The long-term objective of this research program is to define the effects of various physiological perturbations on the pharmacokinetics of rapidly acting intravenous anesthetics to improve understanding of their dose- response relationships.
The specific aim of the proposed work is to describe, from the moment of injection, the simultaneous disposition of inert markers of the three physiological spaces important to drug distribution: indocyanine green (ICG), intravascular space; insulin, interstitial fluid space; and antipyrine, total body water. This multiple indicator dilution technique will allow assessment of changes in the processes responsible for drug distribution: mixing, flow, and diffusion. Traditional pharmacokinetic studies do not characterize the rise, fall, and subsequent oscillations in blood drug concentrations in the seconds after intravenous administration when anesthetic effects are maximal. The first study will further develop a model of initial drug distribution by describing the simultaneous disposition of ICG and antipyrine, from the moment of injection, in dogs anesthetized with halothane. A traditional, multicompartmental model for each physiological marker will for circulatory and tissue transit delays. This modification adds characterization of the blood indicator concentration versus time relationships seen in the seconds after intravenous administration to the traditional pharmacokinetic model. The effect of alterations in both cardiac output and the distribution of cardiac output on drug distribution by mixing, flow, and diffusion will be assessed in the second and third studies. The disposition of the three physiological markers will be described in dogs in two paradigms of altered cardiac output and distribution. One study will evaluate the effects of 1.0%, 1.5%, and 2.0% halothane while the other will examine the effects of moderate and severe hypovolemia and volume loading in the awake animal. Repeat measures Latin square experimental designs will be used to randomize in both of these studies.
