A comparison of pharmacokinetic/pharmacodynamic versus mass-balance measurement of brain concentrations of intravenous anesthetics in sheep.

Background: There are two recognized methods of estimating the brain concentrations of IV anesthetic drugs: (i) use of pharmacokinetic/pharmacodynamic (PK/PD) modeling of drug effect, from arterial concentrations and electroencephalogram changes, and (ii) direct measurement of the uptake of drug in the brain, by simultaneously measuring arterial and jugular concentrations and cerebral blood flow (mass-balance method). These two methods have not been directly compared. Because an accurate estimate of the time taken for transfer of anesthetic drug from arterial blood to its effect-compartment in the brain is critical for accurate effect-compartment dosing in IV anesthesia, we compared the PK/PD and mass-balance methods for propofol, methohexital, and ketamine in a sheep model.

Methods: After instrumentation with arterial and sagittal-sinus cannulae, electrocorticogram, and sagittal sinus Doppler flow measurement seven adult sheep were given a random sequence of short anesthetic infusions with methohexital, ketamine, and propofol. Multiple blood samples were taken for measurement of the time course of the drug concentrations, and the electrocorticogram processed (approximate entropy, for propofol and methohexital and percentage high frequency time, for ketamine) to numerically quantify drug effect.

Results: Using the PK/PD method the t(1/2)K(eo) was 2.0 +/- 0.4 min for ketamine, 2.7 +/- 1.1 min for propofol, and was significantly shorter (0.3 +/- 0.1 min) for methohexital. PK/PD and the mass-balance methods did not differ in the times to peak effect.

Conclusions: Both methods of calculating the delay in transfer of drug from arterial blood to brain give similar values. Methohexital crosses into the brain much faster than either propofol or ketamine.