Estimation of the Plasma Effect Site Equilibration Rate Constant (ke0) of Propofol in Children Using the Time to Peak Effect

2004 ◽  
Vol 101 (6) ◽  
pp. 1269-1274 ◽  
Author(s):  
Hernán R. Muñoz ◽  
Luis I. Cortínez ◽  
Mauricio E. Ibacache ◽  
Fernando R. Altermatt
Keyword(s):  
Rate Constant ◽  
Peak Effect ◽  
Auditory Evoked Potential ◽  
Pharmacokinetic Parameters ◽  
Time To Peak ◽  
Effect Site ◽  
Effect Site Concentration ◽  
Target Effect ◽  
Equilibration Rate ◽  
Plasma Effect

Background Targeting the effect site concentration may offer advantages over the traditional forms of administrating intravenous anesthetics. Because the lack of the plasma effect site equilibration rate constant (ke0) for propofol in children precludes the use of this technique in this population, the authors estimated the value of ke0 for propofol in children using the time to peak effect (tpeak) method and two pharmacokinetic models of propofol for children. Methods : The tpeak after a submaximal bolus dose of propofol was measured by means of the Alaris A-Line auditory evoked potential monitor (Danmeter A/S, Odense, Denmark) in 25 children (aged 3-11 yr) and 25 adults (aged 35-48 yr). Using tpeak and two previously validated sets of pharmacokinetic parameters for propofol in children, Kataria's and that used in the Paedfusor (Graseby Medical Ltd., Hertfordshire, United Kingdom), the ke0 was estimated according to a method recently published. Results The mean tpeak was 80 +/- 20 s in adults and 132 +/- 49 s in children (P < 0.001). The median ke0 in children was 0.41 min(-1) with the model of Kataria and 0.91 min(-1) with the Paedfusor model (P < 0.01). The corresponding t1/2 ke0 values, in minutes, were 1.7 and 0.8, respectively (P < 0.01). Conclusions : Children have a significantly longer tpeak of propofol than adults. The values of ke0 of propofol calculated for children depend on the pharmacokinetic model used and also can only be used with the appropriate set of pharmacokinetic parameters to target effect site in this population.

The Influence of Age on Propofol Pharmacodynamics

1999 ◽  
Vol 90 (6) ◽  
pp. 1502-1516. ◽  
Author(s):  
Thomas W. Schnider ◽  
Charles F. Minto ◽  
Steven L. Shafer ◽  
Pedro L. Gambus ◽  
Corina Andresen ◽  
...  
Keyword(s):  
Rate Constant ◽  
Canonical Correlation ◽  
Drug Effect ◽  
Peak Effect ◽  
Pharmacodynamic Model ◽  
Time To Peak ◽  
Effect Site ◽  
Effect Site Concentration ◽  
Equilibration Rate ◽  
Plasma Effect

Background The authors studied the influence of age on the pharmacodynamics of propofol, including characterization of the relation between plasma concentration and the time course of drug effect. Methods The authors evaluated healthy volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50, 100, or 200 microg x kg(-1) x min(-1)) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The electroencephalogram (EEG) was used to measure drug effect. A statistical technique called semilinear canonical correlation was used to select components of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect with a biphasic pharmacodynamic model. The plasma effect-site equilibration rate constant was estimated parametrically. Estimates of this rate constant were validated by comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propofol infusion. Results Twenty-four volunteers completed the study. Three parameters of the biphasic pharmacodynamic model were correlated linearly with age. The plasma effect-site equilibration rate constant was 0.456 min(-1). The predicted time to peak effect after bolus injection ranging was 1.7 min. The time to peak effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state observations showed increasing sensitivity to propofol in elderly patients, with C50 values for loss of consciousness of 2.35, 1.8, and 1.25 microg/ml in volunteers who were 25, 50, and 75 yr old, respectively. Conclusions Semilinear canonical correlation defined a new measure of propofol effect on the EEG, the canonical univariate parameter for propofol. Using this parameter, propofol plasma effect-site equilibration is faster than previously reported. This fast onset was confirmed by inspection of the EEG data. Elderly patients are more sensitive to the hypnotic and EEG effects of propofol than are younger persons.

Comparison of Plasma Compartment versus  Two Methods for Effect Compartment–controlled Target-controlled Infusion for Propofol

2000 ◽  
Vol 92 (2) ◽  
pp. 399-399 ◽  
Author(s):  
Michel M. R. F. Struys ◽  
Tom De Smet ◽  
Birgit Depoorter ◽  
Linda F. M. Versichelen ◽  
Eric P. Mortier ◽  
...  
Keyword(s):  
Time Course ◽  
Drug Effect ◽  
Peak Effect ◽  
Effect Compartment ◽  
Loss Of Consciousness ◽  
Group Iii ◽  
Time To Peak ◽  
Effect Site ◽  
Effect Site Concentration ◽  
Plasma Effect

Background Target-controlled infusion (TCI) systems can control the concentration in the plasma or at the site of drug effect. A TCI system that targets the effect site should be able to accurately predict the time course of drug effect. The authors tested this by comparing the performance of three control algorithms: plasmacontrol TCI versus two algorithms for effect-site control TCI. Methods One-hundred twenty healthy women patients received propofol via TCI for 12-min at a target concentration of 5.4 microg/ml. In all three groups, the plasma concentrations were computed using pharmacokinetics previously reported. In group I, the TCI device controlled the plasma concentration. In groups II and III, the TCI device controlled the effect-site concentration. In group II, the effect site was computed using a half-life for plasma effect-site equilibration (t1/2k(eo)) of 3.5 min. In group III, plasma effect-site equilibration rate constant (k(eo)) was computed to yield a time to peak effect of 1.6 min after bolus injection, yielding a t1/2keo of 34 s. the time course of propofol was measured using the bispectral index. Blood pressure, ventilation, and time of loss of consciousness were measured. Results The time course of propofol drug effect, as measured by the bispectral index, was best predicted in group III. Targeting the effect-site concentration shortened the time to loss of consciousness compared with the targeting plasma concentration without causing hypotension. The incidence of apnea was less in group III than in group II. Conclusion Effect compartment-controlled TCI can be safely applied in clinical practice. A biophase model combining the Marsh kinetics and a time to peak effect of 1.6 min accurately predicted the time course of propofol drug effect.

scholarly journals Induction Speed Is Not a Determinant of Propofol Pharmacodynamics

2004 ◽  
Vol 101 (5) ◽  
pp. 1112-1121 ◽  
Author(s):  
Anthony G. Doufas ◽  
Maryam Bakhshandeh ◽  
Andrew R. Bjorksten ◽  
Steven L. Shafer ◽  
Daniel I. Sessler
Keyword(s):  
Drug Effect ◽  
Peak Effect ◽  
Population Based ◽  
Pharmacodynamic Modeling ◽  
Time To Peak ◽  
Effect Site ◽  
Rate Of Increase ◽  
Effect Site Concentration ◽  
The Times ◽  
Plasma Effect

Background Evidence suggests that the rate at which intravenous anesthetics are infused may influence their plasma-effect site equilibration. The authors used five different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. The authors concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration. Methods With Human Studies Committee approval, 18 healthy volunteers received five consecutive target-controlled propofol infusions. During each infusion, the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 microg . ml . min. The Bispectral Index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM. Results When the correct rate of plasma-effect site equilibration was determined for each individual (plasma-effect site equilibration = 0.17 min, time to peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of increase of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness. Conclusions : Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM seems useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system.

scholarly journals Pharmacokinetic-Pharmacodynamic Modeling of Propofol in Children

2010 ◽  
Vol 113 (2) ◽  
pp. 343-352 ◽  
Author(s):  
Agnes Rigouzzo ◽  
Frederique Servin ◽  
Isabelle Constant
Keyword(s):  
Peak Effect ◽  
Concentration Effect ◽  
Pharmacodynamic Modeling ◽  
Maximal Effect ◽  
Time To Peak ◽  
Effect Site ◽  
Mixed Effects Modeling ◽  
Effect Site Concentration ◽  
Relationship Of ◽  
The Relationship

Background The aim of this study was to identify the best model to describe pharmacokinetics and pharmacodynamics in prepubertal children and therefore to calculate the corresponding pharmacodynamic parameters. In addition, and to confirm our method, a group of postpubertal subjects was also studied. Methods Sixteen children (9.5 yr, range 6-12) and 13 adults (22 yr, range 13-35) were included. Induction was performed by plasma target-controlled infusion of propofol (6 microg/ml) based on the Kataria model in children and on the Schnider model in adults. The relationship of bispectral index to predicted concentrations was studied during induction using the Kataria, pediatric Marsh, Schüttler, and Schnider models in children. Because the best performance was obtained, strangely enough, with the Schnider model, the two groups were pooled to investigate influence of puberty on pharmacodynamic parameters (kE0 [plasma effect-site equilibration rate constant] and Ce50 [effect-site concentration corresponding with 50% of the maximal effect]). The time-to-peak effect was calculated, and the kE0 was determined for the Kataria model (nonlinear mixed-effects modeling; pkpdtools). Results In children, the predicted concentration/effect relationship was best described using the Schnider model. When the whole population was considered, a significant improvement in this model was obtained using puberty as a covariate for kE0 and Ce50. The time to peak effect, Tpeak (median, 0.71 [range, 0.37-1.64] and 1.73 [1.4-2.68] min), and the Ce50 (3.71 [1.88-4.4] and 3.07 [2.95-5.21] microg/ml) were shorter and higher, respectively, in children than in adults. The kE0 linked to the Kataria model was 4.6 [1.4-11] min. Conclusions In children, the predicted concentration/effect relationships were best described using the Schnider model described for adults compared with classic pediatric models. The study suggests that the Schnider model might be useful for propofol target-control infusion in children.

Targeting Effect Compartment or Central Compartment Concentration of Propofol 

1999 ◽  
Vol 90 (1) ◽  
pp. 92-97 ◽  
Author(s):  
Howard G. Wakeling ◽  
John B. Zimmerman ◽  
Scott Howell ◽  
Peter S. A. Glass
Keyword(s):  
Central Compartment ◽  
Pharmacokinetic Parameters ◽  
Effect Compartment ◽  
Effect Site ◽  
Anesthetic Drugs ◽  
Effect Site Concentration ◽  
American Society ◽  
Target Effect ◽  
American Society Of Anesthesiologists ◽  
To Receive

Background An effect compartment has been postulated, and the ke0 has been quantified for several intravenous anesthetic drugs using electroencephalography (EEG) as the measure of effect. The authors wanted to validate that loss of responsiveness (LOR) was related to targeting an effect compartment concentration rather than a central compartment (plasma) concentration. Methods Twenty American Society of Anesthesiologists physical status I and II patients were randomized to receive propofol administered to a target central compartment or target effect compartment site concentration of 5.4 microg/ml propofol administered by a target-controlled infusion (TCI) using a previously validated set of pharmacokinetic parameters and a ke0 of 0.63 min(-1). Every 30 s for the first 5 min and every minute for the second 5 min the patients were asked to open their eyes. The time to LOR was measured by a blinded investigator. The authors also simulated the time to reach the desired target effect site concentration using varying ke0 values. Results The median time to LOR in the group targeted to a predicted plasma propofol concentration was 3.02 min and 1.23 min in the group targeted to a predicted effect compartment propofol concentration (P < 0.05). LOR to command in both groups occurred at a predicted median effect compartment concentration of 4.55 microg/ml. Simulations demonstrated that the time predicted to LOR targeting an effect site concentration of 5.4 microg/ml is markedly altered by the value chosen for the ke0. Conclusions This study confirms the utility of the ke0 value to describe the effect compartment for propofol. The authors also illustrate the importance of selecting the correct ke0 value for the pharmacokinetic parameters used within the TCI system.

Maximizing Prediction Probability PK as an Alternative Semiparametric Approach to Estimate the Plasma Effect-Site Equilibration Rate Constant ke0

2009 ◽  
Vol 109 (5) ◽  
pp. 1470-1478 ◽  
Author(s):  
Richard K. Ellerkmann ◽  
Joergen Bruhn ◽  
Martin Soehle ◽  
Michael Kehrer ◽  
Andreas Hoeft ◽  
...  
Keyword(s):  
Rate Constant ◽  
Effect Site ◽  
Semiparametric Approach ◽  
Prediction Probability ◽  
Equilibration Rate ◽  
Plasma Effect
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