The influence of hemorrhagic shock on propofol: a pharmacokinetic and pharmacodynamic analysis.
BACKGROUND
Propofol is a common sedative hypnotic for the induction and maintenance of anesthesia. Clinicians typically moderate the dose of propofol or choose a different sedative hypnotic in the setting of severe intravascular volume depletion. Previous work has established that hemorrhagic shock influences both the pharmacokinetics and pharmacodynamics of propofol in the rat. To investigate this further, the authors studied the influence of hemorrhagic shock on the pharmacology of propofol in a swine isobaric hemorrhage model.


METHODS
After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock groups. The shock group was bled to a mean arterial blood pressure of 50 mmHg over a 20-min period and held there by further blood removal until 30 ml/kg of blood was removed. Propofol 200 microg. kg(-1). min(-1) was infused for 10 min to both groups. Arterial samples (15 from each animal) were collected at frequent intervals until 180 min after the infusion began and analyzed to determine drug concentration. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. The pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model.


RESULTS
The raw data demonstrated higher plasma propofol levels in the shock group. The pharmacokinetic analysis revealed slower intercompartmental clearances in the shock group. Hemorrhagic shock shifted the concentration effect relationship to the left, demonstrating a 2.7-fold decrease in the effect site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale.


CONCLUSIONS
Hemorrhagic shock altered the pharmacokinetics and pharmacodynamics of propofol. Changes in intercompartmental clearances and an increase in the potency of propofol suggest that less propofol would be required to achieve a desired drug effect during hemorrhagic shock.
Johnson
Ken B
KB
Department of Anesthesiology, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
Egan
Talmage D
TD
Kern
Steven E
SE
White
Julia L
JL
McJames
Scott W
SW
Syroid
Noah
N
Whiddon
Derek
D
Church
Ty
T
D000465:Algorithms; D000704:Analysis of Variance; D000758:Anesthesia; D018685:Anesthetics, Inhalation / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003198:Computer Simulation; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007530:Isoflurane / Q000494:pharmacology; D019344:Lactic Acid / Q000097:blood; D008297:Male; D017711:Nonlinear Dynamics; D010865:Pilot Projects; D015742:Propofol / Q000493:pharmacokinetics / Q000494:pharmacology*; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D013552:Swine
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D001786:Blood Glucose; D019344:Lactic Acid; D007530:Isoflurane; D015742:Propofol