Comparison of two pharmacokinetic-pharmacodynamic models of rocuronium bromide during profound neuromuscular block: analysis of estimated and measured post-tetanic count effect.

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.

Neuromuscular block in patients 80 years and older: a prospective, controlled study.

BACKGROUND: An increasing number of patients older than 80 years are undergoing anesthesia, but little information is available regarding pharmacodynamic effects of myorelaxants in this population. This study aims to compare the time course of rocuronium neuromuscular block in patients ≥ 80 years with those of younger adults. METHODS: Under total intravenous anesthesia with propofol and sufentanil, time course of a bolus of rocuronium 0.6 mg/kg neuromuscular block was assessed with acceleromyography in patients ≥ 80 and in patients 20-50 years old. Onset time, clinical duration, duration until 90% and 100% recovery of baseline were determined. RESULTS: Data from 32 patients were analyzed, 16 were ≥ 80 years and 16 were 20-50 years old. Demographic data are shown in Table 1. In the group ≥ 80, onset time was 190 s ± 46 s compared to 123 s ± 40 s in the group 20-50, P < 0.001 and the clinical duration was 52 [48-69.5] min and 36 [34-41] min, respectively, P < 0.001. Duration to 90% recovery of baseline was 77.5 [71-88.5] min and duration to 100% recovery of baseline was 91.2 [82.2-98] min in patients ≥ 80 years and the corresponding values in the patients 20-50 years old were 53.5 [49-55.5] min and 59.5 [56.5-70.25] min, respectively, P < 0.001. CONCLUSION: Compared to younger adults rocuronium shifted in patients ≥ 80 years from a rapid onset, intermediate acting compound to a slower onset, long-acting compound. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03551652 (29/05/2018).

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.

The SLCO1A2 -189_-188InsA polymorphism reduces clearance of rocuronium in patients submitted to elective surgeries.

PURPOSE: Rocuronium (ROC) is a neuromuscular blocker mainly eliminated by biliary excretion dependent on organic anion transporting polypeptide 1A2 (OATP1A2) hepatocellular uptake. However, the influence of SLCO1A2 (gene encoding OATP1A2) genetic polymorphism on ROC pharmacokinetics was never described before. The objective of this work was to evaluate the influence of genetic polymorphisms of SLCO1A2 on the pharmacokinetics of rocuronium (ROC). METHODS: Patients undergoing elective surgeries under general anesthesia using rocuronium as a neuromuscular blocker were genotyped for SLCO1A2 polymorphisms in the coding region (41A>G, 382A>T, 404A>T, 502C>T, 516A>C, 559G>A, 830C>A, and 833delA) and in the promoter region (-1105G>A, -1032G>A, -715T>C, -361G>A, and -189_-188insA). Rocuronium pharmacokinetic parameters were estimated by non-compartmental analysis. RESULTS: None of the patients had heterozygous or homozygous variant of 404A>T, 382A>T, 502C>T, 833delA, 830C>A, 41A>G, and -715T>C. A linkage disequilibrium was found between -1105G>A and -1032G>A genotypes. Patients genotyped as -A or AA (n = 17) for SLCO1A2 -189_-188InsA showed reduced total clearance of ROC compared to patients genotyped as -/- (n = 13) (151.6 vs 207.1 mL/min, p ≤ 0.05). The pharmacokinetics parameters of ROC were not significantly different between other SLCO1A2 genotypes. CONCLUSION: SLCO1A2 -189_-188InsA polymorphism is related to the reduced clearance of rocuronium in patients submitted to elective surgeries under general anesthesia. TRIAL REGISTRATION: NCT 02399397 ( ClinicalTrials.gov ).

Rocuronium pharmacokinetics and pharmacodynamics in the adductor pollicis and masseter muscles.

BACKGROUND: The aim of this study was to characterize the dose-effect relationship of rocuronium at the adductor pollicis and masseter muscles. METHODS: Ten, ASA I, adult patients, received a bolus dose of rocuronium 0.3 mg/kg during propofol based anesthesia. Train-of-four (TOF) was simultaneously monitored at the masseter and the adductor pollicis muscles until recovery. Rocuronium arterial serum concentrations were measured during 120 min. The first twitch of the TOF response was used to characterize the time-effect profile of both muscles using pharmacokinetic-pharmacodynamic analysis in NONMEM. A decrease in NONMEM objective function (∆OFV) of 3.84 points for an added parameter was considered significant at the 0.05 level. RESULTS: Onset time at the masseter (mean ± SD, 1.5 ± 0.9 min) was faster than at the adductor pollicis (2.7 ± 1.4 min, P < 0.05). Recovery, measured as the time to TOF ratio = 0.9 was similar between muscles 29.9 ± 6.7 (adductor pollicis) vs. 29.3 ± 8.1 (masseter). (P = 0.77). The estimated pharmacodynamic parameters [mean (95% CI)] of the adductor pollicis muscle and the masseter muscle were; plasma effect-site equilibration half-time (teq) 3.25 (2.34, 3.69) min vs. 2.86 (1.83, 3.29) min, (∆OFV 383.665); Ce50 of 1.24 (1.13, 1.56) mg/l vs. 1.19 (1.00, 1.21) mg/l, (∆OFV 184.284); Hill coefficient of 3.97 (3.82, 5.62) vs. 4.68 (3.83, 5.71), (∆OFV 78.906). CONCLUSIONS: We found that the masseter muscle has faster onset of blockade and similar recovery profile than adductor pollicis muscle. These findings were best, explained by a faster plasma effect-site equilibration of the masseter muscle to rocuronium.

Comparison of distributed and compartmental models of drug disposition: assessment of tissue uptake kinetics.

The utility of a circulatory three-compartment model for the assessment of tissue uptake kinetics is tested by comparison with the respective distributed models using pharmacokinetic data of rocuronium in patients These minimal physiologically based models have a common structure consisting of two subsystems representing the lung and the lumped systemic circulation, with two regions, the vascular and tissue space. The distributed models are based on either diffusion-limited tissue distribution, permeability-limited tissue uptake or the assumption of an empirical transit time density function. With a deviation in the estimate of the permeability-surface area product (PS) of about 18 %, the compartmental approach appears as a useful alternative on condition that a priori knowledge of cardiac output is included. It is also shown that the distribution clearance calculated from the parameters of a mammillary compartment model changes proportional to PS and can be used as an indirect measure of permeability-limited tissue uptake of drugs.

[Simple Formula to Predict Residual Amount of Continuously Infused Rocuronium in the Body].

BACKGROUND: When antagonism is performed using sugammadex after continuous infusion of rocuronium, if the total amount of residual rocuronium can be esti- mated prior to performing antagonism, antagonism without excess or deficiency of sugammadex will be made possible. We therefore prepared a simple formula to predict residual amount of rocuronium in the body, which can be easily applied in clinical setting, and veri- fied it using Tivatrainer©. METHODS: 1. Pharmacokinetics of rocuronium was simulated, using a 3-compartment model. The following assumptions were made to derive the simple for- mula : when rocuronium is continuously infused to reach the steady state plasma concentration, an equal concentration in each compartment is reached. Only the amounts of rocuronium infused to the central com- partment and rocuronium excreted from there are thus considered, and these two amounts are in balance. For pharmacokinetic parameters, we referred to V. Saldien, Anesth Analg 2003 ; 97 : 44-9. 2. The prepared simple formula was verified using Tivatrainero. We considered a model in which initial boluses of 0.3, 0.6, 0.9, and 1.2 mg · kg(-1) were adminis- tered, and continuous infusion began at 30 minutes at the rate of 0.2, 0.3, 0.4, 0.5, 0.6, and 0.8 mg - kg-1 - hr-1. Patients with body weight of 50, 60, 70, and 80 kg were investigated. RESULTS: 1. The derived simple formula was as fol- lows : Q=0.74 X R Q Total residual amount of rocuronium (mg) R Dose per hour (mg · hr(-1)) 2. The predicted value of the total residual amount obtained from the simple formula was consistent with the value predicted by Tivatrainer© with a high preci- sion within the error of 1.4%. Convergence time until the stable state was reached varied depending on the condition. However, it took approximately 150 minutes after the beginning of continuous infusion.for the error between values predicted by the simple formula and Tivatrainer© to stabilize within 5 mg. CONCLUSIONS: We prepared a simple formula to esti- mate the total residual amount of rocuronium at a steady state. The value predicted by the simple for- mula agreed with the value predicted by Tivatrainer) with a high precision.

Use of neuromuscular monitoring to detect prolonged effect of succinylcholine or mivacurium: three case reports.

Mutations in the butyrylcholinesterase gene can lead to a prolonged effect of the neuromuscular blocking agents, succinylcholine and mivacurium. If the anaesthesiologist is not aware of this condition, it may result in insufficient respiration after tracheal extubation. However, this can be avoided with the use of objective neuromuscular monitoring if used adequately. Three case reports of prolonged effect of succinylcholine or mivacurium were presented to illustrate the importance of neuromuscular monitoring during anaesthesia. In the first case, continuous intraoperative neuromuscular monitoring allowed a prolonged neuromuscular blockade to be discovered prior to tracheal extubation of the patient. The patient was extubated after successful reversal of the neuromuscular blockade. On the contrary, neuromuscular monitoring was not used during anaesthesia in the second patient; hence, the prolonged effect of the neuromuscular blocking agent was not discovered until after extubation. In the third patient, the lack of response to nerve stimulation was interpreted as a technical failure and the prolonged effect of succinylcholine was discovered when general anaesthesia was terminated. Both patients had insufficient respiration. They were therefore re-sedated, transferred to the intensive care unit and the tracheas were extubated after full recovery from neuromuscular blockade. We recommend the use of monitoring every time these agents are used, even with short-acting drugs like succinylcholine and mivacurium.

Automatic control of the NMB level in general anaesthesia with a switching total system mass control strategy.

This paper presents a model based switching control strategy to drive the neuromuscular blockade (NMB) level of patients undergoing general anesthesia to a predefined reference. A single-input single-output Wiener system with only two parameters is used to model the effect of two different muscle relaxants, atracurium and rocuronium, and a switching controller is designed based on a bank of total system mass control laws. Each of such laws is tuned for an individual model from a bank chosen to represent the behavior of the whole population. The control law to be applied at each instant corresponds to the model whose NMB response is closer to the patient's response. Moreover a scheme to improve the reference tracking quality based on the analysis of the patient's response, as well as, a comparison between the switching strategy and the Extended Kalman Kilter (EKF) technique are presented. The results are illustrated by means of several simulations, where switching shows to provide good results, both in theory and in practice, with a desirable reference tracking. The reference tracking improvement technique is able to produce a better reference tracking. Also, this technique showed a better performance than the (EKF). Based on these results, the switching control strategy with a bank of total system mass control laws proved to be robust enough to be used as an automatic control system for the NMB level.

[Effects of pri ming different low-dose rocurium on pharmacodynamics of mivacurium].

OBJECTIVE: To explore the effects of pri ming rocuronium on neuromuscular blockade produced by mivacurium. METHODS: Ethical approval was granted by the medical ethics committee of our hospital with a reference number of C-2013-018-01. A total of 120 ASA physical status I and II patients undergoing selective otorhinolaryngologic surgery under general anesthesia signed the form of informed consent. And they were randomly divided by a random number table into 4 groups. After a standardized imidazole-propofol-fentanyl induction, they received a saline placebo injection (GroupI) and a pri ming dose of rocuronium 0.06 mg/kg (GroupII) , rocuronium 0.075 mg/kg (Group III) and rocuronium 0.1 mg/kg (Group IV). An intubating dose of mivacurium 0.15 mg/kg was offered 3 minutes later. Anesthesia was maintained with propofol and remifentanyl continuous infusion. Neuromuscular block was monitored with train of four (TOF) stimulation. The onset time, reappearance of T1 (DUR TOFc 1), times of T1 25% and 75% recovery, recovery index and times of TOF25%, 75% and 90% recovery were recorded. RESULTS: The onset time of mivacurium was significantly shorter and the times of T1 25% and 75% recovery were significantly longer in groups of II, III and IV than those in groupI. No significant difference existed in recovery index among 4 groups. The onset time of mivacurium became progressively shorter with the growing pri ming dose of rocurium among three experiment groups. And it was not statistically significant. CONCLUSIONS: Pri ming rocuronium decreases the onset and intubating times of mivacurium without effect on recovery index. No significant difference exists in drug effect among 3 experiment groups.

[Residual relaxant block due to pseudocholinesterase deficiency - First manifestation in an elderly patient]. / Kasuistik: Relaxansüberhang durch Pseudocholinesterasemangel - Erstmanifestation in höherem Alter.

Pseudocholinesterase or butyrylcholinesterase (BChE) inactivates the relaxant drugs mivacurium and suxamethonium. A deficiency in plasma activity of this enzyme may result in prolonged muscular paralysis and subsequently the need for an extended duration of mechanical ventilation. We report the case of a 65-year-old patient who was diagnosed with butyrylcholinesterase deficiency for the first time during elective surgery. Neuromuscular monitoring constitutes a central diagnostic asset in ensuring patient safety.

Effects of preoperatively administered carbamazepine and phenytoin on rocuronium-induced neuromuscular block under sevoflurane anesthesia: a retrospective clinical study.

We examined the effects of preoperatively administered phenytoin and carbamazepine on rocuronium-induced neuromuscular block under sevoflurane anesthesia in this retrospective clinical study. When compared to patients without anticonvulsant therapy (n = 16), the recovery index (i.e., the time required from 25% of spontaneous return of T1 to 75% of spontaneous return of T1) was significantly lower in patients with anticonvulsant therapy using carbamazepine and/ or phenytoin (n = 17); however, no significant dose-dependent effects of carbamazepine as well as phenytoin on the recovery index were detected. Further studies are required to elucidate the mechanisms underlying the modifying effects of carbamazepine and phenytoin on pharmacokinetics and pharmacodynamics of rocuronium.

Effect of bolus injection of 20 ml saline with arm elevation on the onset time of vecuronium administered via a peripheral vein: a randomised controlled trial.

We investigated whether a bolus injection of 20 ml saline with arm elevation might shorten the onset time of vecuronium administered via a dorsal hand vein. Thirty patients were randomly allocated to the bolus saline group or control group. General anaesthesia was induced and maintained with remifentanil and propofol. Vecuronium 0.1 mg.kg(-1) was administered to all patients, followed in the treatment group by bolus injection of 20 ml saline and arm elevation. Response to train-of-four stimulation was measured by acceleromyography at the adductor pollicis muscle. The mean (SD) lag time was 47.2 (14.5) s in the bolus saline group and 67.9 (12.2) s in the control group (p = 0.0002). The time to 95% block of T1 was 104.6 (29.9) s in the bolus saline group and 128.3 (15.8) s in the control group (p = 0.011). Bolus saline injection results in shortened lag time and onset time of neuromuscular block with vecuronium.

Influence of real-time Bayesian forecasting of pharmacokinetic parameters on the precision of a rocuronium target-controlled infusion.

INTRODUCTION: Bayesian forecasting has been shown to improve the accuracy of pharmacokinetic/pharmacodynamic (PK/PD) models by adding measured values to a population model. It could be done in real time for neuromuscular blockers (NMB) using measured values of effect. This study was designed to assess feasibility and benefit of Bayesian forecasting during a rocuronium target-controlled infusion (TCI). METHODS: After internal review board (IRB) approval and informed consent, 21 women scheduled for breast plastic surgery were included. Anesthesia was maintained with propofol, alfentanil, and controlled ventilation through a laryngeal mask. Rocuronium was delivered in TCI with Stanpump software and the Plaud population model. The target effect was 50% blockade until insertion of breast prosthesis; thereafter it was set to 0%. Response to train of four (TOF) at adductor pollicis was recorded using a force transducer. In ten patients, drug delivery was based on the population model. In the others, repeated measures values were entered in the software, and the PK model was adjusted to minimize the error in predicted effect. Model precision was compared between groups using mean prediction error and mean absolute prediction error. RESULTS: At target 50%, model accuracy was not improved with Bayesian adjustments; conversely, post-infusion errors were significantly decreased. The first two measures had the most influence on the model changes. DISCUSSION: Below clinical utility, such adjustments may be used to explore cofactors influencing interindividual and intraindividual variability in NMB dose-response relationship. Similar tools may also be developed for drugs in which a quantitative effect is available, such as electroencephalography (EEG) for hypnotics. IMPLICATION: Real-time Bayesian forecasting combining measured values of effect with a population model is suitable to guide NMB-agent delivery using Stanpump software.

Dialysability of sugammadex and its complex with rocuronium in intensive care patients with severe renal impairment.

BACKGROUND: Renal excretion is the primary route for the elimination of sugammadex. We evaluated the dialysability of sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment in the intensive care unit (ICU). METHODS: Six patients in the ICU with acute severe renal impairment received general anaesthesia for transoesophageal echocardiography, to replace their tracheal tubes, or for bronchoscopy. Five of the six patients were in the ICU after cardiac/vascular surgery and one for pneumonia-induced respiratory failure. They all received rocuronium 0.6 mg kg(-1), followed 15 min later by sugammadex 4.0 mg kg(-1). Two patients were studied for two dialysis episodes and four patients for four episodes. Rocuronium and sugammadex concentrations were measured in plasma and dialysate at several time points before, during, and after high-flux dialysis. Dialysis clearance in plasma and dialysate, and reduction ratio (RR) (the extent of the plasma concentration reduction at the end of a dialysis episode when compared with before dialysis) were calculated for each dialysis episode. RESULTS: Dialysis episodes lasted on average 6 h. Observed RRs indicated mean reductions of 69% and 75% in the plasma concentrations of sugammadex and rocuronium, respectively, during the first dialysis episode. Reductions were around 50% during sequential dialysis episodes. On average, dialysis clearance of sugammadex and rocuronium in blood was 78 and 89 ml min(-1), respectively. CONCLUSIONS: Haemodialysis using a high-flux dialysis method is effective in removing sugammadex and the sugammadex-rocuronium complex in patients with severe renal impairment.

The pharmacodynamics of vecuronium in chronic renal failure patients: the impact of different priming doses.

PURPOSE: The concept of priming was introduced to facilitate a faster onset of nondepolarizing neuromuscular blocker for endotracheal intubation. Vecuronium is still very much in use for most chronic renal failure patients posted for renal transplantation. The aim of this study was to examine the pharmacodynamics of vecuronium without and with preceding different small doses. METHODS: One hundred chronic renal failure patients were assigned into four groups according to the used vecuronium priming regimen. The first control group (V(0)-group), where no priming dose was given. The other three priming groups (V(10)- , V(15)- , and V(20)-groups), where 10%, 15%, and 20% of ED(95) of vecuronium were administrated 5 min prior to the remaining intubating dose (2 × ED(95)) of vecuronium. Neuromuscular blockade was measured via acceleromyographic response of the ulnar nerve. Train-of-four (TOF) ratio was measured every minute during priming interval. Any unpleasant symptoms during precurarization were recorded. Lag time and onset time (from injection of intubating dose) were recorded. Endotracheal intubation condition was scored blindly. The duration and recovery times were also recorded. RESULTS: The significant higher incidence of symptoms of paresis was encountered in V(20)-group in comparison with other two priming groups. TOF ratio started to decrease significantly at the first minute in V(20)-group, at the second minute in V(15)-group, and at the third minute in V(10)-group, till the fourth minute in the priming interval. Although TOF ratio was still above 0.90 in V(10)-group, it was below 0.80 in V(20)-group. Priming groups did not show significant intergroup difference in onset time. However, duration and recovery times were significantly longer in priming groups in comparison with V(0)-group without priming. CONCLUSION: Priming the chronic renal failure patients with 10% of ED(95) vecuronium dose acquit the best pharmacodynamics with the fewest signs of muscle weakness. Larger vecuronium priming doses are unfavorable and convey no more clinical utility.

Population pharmacokinetic-pharmacodynamic analysis for sugammadex-mediated reversal of rocuronium-induced neuromuscular blockade.

AIMS: An integrated population pharmacokinetic-pharmacodynamic model was developed with the following aims: to simultaneously describe pharmacokinetic behaviour of sugammadex and rocuronium; to establish the pharmacokinetic-pharmacodynamic model for rocuronium-induced neuromuscular blockade and reversal by sugammadex; to evaluate covariate effects; and to explore, by simulation, typical covariate effects on reversal time. METHODS: Data (n= 446) from eight sugammadex clinical studies covering men, women, non-Asians, Asians, paediatrics, adults and the elderly, with various degrees of renal impairment, were used. Modelling and simulation techniques based on physiological principles were applied to capture rocuronium and sugammadex pharmacokinetics and pharmacodynamics and to identify and quantify covariate effects. RESULTS: Sugammadex pharmacokinetics were affected by renal function, bodyweight and race, and rocuronium pharmacokinetics were affected by age, renal function and race. Sevoflurane potentiated rocuronium-induced neuromuscular blockade. Posterior predictive checks and bootstrapping illustrated the accuracy and robustness of the model. External validation showed concordance between observed and predicted reversal times, but interindividual variability in reversal time was pronounced. Simulated reversal times in typical adults were 0.8, 1.5 and 1.4 min upon reversal with sugammadex 16 mg kg(-1) 3 min after rocuronium, sugammadex 4 mg kg(-1) during deep neuromuscular blockade and sugammadex 2 mg kg(-1) during moderate blockade, respectively. Simulations indicated that reversal times were faster in paediatric patients and slightly slower in elderly patients compared with adults. Renal function did not affect reversal time. CONCLUSIONS: Simulations of the therapeutic dosing regimens demonstrated limited impact of age, renal function and sevoflurane use, as predicted reversal time in typical subjects was always <2 min.

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.

Circulatory model of vascular and interstitial distribution kinetics of rocuronium: a population analysis in patients.

The time-course of the neuromuscular blocking effect of rocuronium depends on circulatory mixing and the rate of distribution into the interstitial space. In order to quantitatively evaluate these processes, a physiologically meaningful model of distribution kinetics based on circulatory transport and interstitial diffusion, was fitted to rocuronium disposition data in 10 patients using a population approach. Information on cardiac output and circulatory mixing was obtained from the kinetics of indocyanine green (ICG), which was injected simultaneously with rocuronium. As a compromise between physiological reality and parameter identifiability, the organs of the systemic circulation were lumped into a heterogeneous subsystem, described by an axially distributed model of extravascular diffusion. Diffusion into the interstitial space determines the rate of rocuronium distribution in the body (diffusional time constant 89 min). The resulting whole body distribution kinetics depends both on cardiac output and on the apparent permeability surface area product (0.16 l/min). The analysis of the ICG data revealed that heterogeneity of blood transit time through the systemic circulation decreased and that cardiopulmonary volume increased, respectively, with cardiac output. The approach should be useful for studying the effect of disease states on distribution kinetics of drugs.

[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.