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- 1. Target Controlled Infusion: totally intravenous anesthesia made simple J. VAN HEMELRIJCK K. U. Leuven
- 2. duration of surgery stress theoretic concentration needed for adequate anesthesia apprehension intubation prep. incision awakening
- 3. Anesthesia = titration to needs <ul><li>Pharmacodynamic approach : titrating drugs to effect </li></ul><ul><ul><li>Clinical signs, hemodynamics </li></ul></ul><ul><ul><li>EEG parameters or other techniques to measure “depth” of anesthesia </li></ul></ul><ul><li>Pharmaceutical approach : choosing “forgiving drug” </li></ul><ul><li>Pharmacokinetic approach : knowledge of concentration-effect relationship </li></ul><ul><ul><li>MAC </li></ul></ul><ul><ul><li>Therapeutic window concentrations </li></ul></ul><ul><ul><li>Dosage schemes that pretend to achieve these concentrations </li></ul></ul><ul><ul><li>Target Controlled Infusions </li></ul></ul>
- 4. TARGET PLASMACONCENTRATION HYPNOTICS (µg/ml) µg/ml Cp50 LOC Cp95 LOC Propofol (+ moderate dose narcotics) 5.4 (3.4) 15.2 (4.2) Thiopental 15.6 39.8 Midazolam 0.14 0.25-0.35 Ketamine 0.6 1.2 Etomidate - 0.31-0.5
- 5. Target concentrations opioids
- 6. Three-compartiment open model time concentration V 1 V 2 V 3 k 12 k 21 k 13 k 31 DOSE k 10 C = . e - t + A . e - t + B . e - t
- 7. Pharmacokinetic data-sets for propofol NONMEM: nonlinear mixed effect modeling
- 8. Hysteresis between changes in plasmaconcentration and effect Scott JC et al. Anesthesiology 1985;62:234-241
- 9. Shafer SL, Varvel JR. Anesthesiology 1991;74:53-63
- 10. Effect site effect keo V 1 V 2 V 3 k 12 k 21 k 13 k 31 DOSIS k 10
- 11. Pharmacokinetics in practice <ul><li>Simulation of concentrations that are obtained with dosage scheme used </li></ul><ul><li>Rational use of drugs: </li></ul><ul><ul><li>Which drug best serves the clinical purpose </li></ul></ul><ul><ul><li>Calculating optimal dosage and mode of administration </li></ul></ul><ul><li>Pharmacokinetically controlled infusors: TCI </li></ul><ul><ul><li>Blood concentration controlled </li></ul></ul><ul><ul><li>Effect-site concentration controlled </li></ul></ul>
- 12. TIVA trainer: Copyrights F. Engbers (fengbers@wxs.nl) remi : 0.5 µg/kg sufentanil : 0.25 µg/kg
- 13. remifentanil 0.5 µg/kg alfentanil 20 µg/kg
- 14. remifentanil 0.5 µg/kg
- 15. fentanyl 2 µg/kg
- 16. Continuous infusion stategies <ul><li>constant speed: steady state concentration after 4 - 5 half-lifes </li></ul><ul><li>bolus + progressively decreasing infusion rate: pseudo-plateau </li></ul><ul><li>Bolus-Elimination-Transfer: bolus to fill up Vc, followed by exponentially decreasing infusion rate </li></ul><ul><li>computer controlled infusion </li></ul>
- 17. alfentanil 3 µg/kg/min remifentanil 0.5 µg/kg/min
- 18. fentanyl sufentanil alfentanil remifentanil
- 20. Target Controlled Infusion <ul><li>PK- model used in reverse </li></ul><ul><li>Choosing a desired concentration and the computer calculates the administration rate using the PK-model </li></ul><ul><li>For each time unit the computer calculates the amount of drug needed to keep the desired concentration in the target compartment constant (= the amount of drug leaving the target compartment as a result of elimination and redistribution) </li></ul><ul><li>Several times each minute </li></ul><ul><li>This information drives the infusionpump </li></ul>
- 21. EEG/MLAEP/BIS/.... ANESTHESIST POMP-CONTROL ALGORITHM pharmacokinetic simulation Cp predicted Cp desired Infusion pump delta t infusion rate reported IR PATIENT RESPONSE of PATIENT
- 22. sufentanil TCI remifentanil TCI
- 23. Effect-site TCI <ul><li>TCI but effect-site concentration controlled vs. blood concentration. </li></ul><ul><li>Desired effect is obtained faster (no hysteresis). </li></ul><ul><li>Blood concentration will be higher at the start: the higher the difference in concentration between blood and effect site (brain), the faster the effect site concentration increases </li></ul><ul><li>The Pk-model choosen and the keo is of utmost importance </li></ul><ul><ul><li>fast keo: small overshoot of blood concentration </li></ul></ul><ul><ul><li>slow keo: large overshoot of blood concentration </li></ul></ul>
- 27. Effect-site TCI <ul><li>Drugs characterized by fast diffusion to the central nervous system are best suited for effect-site concentration controlled infusions </li></ul><ul><li>The largest gain in time to reach the desired effect is to be expected for drugs with slow diffusion </li></ul>
- 28. Limitations of TCI <ul><li>How ACCURATE ???: do the target concentrations correspond to reality ? </li></ul><ul><ul><li>Pk set is determined in a limited number of patients. In how far does the PK parameter set correspond to reality ? </li></ul></ul><ul><ul><li>Is the pharmacokinetic model used applicable to the individual patient: does the patient correspond to the population sample used to determine the PK data ? </li></ul></ul>
- 29. Is it absolutely necessary that the prediction is accurate ? <ul><li>Titration to effect remains necessary </li></ul><ul><li>“ swings” in concentration will be less important than with manual systems </li></ul><ul><li>Modifications in the desired concentration will at least result in proportional changes in real concentration and in effect </li></ul>
- 30. Remi-fusor
- 31. Investigating the validity of the model <ul><li>median prediction error (MDPE): median of the procentual difference, positive or negative, thus the bias of the system </li></ul><ul><li>median absolute prediction error (MDAPE): median of the procentual difference between the measured and the predicted concentration in absolute value (< 30%) </li></ul><ul><li>divergence : the slope of the linear regression analysis of the evolution in time of the MDAPE </li></ul><ul><li>wobble : median of the variability in individual patients </li></ul>
- 32. predicted propofol conc. measured concentration Gepts Kirkpatrick Shafer Gepts Kirkpatrick Shafer time performance error % 0 100 100 100 0 0 -100 Vuyck et al. Anesth. Analg. 1995;81:1275-82
- 33. Accurate performance of TCI
- 34. Performance in individual patients <ul><li>Age: children and elderly persons have different PK </li></ul><ul><li>Weight and body composition: importance depends on the drug </li></ul><ul><li>Disease and hydratation influence PK </li></ul><ul><li>Adapt target to the situation or </li></ul><ul><li>Kinetic libraries: PK-set according to circumstances </li></ul><ul><ul><li>Feed cofactors to the computer: age, weight, height, sex, renal disease… </li></ul></ul><ul><ul><li>Computer determines suitable kinetic parameter set </li></ul></ul><ul><ul><li>E.g. PAEDfusor for propofol: age and weight </li></ul></ul>
- 35. Kinetic libraries
- 36. What if we use several interacting drugs ?
- 37. Farmacodynamic interactions One predefined degree of the combined drug effect: isobologram
- 38. Farmacodynamic interactions: surface modelling Any degree of combined drug effect: response surface modelling
- 39. Probability of no response to laryngoscopy Mertens et al. Anesthesiology 2003;99:347-359
- 40. Probability of unconsciousness
- 42. The future of TCI <ul><li>Multidrug TCI apparatus </li></ul><ul><li>Kinetic libraries: adaptation of the PK model to the individual patients needs </li></ul><ul><li>Pharmacodynamic interactions: suggestions for dosing according to the data of surface modelling </li></ul><ul><li>Closed-loop systems with automated effect evaluation for depth of anesthesia and paincontrol (?) </li></ul>

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