Beta blockade increases pulmonary and systemic transit time heterogeneity: evaluation based on indocyanine green kinetics in healthy volunteers Michael Weiss 1 , Tom C. Krejcie 2 and Michael J. Avram 2 1 Department of Pharmacology, Martin Luther University Halle-Wittenberg, Halle, Germany and 2 Department of Anesthesiology and the Mary Beth Donnelley Clinical Pharmacology Core Facility, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Summary Correspondence Michael Weiss, Department of Pharmacology, Martin Luther University Halle-Wittenberg, D-06097 Halle, Saale, Germany E-mail: michael.weiss@medizin.uni-halle.de Accepted for publication Received 9 April 2015; accepted 29 June 2015 Key words cardiac output; flow heterogeneity; propranolol; recirculatory model; transit time distribution Knowledge of factors influencing the heterogeneity of blood transit times is important in cardiovascular physiology. The aim of the study was to investigate the effect of beta-adrenergic blockade on blood transit time dispersion in awake, anxious volunteers. Recirculatory modelling of the disposition of intravascular markers using parametric forms for transit time distributions, such as the inverse Gaussian distribution, provides the opportunity to estimate the systemic and pul- monary transit time dispersion in vivo. The latter is determined by the flow heterogeneity in the microcirculatory network. Using this approach, we have analysed indocyanine green (ICG) disposition data obtained in four subjects by frequent early arterial blood sampling before and after beta-adrenergic blockade by propranolol. Propranolol decreased cardiac output from 9Á3 Æ 2Á8 l min À1 to 3Á5 Æ 0Á47 l min À1 (P<0Á05). This reduction was accompanied by a 4Á5 Æ 0Á6-fold and 2Á1 Æ 0Á3-fold increase (P<0Á001) in the relative dispersion (dimensionless variance) of blood transit times through the systemic and pulmonary circulation, respectively. Introduction The dispersion of blood transit times through the circulation plays an important role in physiology (affecting blood–tissue exchange kinetics) (King et al., 1996). In particular, there has been a special interest in the information given by the hetero- geneity of blood transit times within the cardiopulmonary sys- tem (Caruthers et al., 1995; Clough et al., 1998; Kuikka et al., 1999). While in the systemic circulation, blood flow and flow heterogeneity have been mostly measured in skeletal muscle using positron emission tomography (Kalliokoski et al., 2003; Heinonen et al., 2012), the heterogeneity in the whole circula- tion can be estimated using transit time distributions of intravascular indicators such as indocyanine green (ICG). By analysing ICG kinetic data obtained by frequent early arterial blood sampling with a recirculatory model, it was possible to determine the transit time distribution through the pulmonary and systemic circulation in dogs (Weiss et al., 2006) and, recently, in humans (Weiss et al., 2011). The latter study showed that the transit time dispersion in the systemic circula- tion decreased linearly with increasing cardiac output. The underlying mechanism is not well understood, although its distribution may become more homogeneous with increasing flow, as it is in skeletal muscle (Kalliokoski et al., 2003; Hei- nonen et al., 2012) and lung (Kuikka, 2000). To get more insight into this problem, we reanalysed ICG data measured in awake volunteers before and after beta-adren- ergic blockade with propranolol, which decreased cardiac out- put by 60% (Niemann et al., 2000), to determine the accompanying changes in pulmonary and systemic transit time dispersion. The original analysis did not provide this informa- tion because it was based on splitting the systemic circulation into two channels (fast and slow peripheral volumes as homo- geneous compartments). Here, in contrast, a continuous distri- bution of transit times was assumed. As previously described, we used the inverse Gaussian (IG) density as empirical probabil- ity density function of transit times (Weiss et al., 2006, 2011). The density distributions of the reciprocal transit times were derived from the estimated parameters to better understand the effect of beta blockade on flow heterogeneity. Our results demonstrate that different modelling approaches can provide different insights into the effect of altered physiological states on the distribution of cardiac output. Methods ICG disposition was determined twice in four adult male vol- unteers, once during a propranolol infusion that decreased cardiac output, after obtaining institutionally approved, writ- ten informed consent (Niemann et al., 2000). Twenty-four Clin Physiol Funct Imaging (2015) doi: 10.1111/cpf.12295 1 © 2015 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd