During cardiopulmonary bypass, a significant increase in the concentration of unbound propofol occurred without alteration in the total propofol concentration in blood. The effect of the changes of propofol's protein binding on its kinetics was consistent with the predictions based on the well-stirred model of hepatic elimination for an intravenously infused high-clearance drug. Our finding on propofol pharmacokinetics may be the first example demonstrating the theoretic prediction of the well-stirred model.

Background and Purpose-The purpose of this study was to examine the effects of diabetes mellitus and its severity on the cerebral vasodilatory response to hypercapnia. Methods-Thirty diabetic patients consecutively scheduled for elective major surgery were studied. After induction of anesthesia, a 2.5-MHz pulsed transcranial Doppler probe was attached to the patient's head at the right temporal window, and mean blood flow velocity of the middle cerebral artery (Vmca) was measured continuously. After the baseline Vmca, arterial blood gases, and cardiovascular hemodynamic values were measured, end-tidal CO 2 was increased by reducing ventilatory frequency by 2 to 5 breaths per minute. Measurements were repeated when end-tidal CO 2 increased and remained stable for 5 to 10 minutes. Results-Significant differences were observed in absolute and relative CO 2 reactivity between the diabetes and control groups (absolute CO 2 reactivity: control, 2.8Ϯ0.7; diabetes mellitus, 2.1Ϯ1.3; PϽ0.01; relative CO 2 reactivity: control, 6.3Ϯ1.4; diabetes mellitus, 4.5Ϯ2.7; PϽ0.01, Mann-Whitney U test). Significant differences were also found between diabetic patients with retinopathy and those without retinopathy in absolute (Pϭ0.002) and relative (Pϭ0.002) CO 2 reactivity, glycosylated hemoglobin (Pϭ0.0034), and fasting blood sugar (Pϭ0.01) (Scheffé's test, Mann-Whitney U test). There was an inverse correlation between absolute CO 2 reactivity and glycosylated hemoglobin (rϭ0.69, PϽ0.001). Conclusions-Insulin-dependent diabetic patients have an impaired vasodilatory response to hypercapnia compared with that of the control group, and the present findings suggest that their degree of impairment is related to the severity of diabetes mellitus.

AimsThe principal site for the metabolism of propofol is the liver. However, the total body clearance of propofol is greater than the generally accepted hepatic blood flow. In this study, we determined the elimination of propofol in the liver, lungs, brain and kidneys by measuring the arterial-venous blood concentration at steady state in patients undergoing cardiac surgery. MethodsAfter induction of anaesthesia, propofol was infused continuously during surgery. For measurement of propofol concentration, blood samples were collected from the radial and pulmonary artery at predetermined intervals. In addition, blood samples from hepatic and internal jugular vein were collected at the same times in 19 patients in whom a hepatic venous catheter was fitted and the other six in whom an internal jugular venous catheter was fitted, respectively. In six out of 19 patients fitted with a hepatic venous catheter, blood samples from the radial artery and the renal vein were also collected at the same time, when the catheter was inser ted into the right renal vein before insertion into the hepatic vein. ResultsHepatic clearance of propofol was approximately 60% of total body clearance. The hepatic extraction ratio of propofol was 0.87 ± 0.09. There was no significant difference in the concentration of propofol between the radial, pulmonary ar teries and internal jugular vein. However, a high level of propofol extraction in the kidneys was observed -the renal extraction ratio being 0.70 ± 0.13. ConclusionsWe have demonstrated substantial renal extraction of propofol in human. Metabolic clearance of propofol by the kidneys accounts for almost one-third of total body clearance and may be the major contributor to the extrahepatic elimination of this drug.

Human kidneys play an important role in the elimination of propofol.