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Simple TCI

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Simple TCI

  1. 1. Target Controlled Infusion: totally intravenous anesthesia made simple J. VAN HEMELRIJCK K. U. Leuven
  2. 2. duration of surgery stress theoretic concentration needed for adequate anesthesia apprehension intubation prep. incision awakening
  3. 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. 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. 5.   Target concentrations opioids
  6. 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. 7. Pharmacokinetic data-sets for propofol NONMEM: nonlinear mixed effect modeling
  8. 8. Hysteresis between changes in plasmaconcentration and effect Scott JC et al. Anesthesiology 1985;62:234-241
  9. 9. Shafer SL, Varvel JR. Anesthesiology 1991;74:53-63
  10. 10. Effect site effect keo V 1 V 2 V 3 k 12 k 21 k 13 k 31 DOSIS k 10
  11. 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. 12. TIVA trainer: Copyrights F. Engbers (fengbers@wxs.nl) remi : 0.5 µg/kg sufentanil : 0.25 µg/kg
  13. 13. remifentanil 0.5 µg/kg alfentanil 20 µg/kg
  14. 14. remifentanil 0.5 µg/kg
  15. 15. fentanyl 2 µg/kg
  16. 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. 17. alfentanil 3 µg/kg/min remifentanil 0.5 µg/kg/min
  18. 18. fentanyl sufentanil alfentanil remifentanil
  19. 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>
  20. 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
  21. 22. sufentanil TCI remifentanil TCI
  22. 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>
  23. 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>
  24. 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>
  25. 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>
  26. 30. Remi-fusor
  27. 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>
  28. 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
  29. 33. Accurate performance of TCI
  30. 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>
  31. 35. Kinetic libraries
  32. 36. What if we use several interacting drugs ?
  33. 37. Farmacodynamic interactions One predefined degree of the combined drug effect: isobologram
  34. 38. Farmacodynamic interactions: surface modelling Any degree of combined drug effect: response surface modelling
  35. 39. Probability of no response to laryngoscopy Mertens et al. Anesthesiology 2003;99:347-359
  36. 40. Probability of unconsciousness
  37. 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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