Transit time dispersion in pulmonary and systemic circulation: effects of cardiac output and solute diffusivity

Abstract

We present an in vivo method for analyzing the distribution kinetics of physiological markers into their respective distribution volumes utilizing information provided by the relative dispersion of transit times. Arterial concentration-time curves of markers of the vascular space [indocyanine green (ICG)], extracellular fluid (inulin), and total body water (antipyrine) measured in awake dogs under control conditions and during phenylephrine or isoproterenol infusion were analyzed by a recirculatory model to estimate the relative dispersions of transit times across the systemic and pulmonary circulation. The transit time dispersion in the systemic circulation was used to calculate the whole body distribution clearance, and an interpretation is given in terms of a lumped organ model of blood-tissue exchange. As predicted by theory, this relative dispersion increased linearly with cardiac output, with a slope that was inversely related to solute diffusivity. The relative dispersion of the flow-limited indicator antipyrine exceeded that of ICG (as a measure of intravascular mixing) only slightly and was consistent with a diffusional equilibration time in the extravascular space of approximately 10 min, except during phenylephrine infusion, which led to an anomalously high relative dispersion. A change in cardiac output did not alter the heterogeneity of capillary transit times of ICG. The results support the view that the relative dispersions of transit times in the systemic and pulmonary circulation estimated from solute disposition data in vivo are useful measures of whole body distribution kinetics of indicators and endogenous substances. This is the first model that explains the effect of flow and capillary permeability on whole body distribution of solutes without assuming well-mixed compartments.

A Minimal Physiological Model of Thiopental Distribution Kinetics Based on a Multiple Indicator Approach

“…As shown previously in other dogs, the disposition kinetics of ICG (Weiss et al, 2006) and antipyrine (Weiss et al, 2007) were well described by the model (Fig. 2).…”

“…Regarding a comparison with other recirculatory models, it is not surprising that we get different answers depending on how we reduce the complexity of the system. Instead of assuming different compartmental organ models for different drugs (e.g., flow-limited versus membrane-limited), the present model provides a unified approach that describes a continuous transition between the limiting cases of whole body distribution kinetics, i.e., from diffusion-limited (PS diff Ͻ Ͻ Q) to flow-limited (PS diff Ͼ Ͼ Q) tissue distribution (Weiss et al, 2006(Weiss et al, , 2007. However, the price to be paid for the assumption of noninstantaneous distribution in the vascular and tissue space is the use of a vascular indicator and the lumped organ approach, respectively, i.e., the reduction of the systemic circulation to only one or two subsystems.…”

“…Accordingly, we have recently developed a minimal physiological circulation model using a multiple indicator approach in which the lumped organs of the systemic circulation were described by an axially distributed capillarytissue exchange model that accounts for intratissue concentration gradients (Weiss et al, 2007). However, until now this model has only been applied to inulin and antipyrine, compounds that do not bind to tissue constituents (Weiss et al, 2006(Weiss et al, , 2007. The aim of this article is to test the suitability of this model for the evaluation of thiopental disposition kinetics in dogs and to explain the difference between distribution kinetics of thiopental and antipyrine.…”

Clinical Pharmacokinetic Applications of Recirculatory Models

“…The relative dispersion of the tracer ( RD 2 ) may be calculated as a normalized variance of the transit times according to the following expression [14]:…”

“…The relative dispersion ( RD 2 ) may be used for the interpretation of the intravascular mixing of markers [14,15].…”