BACKGROUND: Previous work had shown dysequilibrium between the arterial blood and brain concentrations of the intravenous anaesthetic agent propofol following its rapid administration over 2 min to sheep. The extent of dysequilibrium was examined following slower administration as a constant rate 45-min infusion (10 mg/min). METHODS: Six sheep were prepared with arterial and sagittal sinus (effluent from the brain) blood sampling catheters and a Doppler flow probe for measuring an index of cerebral blood flow. Propofol concentrations in arterial and sagittal sinus blood during and after the infusions were measured using high-performance liquid chromatography with fluorescence detection. Brain concentrations were calculated from these concentrations and cerebral blood flow using direct mass balance methods. RESULTS: There was dysequilibrium between the arterial blood and brain concentrations until approximately 30 min after the start of the infusion, with marked hysteresis between the arterial blood and brain concentrations for the duration of the study. The equilibrium half-life between the blood and the brain was 3.5 min, which is comparable to the value of 4.3 min derived from the earlier rapid administration data, suggesting there was no time dependency in the kinetics of cerebral uptake. The mass of propofol entering the brain via arterial blood was the same as the mass leaving the brain via sagittal sinus blood, suggesting minimal metabolism of propofol in the brain of sheep. CONCLUSION: It is clear that pharmacokinetic analysis based on arterial blood concentrations alone cannot accurately account for the concentrations of propofol at its site of action in the brain.
BACKGROUND: Previous work had shown dysequilibrium between the arterial blood and brain concentrations of the intravenous anaesthetic agent propofol following its rapid administration over 2 min to sheep. The extent of dysequilibrium was examined following slower administration as a constant rate 45-min infusion (10 mg/min). METHODS: Six sheep were prepared with arterial and sagittal sinus (effluent from the brain) blood sampling catheters and a Doppler flow probe for measuring an index of cerebral blood flow. Propofol concentrations in arterial and sagittal sinus blood during and after the infusions were measured using high-performance liquid chromatography with fluorescence detection. Brain concentrations were calculated from these concentrations and cerebral blood flow using direct mass balance methods. RESULTS: There was dysequilibrium between the arterial blood and brain concentrations until approximately 30 min after the start of the infusion, with marked hysteresis between the arterial blood and brain concentrations for the duration of the study. The equilibrium half-life between the blood and the brain was 3.5 min, which is comparable to the value of 4.3 min derived from the earlier rapid administration data, suggesting there was no time dependency in the kinetics of cerebral uptake. The mass of propofol entering the brain via arterial blood was the same as the mass leaving the brain via sagittal sinus blood, suggesting minimal metabolism of propofol in the brain of sheep. CONCLUSION: It is clear that pharmacokinetic analysis based on arterial blood concentrations alone cannot accurately account for the concentrations of propofol at its site of action in the brain.