The long-term objective of this research program is to improve the understanding of the dose-response relationships of rapidly acting intravenous (IV) anesthetics by describing physiologic factors affecting their pharmacokinetics. The investigators have developed a powerful new pharmacokinetic methodology that enables characterization of blood concentration history from the moment of IV drug administration. The pharmacokinetic analysis uses a recirculatory model which describes the simultaneous disposition of physiologic markers: indocyanine green, blood flow and intravascular space; inulin, free water diffusion and extracellular space; and antipyrine, tissue perfusion and water space. The area under the blood drug concentration vs. time relationship is doubled in halothane-anesthetized (vs. awake) dogs in the first minutes after IV injection due to increased blood flow to tissues with negligible distributional capacity. This observation will be extended by studying the disposition of the three physiologic markers in dogs in several other paradigms of changes in cardiac output and altered distribution of cardiac output due to regional changes in vascular resistance. One study will evaluate the effects of l.7%, 2.6%, and 3.5% isoflurane while the other study will determine the effects of the infusions of phenylephrine, sodium nitroprusside, and dexmedetomidine in awake animals. Thiopental will be administered by a constant rate infusion to young and elderly patients of both sexes and sex- and age-related reactivity differences will be evaluated with a recirculatory pharmacokinetic- pharmacodynamic model. However, drug administration by infusion to obtain proper effect data precludes accurately characterizing the mixing phase of a recirculatory pharmacokinetic model. Thus, antipyrine and ICG will be used as surrogate pharmacokinetic markers to determine the mixing phase kinetics of thiopental during its continuous infusion. Later disposition phases will be determined from blood thiopental concentrations. EEG aperiodic analysis will provide a continuous pharmacodynamic measure.
