild hypothermia.

Merging PK/PD information in a minimally parameterized model of the neuromuscular blockade.

A recursive system identification algorithm that merges PK/PD information in a minimally parameterized Wiener model for the NMB level is presented. The results show that the coupling between one parameter from the linear block and one from the static nonlinearity is advantageous, when evaluated on a database of 60 real collected NMB cases.

[Clopidogrel and its salts: any clnical implication?]. / Le clopidogrel et ses differents sets: existe-t-il une pertinence clinique?

Clopidogrel hydrogen sulfate is an antiplatelet agent administered, alone or in combination with acetyl salicylic acid, approved in the prevention of cardiovascular events based on large-scale clinical trials. The new salt formulations clopidogrel where approved based on pharmacokinetic measurements of the inactive prodrug on few healthy volunteers, without any other medication. Clopidogrel hydrogen sulfate has a wide variability in platelet response and the pharmacokinetic of the active metabolite is not dose-linear. Ideally, new clopidogrel salts should be tested for therapeutic equivalence in the target patient population. Should this not be feasible, consistent bioequivalence data should be obtained for the active metabolite, using a properly validated and standardized test method.