Intravenous Drug Delivery Systems

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IntravenousDrug Delivery Systems

• Steven L. Shafer, M.D.
• Professor of Anesthesia, Stanford University
• Adjunct Professor of Biopharmaceutical Sciences,
  UCSF
• Talmage Egan, MD
• Professor of Anesthesia, University of Utah

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Sir Christopher Wren
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Sir Frederick Roller
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Sir James Dialaflow
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Calculator Pumps
Remifentanil
Propofol
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2000
1900
100 years of research and this is all we get ???
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Three Compartment Model
Rapid
Intermediate
Slow
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Fentanyl Target 1 ng/ml
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First TCI System for Anesthetics(Schwilden et
al, Bonn)
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First TCI System for Relaxants (Westenskow et al,
Utah)
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CACI First TCI System in the US (Reves, Jacobs,
Glass, Duke)
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STANPUMP TCI Platform (Shafer, Stanford)
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Barvais System (Belgium)
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Rugloop Platform (De Smet, Struys,Ghent)
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The Diprifusor the first commercial product
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Start with bolus drug kinetics

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Give by computer controlled infusion

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Test refined kinetics

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TCI Performance
Shafer (Anes-thesiology 1990)
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TCI Performance with 3 different fentanyl data
sets
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Remifentanil TCI

Predicted remifentanil concentration (ng/ml))
50
60
70
80
90
Measured remifentanil concentration (ng/ml)
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Drugs with PK that havebeen verified for use
with TCI

• Propofol
• Fentanyl
• Alfentanil
• Sufentanil
• Remifentanil

• Thiopental
• Lidocaine
• Midazolam
• Lorazepam
• Dexmedetomidine

And this is just the Stanford research
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TCI permits surfing the concentration vs.
response relationship
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Thiopental EEG Trial
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Titrating the Plasma
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Performs poorly at the site of drug effect!
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Targeting the Effect Site
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Plasma controlled vs. effect site controlled
propofol TCI (Rugloop)
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Improved outcomes Demonstrated with Rugloop
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Propofol PK Changes With Alfentanil
Pavlin, et al
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Thiopental Pharmacodynamic Trial
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Thiopental Pharmacodynamics
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Propofol for ICU Sedation

• Acknowledgements
• Dr. Juliana Barr
• Katie Zomorodi
• David Goodale

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Study Design
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Propofol ICU Pharmacokinetics
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Optimal Pharmacokinetic Model
Best 13 MDAPE
Worst 70MDAPE
Plasma Propofol Concentration (mg/ml)
Hours Since Initial Dose
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Propofol Dosing in the ICU
For 25, 50, and 75 mg/kg/min
2.5

Women
Men
2.0
75
1.5
50
1.0
Small
25
0.5
0.0
2.5
2.0
Plasma Propofol Concentration (mg/ml)
1.5
Big
1.0
0.5
0.0
2.5
2.0
1.5
Obese
1.0
0.5
0.0
1
10
100
1000
10000
1
10
100
1000
10000
Minutes Since Beginning of Infusion
Based on Lean Body Mass correction for gender
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CSHT calculations are actually TCI simulations
Egan et al (Anesthesiology 1993)
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How do you want to fly ???
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Propofol Sedation Delivery System
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The Automated Responsiveness Measure for
Procedural Sedation

• Invented by Randy Hickle, MD
• Potential as a feedback system for sedation
  delivery

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Continuum of Depth of SedationDefinition of
General Anesthesia and Levels of Sedation /
Analgesia(Developed by the American Society of
Anesthesiologists)(Approved by ASA House of
Delegates on October 13, 1999)
Reflex withdrawal from a painful stimulus is
NOT considered a purposeful response
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First Loss of ARMvs. Transition to Deep Sedation
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Loss of ARM
4.5
Transition to Deep Sedation
g/ml)
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3.5
3
2.5
Propofol Effect Site (
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1.5
1
0.5
0
0
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Subject
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ARM Summary

• First loss of ARM consistently precedes deep
  sedation
• Alerts clinician to sedation level
• Automatically reduces dose if patient remains
  non-responsive
• Override required for increasing dose
• ARM provides basis to individualize dosing
• Assessment of drug effect for non-anesthesiologist
  
• Reduces risk of transition to general anesthesia

Doufas et al. Anesthesiology. 2004 1011112-21.
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Software

• STANPUMP (Original DOS)
• STELPUMP (DOS)
• RUGLOOP (Windows)
• IVA-SIM (DOS - obsolete)
• http//anesthesia.stanford.edu/pkpd