with Ephedrine

1. TIVA TIVAE Total IntraVenous Anesthesia Total IntraVenous Awareness Total IntraVenous Anesthesia with Ephedrine Steven L. Shafer, MD Professor of Anesthesia, Stanford University Adjunct Professor of Biopharmaceutical Science, UCSF Staff Anesthesiologist, Palo Alto VA Health Care System

2. What is TIVA in 2005? • Pure: • Propofol @ 50-75 mg/kg/min • Remifentanil @ 0.1-0.3 mg/kg/min • Cheating: • Propofol @ 20-75 mg/kg/min • Remifentanil @ 0.01-0.3 mg/kg/min • 70% Nitrous Oxide

3. Are there any questions?

4. Basic PharmacologicalPrinciples of TIVA

5. Simple Pharmacokinetic Model: Volume of Distribution Volume Amount = Concentrat ion Volume

6. Simple Pharmacokinetic Model: Clearance

7. More complex PK Model:Multi-compartment 100 Rapid 10 Concentration Intermediate Slow 1 0 120 240 360 480 600 Minutes since bolus injection

8. Opioid Half-Lives (minutes)

9. Opioid Pharmacokinetics 100 10 Percent of peak plasma opioid concentration fentanyl 1 sufentanil alfentanil 0.1 360 480 600 240 0 120 Minutes since bolus injection

10. Context-Sensitive Half-Time 120 fentanyl 90 alfentanil Minutes required 60 sufentanil 30 0 240 360 480 600 0 120 Minutes since beginning of infusion Hughes MA, Glass PS, Jacobs JR. Anesthesiology. 1992 76:334-41.

11. Awake EEG Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992

12. Profound Opioid EEG Effect Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992

13. EEG Time Course with Fentanyl Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

14. EEG Time Course with Alfentanil Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

15. Extended PK/PD Concept: The “Effect Site”

16. Effect site concentrations over time

17. 50% Effect Site Decrement Time

18. 80% Effect Site Decrement Time

19. Remifentanil vs. other opioids 100 remifentanil 80 state - 60 alfentanil effect site opioid concentration Percent of steady 40 sufentanil 20 fentanyl 0 0 10 20 30 40 50 60 Minutes since beginning of continuous infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

20. Remifentanil vs. other opioids 100 10 Percent of peak plasma opioid concentration fentanyl 1 sufentanil alfentanil remifentanil 0.1 360 480 600 240 0 120 Minutes since bolus injection

21. Remifentanil vs. other opioids 100 sufentanil 80 fentanyl 60 Percent of peak effect site opioid concentration 40 alfentanil 20 remifentanil 0 4 6 8 10 0 2 Minutes since bolus injection

22. 50% effect sitedecrement curves Minutes required Minutes since beginning of infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

23. 80% effect sitedecrement curves Minutes required Minutes since beginning of infusion Shafer SL, ASA Refresher Course, Chapter 19, 1996

24. Propofol/opioid vs Isoflurane/opioid

25. Propofol/opioid vs Isoflurane/opioid

26. Propofol-RemifentanilInteraction and TIVA

27. Propofol/Alfentanil Interaction 400 • Adapted from Vuyk et al, Anesthesiology 83:8-22, 1995 • Characterizes the concentrations for • intubation • maintenance • on emergence • Concentrations are 50% response level Intubation 300 Maintenance 200 Alfentanil Concentration (ng/ml) Emergence 100 0 0 2 4 6 8 10 Propofol Concentration (mg/ml)

28. Propofol/Remifentanil TIVA • Remifentanil: • 0.25 mg/kg/min • Propofol: • 80 mg/kg/min • Requires controlled ventilation Shafer SL, ASA Refresher Course, Chapter 19, 1996 • Little tolerance for interruption of remifentanil or propofol infusion

31. 10 Minute Infusion Alfentanil Fentanyl Remifentanil Sufentanil

32. 60 Minute Infusion Alfentanil Fentanyl Remifentanil Sufentanil

33. 600 Minute Infusion Alfentanil Fentanyl Remifentanil Sufentanil

34. Hierarchical Model of Drug Interaction Opioids,N2O Hypnotics Conscious,Responsive Cortex AmbientStimuli Unconscious,Unresponsive SystemicOpioids Pain projection Midbrain, Thalamus N2O Severe to cortex None Spinal Local Opioids Anesthetics Pain projection Severe to midbrain Peripheral nerves, Spinal cord None Inspired by: Glass PS.. Anesthesiology. 1998 88:5-6. Pain

35. Hierarchical Model of Drug Interaction AmbientStimuli Afferent Stimuli Pain projection to cortex Pain Pain

36. Propofol-RemifentanilInteraction Surface: Laryngoscopy Bouillon et al, Anesthesiology 2004

37. Propofol-RemifentanilInteraction Surface: Laryngoscopy Bouillon et al, Anesthesiology 2004

38. Propofol-RemifentanilInteraction Surface: BIS Bouillon et al, Anesthesiology 2004

39. Propofol-RemifentanilInteraction Surface: BIS Bouillon et al, Anesthesiology 2004

40. Awareness and TIVA

41. My two cases 1. Treat light anesthesia, then pontificate. 2. Don’t turn off your anesthetic for extended periods.

42. The ASPECT Data Base • Patient trials (movement): • Thiopental • Propofol • Fentanyl/Alfentanil/Sufentanil • Isoflurane • Nitrous Oxide • Volunteer trials (recall, sedation, eyelash): • Propofol • Isoflurane • Alfentanil • Midazolam

43. Recall vs. Heart Rate and Blood Pressure

44. RecallBIS vs Blood Pressure

45. RecallBispectral Index vs Concentration

46. MovementD Heart Rate vsD Blood Pressure

47. Predictors of Movement Measure Pk 0.74 Blood propofol 0.76 Effect-site propofol Bispectral Index 0.86 Relative delta power 0.79 Relative beta power 0.83 95% SEF (Hz) 0.81 Median Frequency (Hz) 0.8 Leslie et al, Anesthesiology 84:52-63, 1996

48. Sedation, BIS, and Propofol Glass et al, Anesthesiology 86:836-847, 1997

49. BIS Interpretation

50. Conscious/Unconscious Prediction (Pk) Target Measured Agent (n) BIS Concentration Concentration Propofol (399) 0.976 ± 0.006* 0.936 ± 0.010 0.937 ± 0.013 Isoflurane (70) 0.959 ± 0.021 0.965 ± 0.015 0.967 ± 0.016 Midazolam (50) 0.885 ± 0.047 0.859 ± 0.045 0.886 ± 0.048 Significantly different from Pk value for Target Concentration (p < 0.001), and Measured concentration (p < 0.01) Glass et al, Anesthesiology 86:836-847, 1997