Changes in the effect of propofol in response to altered plasma protein binding during normothermic cardiopulmonary bypass.
BACKGROUND
During normothermic cardiopulmonary bypass (CPB), the effect on propofol pharmacokinetics of changes in its binding to plasma proteins is consistent with the predictions of the well-stirred model of hepatic elimination for nonrestrictively cleared drug. However, whether changes in binding lead to clinically significant changes in the drug effect remains unclear. The purpose of this study was to assess changes in the drug effect of propofol in response to altered plasma binding using quantitative EEG measurements.


METHODS
Thirty patients undergoing cardiac surgery were assigned randomly to receive propofol infusions at 4 (Group P-4) or 6 (Group P-6) mg kg(-1) h(-1) during surgery. The concentration of propofol in blood samples, collected from the radial artery at predetermined intervals, was determined by HPLC. The unbound fraction of drug in plasma was estimated using equilibrium dialysis. Bispectral index (BIS) and burst suppression ratio (BSR) were measured at the time blood samples were collected.


RESULTS
The total concentration of propofol in blood was unchanged during CPB relative to the pre-CPB value in both groups. However, the fraction of unbound propofol in blood increased by 2-fold during CPB. While BIS values were unchanged during CPB in Group P-4, there was a slight, but significant, decrease in Group P-6. In both groups, BSR significantly increased during CPB. BIS values showed a weak correlation with the concentration of unbound propofol (r(2)=0.19, P<0.001). BSR showed a moderate correlation with the concentration of unbound propofol (r(2)=0.56, P<0.001).


CONCLUSIONS
The anaesthetic effect of propofol significantly increased during CPB without any alteration in the total drug concentration. The enhanced efficacy may be caused by a reduction in plasma binding of the drug.
Takizawa
E
E
Department of Anaesthesiology, Saitama Cardiovascular and Pulmonary Centre, 1696 Itai Konan-machi Osato-gun, Saitama 360-0105, Japan.
Hiraoka
H
H
Takizawa
D
D
Goto
F
F
D000328:Adult; D000368:Aged; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism*; D002315:Cardiopulmonary Bypass; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004334:Drug Administration Schedule; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006801:Humans; D007432:Intraoperative Period; D008297:Male; D008875:Middle Aged; D016343:Monitoring, Intraoperative / Q000379:methods; D015742:Propofol / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D011485:Protein Binding
D018686:Anesthetics, Intravenous; D001798:Blood Proteins; D015742:Propofol