Rocuronium is an aminosteroid muscle relaxant with a short onset time [1,2]. It has an intermediate duration of action and may therefore be administered in a continuous infusion during prolonged anaesthesia. The effects of various anaesthetic techniques on the relation between the dose and response of rocuronium have been studied recently both after the administration of a bolus and during an infusion of the drug [3-6]. However, the relation between the concentration of rocuronium and response appears to have been studied only after the bolus administration [7,8]. If the results of combined pharmacokinetic/pharmacodynamic modelling obtained after a single bolus are extrapolated beyond the data upon which they are derived, biased conclusions are possible. Therefore, we considered it important to study the pharmacokinetics and pharmacodynamics of rocuronium infusion during general anaesthesia with intravenous (i.v.) and volatile anaesthetics.
Patients and methods
After approval of the local Medical Ethics Committee and after obtaining informed written consent from each patient, we studied 20 patients scheduled for abdominal or thyroid surgery estimated to last at least 3 h. The patients were aged 18-67 years and their ASA physical status was I or II. Patients with renal, hepatic or neurological diseases or patients receiving medication known to affect neuromuscular transmission were excluded from the study.
Patients were premedicated with oral diazepam 0.1-0.2 mg kg−1 1 h before the induction of anaesthesia. Anaesthesia was induced with fentanyl (1-3 μg kg−1) and propofol (2-3 mg kg−1). The patients were then randomly assigned to one of the two study groups. The first group received a continuous infusion of propofol (5-10 mg kg−1 h−1) and nitrous oxide in oxygen (2:1). In the second group anaesthesia was maintained with isoflurane 1.15% end-tidal concentration, corresponding to 1 MAC and nitrous oxide in oxygen (2:1). Additional fentanyl boluses (1-2 μg kg−1) were given to both groups if anaesthesia was considered insufficient as indicated by salivation, lacrimation or changes in cardiovascular parameters (>15% increase in blood pressure or heart rate; baseline values were measured just before the induction of anaesthesia). End-tidal CO2 tension was maintained at 4-5 kPa and the peripheral skin temperature was measured and kept over 32°C. Neuromuscular block was monitored with electromyography (Relaxograph, Datex, Helsinki, Finland). The surface electrodes were placed over the ulnar nerve at the wrist and the nerve stimulated supramaximally with a train-of-four sequence (frequency of stimuli, 2 Hz; pulse width 100 μs). The compound electromyogram was recorded from electrodes placed over the first dorsal interosseus muscle and on the base of the index finger. The degree of neuromuscular block was defined as the ratio of the measurement of the first twitch in a train-of-four sequence to the corresponding control value. The monitoring device was calibrated immediately after induction of anaesthesia and a stable base-line calibration signal was awaited for 5-10 min and after that a second calibration was performed. In addition to the above recordings, normal monitoring was used.
All patients received rocuronium 0.35 mg kg−1 calculated per lean body mass  to facilitate tracheal intubation. The bolus dose was followed by a continuous infusion of rocuronium through an indwelling catheter in a forearm vein. The infusion rate was controlled by a model-driven closed-loop system described previously . An infusion pump (Fresenius infusomat CP-IS, Fresenius AG, Bad Homburg, Germany) and the Relaxograph were attached to a Compaq Portable 386 Computer (Compaq, Houston Texas, USA) by means of a serial RS232 interface. The neuromuscular block was kept stable at 90% for the first 90 min study period. Then the set-point was lowered to 50% and maintained at that level for 45 min. During the closed-loop feedback infusion of rocuronium the measured values of effect and rate of the infusions were stored on the computer. The controller performance was measured by calculating the mean offset from the set-point and the mean standard deviation from the set-point during feedback infusion . The asymptotic steady-state rates of infusion (I90 and I50) of rocuronium for the two levels of neuromuscular block were estimated by non-linear regression, used to fit the following formula to the curve representing the cumulative dose requirement for rocuronium . Equation 1 where D=amount of rocuronium in its apparent distribution volume, k=relative rate of distribution of rocuronium, Iss=asymptotic steady-state rate of infusion of rocuronium, t=duration of rocuronium administration. At 90% neuromuscular block Iss=I90 and at 50% Iss=I50. To evaluate the possible time dependency of the infusion requirements, the cumulative rocuronium requirements were calculated at 30 min intervals during 90% neuromuscular block.
Blood samples for the determination of plasma rocuronium concentrations were drawn from a venous cannula placed in the arm without the infusion. The first sample was taken before the induction of anaesthesia. The next sample was drawn when neuromuscular block reached the setpoint for the first time after the initial overshoot following the bolus dose of rocuronium. Thereafter the samples were drawn at ≈15 min intervals until the set-point was changed to 50%. At 50% neuromuscular block the first sample was taken when the 50% level was reached for the first time after the change of the set-point. Further samples were then taken at ≈15 min intervals until the end of the study. The blood was sampled only after a stable infusion scheme for rocuronium of at least 5-10 min. Plasma was separated within 2 h of sampling and stored at −70°C until the analysis with HPLC .
The steady-state plasma concentrations of rocuronium at 90% and at 50% neuromuscular block (C90 and C50) were determined by linear regression analysis from the concentration data obtained from blood sampling. The C90 was calculated to represent the end of the 90 min study period of 90% neuromuscular block and the C50 to represent the endpoint of the study after 45 min of stable neuromuscular block of 50%. The plasma clearances of rocuronium at 90% and 50% neuromuscular block (CL90 and CL50) were calculated from the formulas CL90=I90/C90 and CL50=I50/C50, respectively.
The study groups were compared with the Mann-Whitney U-test and χ2-test. Intragroup comparisons of the controller performance and plasma clearances of rocuronium calculated at 90% and 50% neuromuscular block were with the Wilcoxon signed ranks test. The possible time-dependency of the cumulative infusion requirements of rocuronium at 30 min intervals were analysed with analysis of variance for repeated measurements and the possible time-dependency of rocuronium plasma concentrations with linear regression analysis. P<0.05 was considered to indicate statistically significant differences. All results are given as mean ±SD.
Table 1 shows the patient characteristics for the two groups. There were no significant differences between the groups with regard to age, weight, height or ASA physical status. Table 2 shows the average controller performance and the mean values of the calculated pharmacokinetic and pharmacodynamic variables. At 90% neuromuscular block there were no differences in controller performance between the study groups, but at 50% block the mean offset from the set-point was smaller in patients anaesthetized with propofol (P<0.005).
The steady-state infusion requirements of rocuronium were significantly lower in the group receiving isoflurane. Isoflurane reduced the mean I90 by 35% and mean I50 by 52% (P<0.005), respectively (Table 2; Fig. 1). The corresponding reduction in C90 was 35% (P<0.005) and in C50 59% (P<0.001). The values for CL90 and CL50 and were unaffected by the type of anaesthesia.
The cumulative dose requirements of rocuronium calculated at 30-min intervals during 90 min for 90% neuromuscular block were 46.3±11.0, 21.2±6.3 and 19.4±5.0 mg in patients anaesthetized with propofol and 41.6±11.2, 14.8±4.5 and 13.4±5.1 mg in patients anaesthetized with isoflurane, respectively. The cumulative dose requirements decreased in both groups from the first to the second study period (P<0.001) but thereafter no statistically significant changes were observed. After the initial 30-min period, the cumulative rocuronium requirements were smaller (P<0.05) in the isoflurane group. Linear regression analysis revealed a time-dependent reduction in the plasma rocuronium concentration with 90% neuromuscular block in only four patients receiving isoflurane. In the patients anaesthetized with propofol the plasma concentrations did not change with time. At 50% neuromuscular block the plasma concentrations of rocuronium remained at the same level in both groups.
Isoflurane clearly affected the relation between dose and response and the concentration and response to rocuronium administered by computer-controlled infusion by changing the pharmacodynamic behaviour. While the values for CL90 and CL50 and were unaffected by the type of anaesthesia, isoflurane reduced both the behaviour values for I90 and I50 and C90 and C50.
Pharmacokinetic-dynamic modelling of the effects of muscle relaxants has become very popular since the pioneering work of Hull et al. and Sheiner et al.. The employment of the effect compartment approach has made it possible to model the relation between the drug concentrations and effects in a nonsteady-state situation. However, the concentrations in the effect compartment are hypothetical and there is no direct information on the actual concentrations at the site of action in vivo. Pharmacokinetic-dynamic modelling has mainly been used to describe the pharmacokinetic-dynamic relation of bolus doses or short-term infusions. However, if models are extrapolated beyond the data upon which they are derived, biased conclusions are possible. It has also been shown that infusion regimens designed from prior pharmacokinetic studies may not perform well during time periods not sampled in the original research . We therefore found it important to study the relation between dose and response and concentration and response for rocuronium during continuous infusion.
The degree of the neuromuscular block was controlled by a model-driven computerized infusion, which has previously been shown to be suitable for the control of muscle relaxation using atracurium, mivacurium, rocuronium and vecuronium . Also in the present study the computer-controlled closed-loop infusion of rocuronium kept the neuromuscular block at a relatively constant level. At 90% neuromuscular block there were no differences between the groups in the controller performance; the mean offset values from the set-point were less than 1%. When the set-point was lowered to 50%, there were statistically but hardly clinically significant differences in the controller performance between the two groups. Thus, the calculated pharmacodynamic and pharmacokinetic variables of the two groups could be compared.
Previous pharmacokinetic/pharmacodynamic studies using the effect compartment approach with rocuronium have been carried out after bolus administration or short-term infusion [7,8]. In the present study no effect compartment was modelled but the methodology was based on the assumption that, when a steady-state is approached during computer-controlled infusion, the concentration at the site of action of rocuronium is equal to the concentration in the sampling site i.e. the plasma. During rocuronium infusions lasting no longer than about 2 h, a true steady-state is not reached. However, it can be estimated that a drug, with a termination of effect mainly because of redistribution, will also essentially approach the steady-state in a much shorter time than could be predicted on the basis of the elimination half-life . Present methodology also assumes that the pharmacokinetics of rocuronium are time-independent and previous studies suggest that this is a valid assumption . In contradistinction with previous pharmacokinetic studies that have shown that the potentiation of the neuromuscular blocking action of muscle relaxants, by volatile anaesthetics, is a time-dependent phenomenon [18-20]; therefore in the present study the C90 and C50 were determined by linear regression analysis instead of by simply calculating the mean values. However, in only four patients receiving isoflurane did the plasma concentrations of rocuronium, associated with 90% neuromuscular block decrease with time and at 50% neuromuscular block there was no change in the plasma concentrations in any of the patients. Cumulative infusion requirements calculated at 30-min intervals at 90% neuromuscular block demonstrated that, after the initial 30 min, the requirements remained at the same level and no major potentiation occurred beyond this point. The time-dependent potentiation of the neuromuscular blocking effect of rocuronium by isoflurane was also taken into account by using the asymptotic steady-state rate of infusion of rocuronium in the calculations instead of by using the actual infusion rates. By calculating the asymptotic steady-state rate of infusion as suggested by Keéri-Szanto , it is possible to estimate the rate of infusion during the steady-state although true steady-state would never be reached.
In the present study the concentration at half-maximal effect, C50, was 1077±244 ng mL−1 during propofol anaesthesia, which is at the same level as that observed previously during i.v. anaesthesia [7,8]. Thus, our results suggest that the concentrations at half-maximum effect calculated in a non-steady-state situation by using the effect compartment approach are valid and reflect the concentrations at the site of action. There is no previous information available on C50 values during anaesthesia with volatile anaesthetics. In the present study isoflurane 1 MAC reduced C50 by ≈59%.
The plasma clearance of rocuronium was sligthly different when calculated using I90 and C90 compared with the values calculated using I50 and C50 because steady-state was obviously not reached during a 90 min of infusion of rocuronium at 90% neuromuscular block and the values obtained at 50% neuromuscular block represent a well established steady-state. The values for plasma clearance were not affected by the anaesthetic technique, which concurs with the results of earlier investigations which demonstrated that volatile anaesthetics do not change the pharmacokinetics of neuromuscular blocking drugs [21,22]. Compared with previous studies, the values for plasma clearance were at the same level [17,22,23].
The steady-state infusion rate of rocuronium required to maintain 90% neuromuscular block during propofol anaesthesia in the present study is comparable with the earlier reports during i.v. anaesthesia [5,6]. In our previous study isoflurane 0.6 MAC reduced the infusion requirement for rocuronium required to maintain 90% neuromuscular block by 35-40% compared with i.v. anaesthesia . Isoflurane 0.8 MAC or enflurane reduce the infusion requirements for rocuronium at 95% neuromuscular block by 40% . In the present study the reduction in the infusion requirements was 35% at 90% and 52% at 50% block during isoflurane anaesthesia. The greater reduction of infusion requirement at 50% block might be due in part to the longer duration of isoflurane administration when the steady-state rate of infusion of rocuronium was estimated at 50% block.
We conclude that isoflurane reduces the infusion requirements of rocuronium by reducing the concentration at half-maximal effect. The pharmacokinetics of rocuronium is unaffected by isoflurane.
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