Metabolite mean transit times in the liver as predicted by various models of hepatic elimination

Predicted area under curve (AUC), mean transit time (MTT) and normalized variance (CV2) data have been compared for parent compound and generated metabolite following an impulse input into the liver, Models studied were the well-stirred (tank) model, tube model, a distributed tube model, dispersion model (Danckwerts and mixed boundary conditions) and tanks-in-series model. It is well known that discrimination between models for a parent solute is greatest when the parent solute is highly extracted by the liver. With the metabolite, greatest model differences for MTT and CV2 occur when parent solute is poorly extracted. In all cases the predictions of the distributed tube, dispersion, and tasks-in-series models are between the predictions of the rank and tube models. The dispersion model with mixed boundary conditions yields identical predictions to those for the distributed tube model (assuming an inverse gaussian distribution of tube transit times). The dispersion model with Danckwerts boundary conditions and the tanks-in series models give similar predictions to the dispersion (mixed boundary conditions) and the distributed tube. The normalized variance for parent compound is dependent upon hepatocyte permeability only within a distinct range of permeability values. This range is similar for each model but the order of magnitude predicted for normalized variance is model dependent. Only for a one-compartment system is the MIT for generated metabolite equal to the sum of MTTs for the parent compound and preformed metabolite administered as parent.

Pulse transit time as a derived noninvasive mean to monitor arterial distensibility changes in children

Changes in arterial distensibility have been widely used to identify the presence of cardiovascular abnormalities like hypertension. Pulse wave velocity (PWV) has shown to be related to arterial distensibility. However, the lack of suitable techniques to measure PWV nonintrusively has impeded its clinical usefulness. Pulse transit time (PTT) is a noninvasive technique derived from the principle of PWV. PTT has shown its capabilities in cardiovascular and cardiorespiratory studies in adults. However, no known study has been conducted to understand the suitability and utility of PTT to estimate PWV in children. Two computational methods to derive PWV from PTT values obtained from 23 normotensive Caucasian children (19 males, aged 5-12 years old) from their finger and toe were conducted. Furthermore, the effects of adopting different postures on the PWV derivations were investigated. Statistical analyses were performed in comparison with two previous PWV studies conducted on children. Results revealed that PWV derived from the upper limb correlated significantly (P

Use of pulse transit time to distinguish respiratory events from tidal breathing in sleeping children

Study objectives: Currently, esophageal pressure monitoring is the "gold standard" measure for inspiratory efforts, hut its invasive nature necessitates a better tolerated and noninvasive method to be used on children. Pulse transit time (PTT) has demonstrated its potential as a noninvasive surrogate marker for inspiratory efforts. The principle velocity determinant of PTT is the change in stiffness of the arterial wall and is inversely correlated to BP. Moreover, PTT has been shown to identify changes in inspiratory effort via the BP fluctuations induced by negative pleural pressure swings. In this study, the capability of PTT to classify respiratory, events during sleep as either central or obstructive in nature was investigated. Setting and participants: PTT measure was used in adjunct to routine overnight polysomnographic studies performed on 33 children (26 boys and 7 girls; mean +/- SD age, 6.7 +/- 3.9 years). The accuracy of PTT measurements was then evaluated against scored corresponding respiratory events in the polysomnography recordings. Results: Three hundred thirty-four valid respiratory events occurred and were analyzed. One hundred twelve obstructive events (OEs) showed a decrease in mean PTT over a 10-sample window that had a probability of being correctly ranked below the baseline PTT during tidal breathing of 0.92 (p < 0.005); 222 central events (CEs) showed a decrease in the variance of PTT over a 10-sample window that had a probability of being ranked below the baseline PTT of 0.94 (p < 0.005). This indicates that, at a sensitivity of 0.90, OEs can be detected with a specificity of 0.82 and CEs can be detected with a specificity of 0.80. Conclusions: PTT is able to categorize CEs and OEs accordingly in the absence of motion artifacts, including hypopneas. Hence, PTT shows promise to differentiate respiratory, events accordingly and can be an important diagnostic tool in pediatric respiratory sleep studies.< 0.005); 222 central events (CEs) showed a decrease in the variance of PTT over a 10-sample window that had a probability of being ranked below the baseline PTT of 0.94 (p < 0.005). This indicates that, at a sensitivity of 0.90, OEs can be detected with a specificity of 0.82 and CEs can be detected with a specificity of 0.80. Conclusions: PTT is able to categorize CEs and OEs accordingly in the absence of motion artifacts, including hypopneas. Hence, PTT shows promise to differentiate respiratory, events accordingly and can be an important diagnostic tool in pediatric respiratory sleep studies.');"

Pulse transit time changes observed with different limb positions

Pulse transit time (PTT) is a non-invasive measure of arterial compliance. It can be used to assess instantaneous blood pressure (BP) changes in continual cardiovascular measurement such as during overnight respiratory sleep studies. In these studies, periodic changes in limb position can occur randomly. However, little is known about their possible effects on PTT monitored on the various limbs. The objective of this study was to evaluate PTT differences on all four limbs during two positional changes (lowering and raising of a limb). Ten healthy adults (seven male) with a mean age of 27.0 years were recruited in this study. The results showed that the limb that underwent a positional change had significant (p < 0.05) local PTT differences when compared to its nominal baseline value, whereas PTT changes in the other remaining limbs were insignificant (p > 0.05). The mean PTT value measured from a vertically-raised limb increased by 42.7 ms, while it decreased by 28.1 ms with a half-lowered limb. The PTT differences observed during positional change can be contributed to by the complex interactions between hydrostatic pressure changes, autonomic and local autoregulation experienced in these limbs. Hence the findings herein suggest that PTT is able to reflect local circulatory responses despite changes in the position of other limbs. This can be useful in prolonged clinical observations where limb movements are expected.

Differentiating responses to obstructive sleep apnoea using pulse transit time

Conventional overnight polysomnography (PSG) used to determine the respiratory behaviour during sleep can be a complex and expensive procedure. Pulse transit time analysis (PTT) has shown potential to detect obstructive apnoeic and hypopnoeic events in adults. This study was undertaken to determine the potential of PTT to differentiate responses to upper airway obstruction. 103 obstructive respiratory events occurred in PSG studies performed on 11 children (10 male and 1 female, mean age 7.5years). PTT measurements were evaluated against the corresponding PSG results pre-scored by 2 blinded observers. Broadly, there were 2 types of responses. They can be either short period of rapid PTT decreases (Type 1) or prolonged but gradual PTT decreases (Type 2). Type 1 obstructive events showed a mean change of 51.77% (p

Confounding physiologic parameters in pulse transit time monitoring of children

Pulse Transit Time (PTT) measurement has showed potential in non-invasive monitoring of changes in blood pressure. In children, the common peripheral sites used for these studies are a finger or toe. Presently, there are no known studies conducted to investigate any possible physiologic parameters affecting PTT measurement at these sites for children. In this study, PTT values of both peripheral sites were recorded from 64 children in their sitting posture. Their mean age with standard deviation (SD) was 8.2 2.6years (ranged 3 to 12years). Subjects' peripheries path length, heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP) were measured to investigate any contributions to PTT measurement. The peripheral pulse timing characteristic measured by photoplethysmography (PPG) shows a 59.5 8.5ms (or 24.8 0.4%) difference between the two peripheries (p

Commentary: Using the convection-dispersion model and transit time density functions in the analysis of organ distribution kinetics

The convection-dispersion model and its extended form have been used to describe solute disposition in organs and to predict hepatic availabilities. A range of empirical transit-time density functions has also been used for a similar purpose. The use of the dispersion model with mixed boundary conditions and transit-time density functions has been queried recently by Hisaka and Sugiyanaa in this journal. We suggest that, consistent with soil science and chemical engineering literature, the mixed boundary conditions are appropriate providing concentrations are defined in terms of flux to ensure continuity at the boundaries and mass balance. It is suggested that the use of the inverse Gaussian or other functions as empirical transit-time densities is independent of any boundary condition consideration. The mixed boundary condition solutions of the convection-dispersion model are the easiest to use when linear kinetics applies. In contrast, the closed conditions are easier to apply in a numerical analysis of nonlinear disposition of solutes in organs. We therefore argue that the use of hepatic elimination models should be based on pragmatic considerations, giving emphasis to using the simplest or easiest solution that will give a sufficiently accurate prediction of hepatic pharmacokinetics for a particular application. (C) 2000 Wiley-Liss Inc. and the American Pharmaceutical Association J Pharm Sci 89:1579-1586, 2000.

Physiologic parameters that affect pulse transit time difference between the upper and lower limbs in children

Pulse wave velocity (PWV) is a known parameter that is related to arterial distensibility. However, its potential is hampered by the absence of appropriate techniques to estimate it noninvasively. PWV can be used as an assessment of increased arterial stiffness that is linked to systolic hypertension, excess cardiovascular morbidity and mortality.(1,2)

On the validity of the dispersion model of hepatic drug elimination when intravascular transit time densities are long-tailed

The dispersion model with mixed boundary conditions uses a single parameter, the dispersion number, to describe the hepatic elimination of xenobiotics and endogenous substances. An implicit a priori assumption of the model is that the transit time density of intravascular indicators is approximated by an inverse Gaussian distribution. This approximation is limited in that the model poorly describes the tail part of the hepatic outflow curves of vascular indicators. A sum of two inverse Gaussian functions is proposed as ail alternative, more flexible empirical model for transit time densities of vascular references. This model suggests that a more accurate description of the tail portion of vascular reference curves yields an elimination rate constant (or intrinsic clearance) which is 40% less than predicted by the dispersion model with mixed boundary conditions. The results emphasize the need to accurately describe outflow curves in using them as a basis for determining pharmacokinetic parameters using hepatic elimination models. (C) 1997 Society for Mathematical Biology.

Relative dispersion of intravascular transit times during isolated human limb perfusions for recurrent melanoma

Aims We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing. Methods A bolus of injectate containing [Cr-51] labelled red blood cells, [C-14]-sucrose and [H-3]-water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [Cr-51] or beta [C-14 and H-3] counting. The moments of the outflow fraction-time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions). Results The availability, mean transit time and normalised variance (CV2) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients. Conclusions The vascular space is not well-stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow-limited blood-tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.