Since the introduction of neuromuscular blocking drugs (NMBD) in clinical pediatric anesthesia, controversies concerning potency and pharmacokinetic-pharmacodynamic (PK-PD) relationships remain. Throughout childhood, the process of maturation of the neuromuscular system, liver and kidney function, redistribution of extracellular water volume, and relative increase in muscle mass as a proportion of body weight are responsible for the age-related responses to NMBD (1). PK and PD data of rocuronium in infants, children, and adults have been primarily obtained from single-bolus studies with determination of plasma concentrations (2–5). The use of a bolus injection followed by a continuous infusion has the advantage of achieving a relatively rapid and stable level of neuromuscular blockade (NMB). Continuous IV infusion can also be performed by means of computer-based PK software controlling a syringe driver to target a theoretical plasma concentration (Cp). At steady-state, the PKs are compensated for by target-controlled infusions (TCI), and a stable effect can be observed. At this point, the calculated Cp may represent the effect-site concentration (EC). Clinical experience with TCI of NMB is not available in the pediatric population.
Rocuronium, an intermediate-acting muscle relaxant with a faster onset of action has the PK properties suitable for continuous infusion (5). Wierda et al. (2,6) determined the PKs and PK/PD relationships of rocuronium and calculated the concentration in the effect compartment associated with a 50% drug effect (EC50) in adults, children, and infants by using the Sheiner model and the Hill equation (7–9).
The aim of this study was to analyze the PK/PD relationship during TCI of rocuronium in infants, children, and adults. The EC concentration-effect relationship was studied, and EC50 as a variable of potency and EC90 as a target figure for surgical relaxation were defined.
This study was approved by the institutional Medical Ethics Committee, and informed consent was obtained from parents or patients. Thirty-seven children and 21 adults, ASA physical status I–II, undergoing elective surgical procedures with minimal blood loss, were included. Overweight patients, those with a history of neuromuscular disease, malignant hyperthermia, or renal or hepatic dysfunction, and those taking medication with potential interference with neuromuscular transmission were excluded. Three groups of patients were included, according to age: infants, 1–10 mo; children, 2–10 yr; and adults, 20–50 yr. Infants received no premedication, children received oral midazolam 0.5 mg/kg, and adults received sublingual lorazepam 2.5 mg. All children received eutectic mixture of local anesthetics crème (AstraZeneca) on two places evident for IV puncture.
A peripheral IV catheter was placed at arrival in the operating room in the same arm used for neuromuscular transmission assessments. Standard monitoring included electrocardiogram (ECG), pulse oximetry, noninvasive blood pressure, capnography, and rectal and palmar skin temperature. Anesthesia was induced with 2 μg · kg−1 · min−1 of remifentanil and propofol 12 mg · kg−1 · h−1 in infants and children and with propofol TCI (Diprifusor; Zeneca Pharmaceuticals, Macclesfield, UK) to a theoretical target blood concentration (Cpth) of 6 μg/mL in adults. This combination of remifentanil and propofol allowed us to intubate the trachea without muscle relaxants. No incidents such as bradycardia, hypotension, or severe muscle rigidity were encountered. A second IV catheter was placed in a larger vein in the other arm or foot for blood sampling. Ventilation of the lungs with a 50% oxygen/air mixture was controlled to maintain an end-tidal CO2 of 32–38 mm Hg. Anesthesia was maintained with propofol and remifentanil according to clinical needs. No inhaled anesthetics were used.
Neuromuscular transmission was evaluated by using the acceleromyographic method (TOF-Guard; Organon Teknika, Oss, The Netherlands). Surface stimulation electrodes were placed over the ulnar nerve at the wrist, and the acceleration transducer was attached to the thumb, allowing free movements, while the other fingers and arm were taped in the extension position. The ulnar nerve was stimulated supramaximally with a duration of 0.2 ms in a train-of-four (TOF) mode at a frequency of 2 Hz every 15 s. After calibration, a stable response was awaited before the administration of rocuronium. The first twitch (T1) of the TOF and the T4/T1 ratio were assessed, electronically stored on memory cards, and read into a computer program (TOF-Guard Card Reader, Version 1.0; Organon).
The peripheral skin temperature was kept >33°C by using a Bair Hugger system (Augustine Medical Inc.) during all measurements. After the infusion was stopped, spontaneous recovery was observed up to a T4/T1 ratio of 0.9, after which all patients were fully recovered and tracheally extubated.
Rocuronium 2 mg/mL for infants and children and 10 mg/mL for adults in a 10-mL syringe was given with a Graseby 3400 syringe driver in a target blood concentration controlled manner. The Cpth and the infusion rate were calculated by Stanpump (10) every 10 s (Stanpump Pharmacokinetic Software; Stanford University, Stanford, CA). Stanpump was programmed for TCI rocuronium according to PK sets found in the literature for infants, children, and adults (2,6–8) (Table 1). Patients received three to six of the following ascending levels of TCI rocuronium (ng/mL)—t0 = 0, t1 = 850, t2 = 1000, t3 = 1300, t4 = 1600, t5 = 1900, t6 = 2200, and t7 = 2500—according to the neuromuscular transmission response. The ascending TCI targets were chosen to avoid complete NMB. Between each two target concentrations, there was an interval of at least 3 times t1/2 keo to obtain a steady-state (t1/2 keo = ln2/keo); t1/2 keo is a calculated variable for the expected interval between the administration of the drug and the maximum concentration of the drug in the effect compartment (11). This variable is drug specific and age dependent: respectively 2.2, 2.8, and 4.1 min for children, infants, and adults. Just before each increase of TCI, target venous blood samples were taken (0.5 mL in infants and children and 2 mL in adults) and stored in lithium heparinized tubes on ice until centrifugation. After centrifugation, plasma samples were stored at −20°C. Measured plasma concentrations (Cpm) of rocuronium were measured by a sensitive and selective high-performance liquid chromatography method (12). The accuracy of analysis was expressed as a coefficient of variation of the calibration curves and was <15%. The lower limit of quantification for rocuronium in plasma was 10 ng/mL, with a coefficient of variation of <15%.
TOF-Guard created an output file that allowed the analysis of twitch response, T4/T1 ratio, and skin temperature every 15 s for each Cpth. The PD variables derived from these files were maximum effect, time to maximum effect, time to recovery of T1 to 25% and 75% of its baseline value, recovery index (RI; time from 25% to 75% recovery), and time to a TOF ratio of 0.70. Stanpump created an output file that allowed analysis of the achievement of each Cpth, the duration of each target, and the total dose given at the end of the infusion. For each Cpm during steady-state, the corresponding effect was determined. These data allowed us to define the individual correlation between NMB and Cpm by sigmoidal regression analysis with the Hill equation (effect = Ceγ/Ceγ + EC50γ) (13) and to determine the EC50 for infants, children, and adults. In analogy, we calculated the EC90 as follows (13):
The accuracy of the three PK sets of TCI was assessed by performance error (PE), median PE (MDPE), and median absolute PE (MDAPE) (14):
Values are presented as mean (sd) or mean (range). The Hill equation was used to model effect-EC concentration (SigmaPlot; SPSS Inc., Chicago, IL). Data were compared by analysis of variance. The Scheffé test was used for further comparison. Statistical significance was defined at P < 0.05.
The demographic and procedural data of the three groups of patients are shown in Table 2. Although the total duration of TCI rocuronium did not differ between the groups, the weight-corrected dose of rocuronium was significantly larger in children to obtain the same level of NMB. The duration of infusion of each Cp target was at least 3 times t1/2 keo and was not significantly different between the groups.
The maximum block achieved at the TCI targets—1000, 1300, and 1600 ng/mL—differed between the groups (Table 3). The maximum effect in infants and adults was significantly greater compared with in children (P < 0.05). The maximum effect was similar in the infants and adults. The time necessary to reach the maximum effect was comparable in all study groups.
The RI was smaller and the time to recovery of the TOF ratio to 0.70 was significantly shorter in children than in infants and adults, although the maximum percentage block after the last TCI did not differ among groups. All Cpm values were plotted against the corresponding NMB by using a sigmoidal dose-response nonlinear regression fitting (Fig. 1). The EC50, calculated from individual response data, differed significantly among all groups (Table 4). The EC90 was significantly smaller in infants compared with children and adults (Table 4).
The Cpm was significantly smaller than the Cpth in infants at the smaller rocuronium TCI targets (1000 and 1300 ng/mL) (P < 0.05). At the TCI target 850 ng/mL, only in six infants was a clinically measurable block achieved. At the 2200 and 2500 ng/mL targets, 12 and 2 children, respectively, still had a clinically measurable NMB. Measurable neuromuscular transmission could be observed in only one adult during the TCI target 2200 ng/mL. The PE was significantly larger in infants (39%) than in children and adults (respectively, 23% and 16%) (P < 0.0001).
TCI of rocuronium allowed us to compare PD differences among infants, children, and adults. We were able to establish steady-state NMB at different TCI targets. Further, TCI may have the clinical advantage of providing a stable Cp and a stable effect with minimal intervention of the anesthesiologist. EC50 was significantly smaller in infants in comparison with children and adults, whereas EC50 was larger in children versus adults. Targets necessary for intubation or surgical relaxation were smaller for infants.
PK/PD characteristics for different age groups are mainly studied after bolus injection or short continuous infusion of NMBD. The effect data obtained from these studies, however, are the combined results of both PK and PD differences among infants, children, and adults. TCI was used in this study to establish steady-state PK/PD at different Cpth levels by waiting at least 3 times the t1/2 keo before a blood sample was taken for assessment of rocuronium Cp (three to five samples per patient). The rate constant keo defines the time delay between the blood concentration of the drug and the corresponding effect. This keo can be transformed into a half-life of equilibration (t1/2 keo = ln2/keo). This variable allows comparison of the expected interval between administration and maximum concentration of the drug in the effect compartment between different age groups.
The combination of these values representing EC and the measured corresponding NMB allowed us to study the EC versus effect relationship of rocuronium in the three age groups. TCI can have several advantages for the design of studies of muscle relaxants. With bolus studies, PK/PD results are affected by unknown varying times of plasma peak concentrations, minimal shifts in the time specification of PD data, and, especially, the magnitude of the administered bolus dose (15). Infusion rate studies create only one steady-state target from which mean infusion rates can be predicted. TCI allowed us, at different predetermined target concentrations, to explore PK/PD relationships while bypassing PK differences.
Wierda et al. (2,11) used multiple blood sampling and a three-compartment model-fitting procedure to determine the PK characteristics and the PK/PD relationships in infants, children, and adults. This methodology implied a larger number of blood samples (n = 17) per patient. Consequently, the number of patients was limited in infants. The PK sets they obtained reflect the age-dependent PK differences. The volume of distribution at steady state (Vdss) is smaller in children than in infants and adults. Particularly, the volume of the second compartment is smaller in children, whereas k10, as a variable of clearance from the central compartment, is larger in children. This resulted for children in a PK explanation for the fast recovery. The k12 time constant for equilibration between the central and rapidly equilibrating compartment is smallest in adults, resulting in a faster onset time in children and infants (3,16). Also, the faster keo constant in children explains the faster onset of NMBD in a previous study (17). The methods we used may largely compensate for these age-related PK differences. By doing this, we tried to study only the PD differences among adults, children, and infants.
In this study, time to maximum block did not differ significantly among groups. Contradictory data are found in the literature. Taivainen et al. (17) found a shorter onset time in children, whereas Driessen et al. (16) and Woelfel et al. (3) reported a shorter onset time in infants. In our study, maximum block was significantly larger in infants and adults at every target Cp compared with children. This is in agreement with other studies that used a bolus dose of rocuronium (16,17). We found, at the termination of TCI, a similar degree of NMB in all age groups. The recovery in children, however, was significantly faster than in adults and infants. There was no significant difference in recovery times between infants and adults. After a dose of 0.6 mg/kg (3) and of 0.3 mg/kg, 1 the duration of effect, as well as the RI, in infants was twice as long as compared with children. However, after an ED95 dose, only adults needed a longer time to achieve a TOF ratio of 0.70, but the RI was shorter in children than in infants (18). Spontaneous recovery after a small dose of rocuronium is terminated more by distribution than by elimination. As for vecuronium (19), age-related changes in Vdss and clearance by liver and kidney resulted in a longer residence time for rocuronium in infants (2). Our methodology compensated for PK differences during TCI. During steady-state, the computer-driven pump delivered an amount of rocuronium related to the age-dependent differences in clearance and Vdss. During this steady-state, we were able to determine differences in sensitivity among different age groups. During recovery after TCI was stopped, however, normal PK mechanisms became apparent. Consequently, children recovered faster from NMB. A smaller Vdss, a faster clearance rate, and less sensitivity resulted in larger consumption of rocuronium. The effect of duration of TCI on recovery from NMB is probably another aspect that requires further investigation.
Data of this study showed that infants needed the smallest EC and children the largest for the same degree of NMB. The EC50 for adults (954 ng/mL) found in our study was in agreement with results of Plaud et al. (7) (823 ng/mL). In contrast, Wierda et al. (2) reported a much larger EC50 for infants and children (1190 and 1650 ng/mL, respectively). The difference in methodology may explain this discrepancy. Wierda et al. extended their PK analysis to PD analysis by adding a theoretical model (Sheiner model and Hill equation) to their PK data. Depending on the accuracy of the variables used in this extrapolation, they might have introduced some inaccuracy into their EC50 results. The smaller EC50 in infants is the result of structural and biochemical differences of the neuromuscular junction: an incomplete myelinization of the nerve fibers, diffusely large motor units (18), a smaller number of diffusely distributed acetylcholine receptors, a smaller muscle compartment with a relatively smaller content of type I muscle fibers (20), a lower excitation threshold, and a decreased released quantum of acetylcholine resulting in a reduced safety factor (21). During childhood, immature acetylcholine receptors with a half-life of <24 hours convert to metabolically stable receptors with a half-life of 2 weeks (22). The relative resistance of children to NMBD can therefore be explained by the relatively fast-growing muscle compartment, as can be concluded from PK studies (17), and by the large amount of new resistant acetylcholine receptors. At larger ECs, PD differences became less apparent, except for in infants. Other authors demonstrated that children required a larger dose of rocuronium to achieve the same level of NMB, on the basis of the cumulative log-dose probit-response relationship (17).
TCI was a convenient tool to establish a target Cp and to control steady-state PK/PD, but a large deviation was noticed between the target and Cpm values, especially in infants. Two reasons may be noted to explain this. First, the large PE may be due to the small number of infants included in the studies from which the TCI PK variables were taken. The PK sets for adults were based on a larger number of patients, and consequently the PE is smaller (8).
Second, the relatively large range of ages during a period of crucial development and maturation may have caused too much nonhomogeneity in this study group. Various techniques of anesthesia make comparison between studies difficult, especially potency studies comparing infants, children, and adults. PKs of rocuronium are not influenced by the type of anesthetic technique (11), but the NMB can be potentiated by inhaled anesthesia in a time- and age-dependent manner (23). 1 Remifentanil/propofol-based anesthesia, as used in our study, offers a consistent technique suitable for comparison with other studies performed under opioid/hypnotic anesthesia.
In conclusion, TCI rocuronium allowed us to define the EC50/effect relationship in a standardized way in a relatively large number of children and infants with a limited number of blood samples. Further, we were able to distinguish PK differences from PD differences in infants, children, and adults.
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