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).

Simultaneous quantification of propofol, ketamine and rocuronium in just 10 µL plasma using liquid chromatography coupled with quadrupole mass spectrometry and its pilot application to a pharmacokinetic study in rats.

The combination of propofol, ketamine and rocuronium can be used for anesthesia of ventilated rats. However, reliable pharmacokinetic models of these drugs have yet to be developed in rats, and consequently optimal infusion strategies are also unknown. Development of pharmacokinetic models requires repeated measurements of drug concentrations. In small animals, samples must be tiny to avoid excessing blood extraction. We therefore developed a drug assay system using high-performance liquid chromatography coupled with quadrupole mass spectrometry that simultaneously determines the concentration of all three drugs in just 10 µL rat plasma. We established a plasma extraction protocol, using acetonitrile as the precipitating reagent. Calibration curves were linear with R2 = 0.99 for each drug. Mean recovery from plasma was 91-93% for propofol, 89-93% for ketamine and 90-92% for rocuronium. The assay proved to be accurate for propofol 4.1-8.3%, ketamine 1.9-7.8% and rocuronium -3.6-4.7% relative error. The assay was also precise; the intra-day precisions were propofol 2.0-4.0%, ketamine 2.7-2.9% and rocuronium 2.9-3.3% relative standard deviation. Finally, the method was successfully applied to measurement the three drugs in rat plasma samples. Mean plasma concentrations with standard deviations were propofol 2.0 µg/mL ±0.5%, ketamine 3.9 µg/mL ±1.0% and rocuronium 3.2 µg/mL ±0.8% during ventilation.

Effect of sevoflurane anesthesia on neuromuscular blockade produced by rocuronium infusion in dogs.

This study evaluated the effect of sevoflurane anesthesia on neuromuscular blockade with rocuronium in dogs. Six healthy beagle dogs were anesthetized four times with a minimum 14-day washout period. On each occasion, the dogs were administered 1.25-, 1.5-, 1.75-, or 2.0-fold of the individualized minimum alveolar concentration (MAC) of sevoflurane and received an infusion of rocuronium (0.5 mg/kg followed by 0.2 mg/kg/hr) for 120 min. Neuromuscular function was monitored with acceleromyography and train-of-four (TOF) stimulation of the left hind limb. Time to achieve TOF count 0 (onset time), time from the onset of neuromuscular blockade to the reappearance of TOF count 4 (blockade period), and time from the onset of rocuronium infusion to attaining a 70 or 90% TOF ratio (TOFR70 or TOFR90) were recorded. There were no significant differences in the onset time, blockade period, and plasma rocuronium concentration between the sevoflurane MAC multiples. The TOFR70 and TOFR90 were dose-dependently prolonged with the sevoflurane MAC multiples. There were significant differences in the TOFR70 and TOFR90 between the 1.25 sevoflurane MAC (median: 55 and 77.5 min, respectively) and 1.75 sevoflurane MAC (122.0 and 122.6 min; P=0.020 and P=0.020, respectively), 1.25 sevoflurane MAC and 2.0 sevoflurane MAC (126.0 and 131.4 min; P=0.020 and P=0.020), and 1.5 sevoflurane MAC (97.5 and 121.3 min) and 2.0 sevoflurane MAC (P=0.033 and P=0.032). In dogs, sevoflurane anesthesia produced dose-dependent prolongation of recovery from neuromuscular blockade produced by rocuronium.

Rocuronium pharmacodynamic models for published five pharmacokinetic models: age and sex are covariates in pharmacodynamic models.

PURPOSE: Equilibration rate constant is necessary to calculate effect-site concentration, which is useful to control drug effect. We developed pharmacodynamic models for published five compartmental pharmacokinetic models published by Wierda, Szenohradszky, Cooper, Alvarez-Gomez, and McCoy. METHODS: We used 3848 train-of-four ratios from 15 male and nine female patients (21-76 years; 44-93 kg body weight; 148-181 cm height; and 17.3-29.8 kg/m2 body mass index) as pharmacodynamic measures, which were collected at the start of 0.6 mg/kg rocuronium administration until the end of the surgery. Effect compartment was assumed to be connected to central compartment of the pharmacokinetic model with equilibration rate constant (ke0). Sigmoid Emax model was fitted to describe the relationship between train-of-four ratio and effect-site concentration. Age, sex, and body mass index were assessed as possible covariates of the following model parameters: ke0, effect-site concentration for half of maximum effect, and the steepness of the effect-site concentration versus effect relationship. RESULTS: The duration of neuromuscular monitoring was 69 (37-129) [median (range)] min. All pharmacodynamic models included age and three included sex as significant covariates. Ke0 values ranged between 0.0820 and 0.247 depending on the pharmacokinetic model. The time-courses of the effect-site concentration were similar among the pharmacodynamic models for Wierda, Cooper, and Alvarez-Gomez pharmacokinetic models, which were lower than that for the Szenohradszky pharmacokinetic model. CONCLUSION: Each pharmacodynamic model with the corresponding pharmacokinetic model can be described the time course of rocuronium effect appropriately. The required effect-site concentration of rocuronium for a pharmacodynamic effect was depending on the applied models.

[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.