A Dose–Response Study of the Influence of Propofol on Cerebral Blood Flow, Metabolism and the Electroencephalogram in the Rabbit

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Abstract
This experiment was designed to study the effect of progressively increasing blood propofol concentrations on cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2), and the electroencephalogram (EEG). Nine New Zealand White rabbits were anesthetized with morphine (10 mg kg−1 bolus and 2 mg/kg/h infusion) and 70% N2O. Both normothermia and normocarbia were maintained throughout the study. A 300 μm diameter platinum electrode and a 20 gauge sampling needle were inserted into the confluence of venous sinuses to permit the measurement of forebrain CBF and CMRO2. Cerebral blood flow was determined using the H2 clearance method and CMRO2 was calculated as CBF x arteriovenous O2 content difference. A single bifrontal EEG signal was also recorded. After baseline data were collected, a propofol infusion was begun, and the dose increased in a stepwise fashion from 0.28 to 1.11 mg/kg/min over 90 min (total dose 62.6 mg/kg). Every 22.5 min CBF, CMRO2, and EEG were recorded and arterial blood was sampled for the determination of propofol concentrations (by high-performance liquid chromatography). Angiotensin II was used to maintain mean arterial pressure ≥80 mm Hg. Eight animals completed the protocol. Blood propofol concentrations rose progressively in all animals, reaching a mean of 34 ± 12 μg/ml (±SD) at the end of 90 min. Electroencephalogram changes during the early stages of the infusion were extremely variable. However, concentrations above ∼20 μg/ml were associated with progressive EEG suppression, and isoelectricity developed in two animals, at blood concentrations of 41 and 52 μg/ml. There was a progressive dose-related decrease in CBF, which reached a value of ∼62% of baseline at a concentration of 40 μg/ml (as predicted by a polynomial curve fitted to a plot of CBF versus blood concentration). The CMRO2 also decreased progressively, reaching ∼57% of baseline at 40 μg/ml. A plot of CMRO2 versus EEG total power suggests that isoelectricity should be associated with a CMRO2 approximately equal to 53% of baseline. We conclude that propofol produces a dose-related decrease in CBF and CMRO2. The relationship between EEG suppression and CMRO2 is qualitatively similar to that seen with barbiturates.

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