Pulsatile cerebral paraarterial flow by peristalsis, pressure and directional resistance.

BACKGROUND: A glymphatic system has been proposed that comprises flow that enters along cerebral paraarterial channels between the artery wall and the surrounding glial layer, continues through the parenchyma, and then exits along similar paravenous channels. The mechanism driving flow through this system is unclear. The pulsatile (oscillatory plus mean) flow measured in the space surrounding the middle cerebral artery (MCA) suggests that peristalsis created by intravascular blood pressure pulses is a candidate for the paraarterial flow in the subarachnoid spaces. However, peristalsis is ineffective in driving significant mean flow when the amplitude of channel wall motion is small, as has been observed in the MCA artery wall. In this paper, peristalsis in combination with two additional mechanisms, a longitudinal pressure gradient and directional flow resistance, is evaluated to match the measured MCA paraarterial oscillatory and mean flows. METHODS: Two analytical models are used that simplify the paraarterial branched network to a long continuous channel with a traveling wave in order to maximize the potential effect of peristalsis on the mean flow. The two models have parallel-plate and annulus geometries, respectively, with and without an added longitudinal pressure gradient. The effect of directional flow resistors was also evaluated for the parallel-plate geometry. RESULTS: For these models, the measured amplitude of arterial wall motion is too large to cause the small measured amplitude of oscillatory velocity, indicating that the outer wall must also move. At a combined motion matching the measured oscillatory velocity, peristalsis is incapable of driving enough mean flow. Directional flow resistance elements augment the mean flow, but not enough to provide a match. With a steady longitudinal pressure gradient, both oscillatory and mean flows can be matched to the measurements. CONCLUSIONS: These results suggest that peristalsis drives the oscillatory flow in the subarachnoid paraarterial space, but is incapable of driving the mean flow. The effect of directional flow resistors is insufficient to produce a match, but a small longitudinal pressure gradient is capable of creating the mean flow. Additional experiments are needed to confirm whether the outer wall also moves, as well as to validate the pressure gradient.

Practical implications of the erroneous treatment of exposure time in the Eulerian hemolysis power law model.

BACKGROUND: Eulerian and Lagrangian power-law formulations are both widely used for computational fluid dynamics (CFD) to predict flow-induced hemolysis in blood-contacting medical devices. Both are based on the same empirical power-law correlation between hemolysis and the shear stress and exposure time. In the Lagrangian approach, blood damage is predicted by tracking both the stress and exposure time along a finite number of pathlines in the domain. In the Eulerian approach, a scalar transport equation is solved for a time-linearized damage index within the entire domain. Previous analytical work has demonstrated that there is a fundamental problem with the treatment of exposure time in the Eulerian model formulation such that the only condition under which the model correctly represents the true exposure time is in a flow field with no streamwise velocity variation. However, the practical implications of this limitation have yet to be thoroughly investigated. METHODS: In this study, we demonstrate the inaccuracy of Eulerian hemolysis power-law model predictions due to the erroneous treatment of exposure time by systematically considering four benchmark test cases with increasing degrees of flow acceleration: Poiseuille flow through a straight tube, inclined Couette flow, and flow through a converging tube with two different convergence ratios. RESULTS: Compared with Lagrangian predictions, we show that, as flow acceleration becomes more pronounced, the resultant inaccuracy in the Eulerian predictions increases. For the inclined Couette flow case, there is a small degree of flow acceleration that yields a discrepancy in the range of 10% between Lagrangian and Eulerian predictions. For flows with a larger degree of acceleration, as occurs in the converging tube flow cases, the discrepancy is considerably larger (up to 257%). CONCLUSION: The inaccuracy of hemolysis predictions due to the erroneous treatment of exposure time in the Eulerian power-law model can be significant when there is streamwise velocity variation in the flow field. These results may partially explain the extremely large variability in CFD hemolysis predictions reported in the literature between Lagrangian and Eulerian models.

On the Discretization of the Power-Law Hemolysis Model.

Flow-induced hemolysis remains a concern for blood-contacting devices, and computer-based prediction of hemolysis could facilitate faster and more economical refinement of such devices. While evaluation of convergence of velocity fields obtained by computational fluid dynamics (CFD) simulations has become conventional, convergence of hemolysis calculations is also essential. In this paper, convergence of the power-law hemolysis model is compared for simple flows, including pathlines with exponentially increasing and decreasing stress, in gradually expanding and contracting Couette flows, in a sudden radial expansion and in the Food and Drug Administration (FDA) channel. In the exponential cases, convergence along a pathline required from one to tens of thousands of timesteps, depending on the exponent. Greater timesteps were required for rapidly increasing (large exponent) stress and for rapidly decreasing (small exponent) stress. Example pathlines in the Couette flows could be fit with exponential curves, and convergence behavior followed the trends identified from the exponential cases. More complex flows, such as in the radial expansion and the FDA channel, increase the likelihood of encountering problematic pathlines. For the exponential cases, comparison of converged hemolysis values with analytical solutions demonstrated that the error of the converged solution may exceed 10% for both rapidly decreasing and rapidly increasing stress.

In vitro and numerical simulation of blood removal from cerebrospinal fluid: comparison of lumbar drain to Neurapheresis therapy.

BACKGROUND: Blood removal from cerebrospinal fluid (CSF) in post-subarachnoid hemorrhage patients may reduce the risk of related secondary brain injury. We formulated a computational fluid dynamics (CFD) model to investigate the impact of a dual-lumen catheter-based CSF filtration system, called Neurapheresis™ therapy, on blood removal from CSF compared to lumbar drain. METHODS: A subject-specific multiphase CFD model of CSF system-wide solute transport was constructed based on MRI measurements. The Neurapheresis catheter geometry was added to the model within the spinal subarachnoid space (SAS). Neurapheresis flow aspiration and return rate was 2.0 and 1.8 mL/min, versus 0.2 mL/min drainage for lumbar drain. Blood was modeled as a bulk fluid phase within CSF with a 10% initial tracer concentration and identical viscosity and density as CSF. Subject-specific oscillatory CSF flow was applied at the model inlet. The dura and spinal cord geometry were considered to be stationary. Spatial-temporal tracer concentration was quantified based on time-average steady-streaming velocities throughout the domain under Neurapheresis therapy and lumbar drain. To help verify CFD results, an optically clear in vitro CSF model was constructed with fluorescein used as a blood surrogate. Quantitative comparison of numerical and in vitro results was performed by linear regression of spatial-temporal tracer concentration over 24-h. RESULTS: After 24-h, tracer concentration was reduced to 4.9% under Neurapheresis therapy compared to 6.5% under lumbar drain. Tracer clearance was most rapid between the catheter aspiration and return ports. Neurapheresis therapy was found to have a greater impact on steady-streaming compared to lumbar drain. Steady-streaming in the cranial SAS was ~ 50× smaller than in the spinal SAS for both cases. CFD results were strongly correlated with the in vitro spatial-temporal tracer concentration under Neurapheresis therapy (R2 = 0.89 with + 2.13% and - 1.93% tracer concentration confidence interval). CONCLUSION: A subject-specific CFD model of CSF system-wide solute transport was used to investigate the impact of Neurapheresis therapy on tracer removal from CSF compared to lumbar drain over a 24-h period. Neurapheresis therapy was found to substantially increase tracer clearance compared to lumbar drain. The multiphase CFD results were verified by in vitro fluorescein tracer experiments.

Deformation of human red blood cells in extensional flow through a hyperbolic contraction.

Flow-induced damage to red blood cells has been an issue of considerable importance since the introduction of the first cardiovascular devices. Early blood damage prediction models were based on measurements of damage by shear stress only. Subsequently, these models were extrapolated to include other components of the fluid stress tensor. However, the expanded models were not validated by measurements of damage in response to the added types of stress. Recent investigations have proposed that extensional stress might be more damaging to red cells than shear stress. In this study, experiments were conducted to compare human red cell deformation under laminar extensional stress versus laminar shear stress. It was found that the deformation caused by shear stress is matched by that produced by an extensional stress that is approximately 34 times smaller. Assuming that blood damage scales directly with cell deformation, this result indicates that mechanistic blood damage prediction models should weigh extensional stress more than shear stress.

Impact of Neurapheresis System on Intrathecal Cerebrospinal Fluid Dynamics: A Computational Fluid Dynamics Study.

It has been hypothesized that early and rapid filtration of blood from cerebrospinal fluid (CSF) in postsubarachnoid hemorrhage patients may reduce hospital stay and related adverse events. In this study, we formulated a subject-specific computational fluid dynamics (CFD) model to parametrically investigate the impact of a novel dual-lumen catheter-based CSF filtration system, the Neurapheresis™ system (Minnetronix Neuro, Inc., St. Paul, MN), on intrathecal CSF dynamics. The operating principle of this system is to remove CSF from one location along the spine (aspiration port), externally filter the CSF routing the retentate to a waste bag, and return permeate (uncontaminated CSF) to another location along the spine (return port). The CFD model allowed parametric simulation of how the Neurapheresis system impacts intrathecal CSF velocities and steady-steady streaming under various Neurapheresis flow settings ranging from 0.5 to 2.0 ml/min and with a constant retentate removal rate of 0.2 ml/min simulation of the Neurapheresis system were compared to a lumbar drain simulation with a typical CSF removal rate setting of 0.2 ml/min. Results showed that the Neurapheresis system at a maximum flow of 2.0 ml/min increased average steady streaming CSF velocity 2× in comparison to lumbar drain (0.190 ± 0.133 versus 0.093 ± 0.107 mm/s, respectively). This affect was localized to the region within the Neurapheresis flow loop. The mean velocities introduced by the flow loop were relatively small in comparison to normal cardiac-induced CSF velocities.

Modeling and prediction of flow-induced hemolysis: a review.

Despite decades of research related to hemolysis, the accuracy of prediction algorithms for complex flows leaves much to be desired. Fundamental questions remain about how different types of fluid stresses translate to red cell membrane failure. While cellular- and molecular-level simulations hold promise, spatial resolution to such small scales is computationally intensive. This review summarizes approaches to continuum-level modeling of hemolysis, a method that is likely to be useful well into the future for design of typical cardiovascular devices. Weaknesses are revealed for the Eulerian method of hemolysis prediction and for the linearized damage function. Wide variations in scaling of red cell membrane tension are demonstrated with different types of fluid stresses when the scalar fluid stress is the same, as well as when the energy dissipation rate is the same. New experimental data are needed for red cell damage in simple flows with controlled levels of different types of stresses, including laminar shear, laminar extension (normal), turbulent shear, and turbulent extension. Such data can be curve-fit to create more universal continuum-level models and can serve to validate numerical simulations.

On Eulerian versus Lagrangian models of mechanical blood damage and the linearized damage function.

Two limitations have been discovered in the derivation of the Eulerian method of hemolysis prediction using a linearized blood damage function. First is that in the transformation from the Lagrangian material volume of the original power-law model to a fixed Eulerian control volume, the spatial dependence of duration of exposure to fluid stress was neglected. This omission has the implication that the Eulerian method as reported is valid only for steady, uniaxial flow in which velocity is constant along streamlines. The second issue is related to linearization, which involves distributing an exponent across an integral. This operation is valid only for limited conditions that include the exponent being unity (which is not the case for any power-law hemolysis models) or the blood damage function being constant throughout the flow regime. These constraints severely restrict the applicability of the Eulerian method. An example problem is presented that demonstrates that the source term of the Eulerian method as reported does not account for differences in velocity between 2 similar flows. Correcting the source term to match the hemolysis prediction to that of the original, unlinearized method requires an analytical description of the flow field that may not be easily obtained for the complex flows in some cardiovascular devices.

Is bulk flow plausible in perivascular, paravascular and paravenous channels?

BACKGROUND: Transport of solutes has been observed in the spaces surrounding cerebral arteries and veins. Indeed, transport has been found in opposite directions in two different spaces around arteries. These findings have motivated hypotheses of bulk flow within these spaces. The glymphatic circulation hypothesis involves flow of cerebrospinal fluid from the cortical subarachnoid space to the parenchyma along the paraarterial (extramural, Virchow-Robin) space around arteries, and return flow to the cerebrospinal fluid (CSF) space via paravenous channels. The second hypothesis involves flow of interstitial fluid from the parenchyma to lymphatic vessels along basement membranes between arterial smooth muscle cells. METHODS: This article evaluates the plausibility of steady, pressure-driven flow in these channels with one-dimensional branching models. RESULTS: According to the models, the hydraulic resistance of arterial basement membranes is too large to accommodate estimated interstitial perfusion of the brain, unless the flow empties to lymphatic ducts after only several generations (still within the parenchyma). The estimated pressure drops required to drive paraarterial and paravenous flows of the same magnitude are not large, but paravenous flow back to the CSF space means that the total pressure difference driving both flows is limited to local pressure differences among the different CSF compartments, which are estimated to be small. CONCLUSIONS: Periarterial flow and glymphatic circulation driven by steady pressure are both found to be implausible, given current estimates of anatomical and fluid dynamic parameters.

Characterization of erythrocyte membrane tension for hemolysis prediction in complex flows.

Hemolysis is a persistent issue with blood-contacting devices. Many experimental and theoretical contributions over the last few decades have increased insight into the mechanisms of hemolysis in both laminar and turbulent flows, with the ultimate goal of developing a comprehensive, mechanistic hemolysis model. Many models assume that hemolysis scales with a resultant, scalar stress representing all components of the fluid stress tensor. This study critically evaluates this scalar stress hypothesis by calculating the response of the red blood cell membrane to different types of fluid stress (laminar shear and extension, and three turbulent shear and extension cases), each with the same scalar stress. It was found that even though the scalar stress is the same for all cases, membrane tension varied by up to three orders of magnitude. In addition, extensional flow causes constant tension, while tank-treading in shear flow causes periodic tension, with tank-treading frequency varying by three orders of magnitude among the cases. For turbulent flow, tension also depends on eddy size. It is concluded, therefore, that scalar stress alone is inadequate for scaling hemolysis. Fundamental investigations are needed to establish a new index of the fluid stress tensor that provides reliable hemolysis prediction across the wide range of complex flows that occur in cardiovascular devices.

Comparison of Blood Viscoelasticity in Pediatric and Adult Cardiac Patients.

Evidence is accumulating that blood flow patterns in the cardiovascular system and in cardiovascular devices do, in some instances, depend on blood viscoelasticity. Thus, to better understand the challenges to providing circulatory support and surgical therapies for pediatric and adult patients, viscous and elastic components of complex blood viscoelasticity of 31 pediatric patients were compared to those of 29 adult patients with a Vilastic-3 rheometer. A random effects model with categorical age covariates found statistically significant differences between pediatric and adult patients for log viscosity (p = 0.005). Log strain (p < 0.0001) and hematocrit (p < 0.0001) effects were also significant, as were the hematocrit-by-log-strain (p = 0.0006) and age-by-log strain (p = 0.001) interactions. The hematocrit-by-age interaction was not significant. For log elasticity, age differences were insignificant (p = 0.39). The model for log elasticity had significant log strain (p < 0.0001), log strain squared (p < 0.0001) and hematocrit (p < 0.0001) effects, as well as hematocrit-by-log-strain and hematocrit-by-log-strain-squared interactions (p = 0.014). A model for log viscosity with continuous age was also fit to the data, which can be used to refine cardiovascular device design and operation to the age of the patient. We conclude that there are distinct differences between pediatric and adult blood viscosity, as well as substantial variation within the pediatric population, that may impact the performance of devices and procedures.

Impact of Bi-Axial Shear on Atherogenic Gene Expression by Endothelial Cells.

This study demonstrated the effects of the directionality of oscillatory wall shear stress (WSS) on proliferation and proatherogenic gene expression (I-CAM, E-Selectin, and IL-6) in the presence of inflammatory mediators leukotriene B4 (LTB4) and bacterial lipopolysaccharide (LPS) from endothelial cells grown in an orbiting culture dish. Computational fluid dynamics (CFD) was applied to quantify the flow in the dish, while an analytical solution representing an extension of Stokes second problem was used for validation. Results indicated that WSS magnitude was relatively constant near the center of the dish and oscillated significantly (0-0.9 Pa) near the side walls. Experiments showed that LTB4 dominated the shear effects on cell proliferation and area. Addition of LPS didn't change proliferation, but significantly affected cell area. The expression of I-CAM1, E-Selectin and IL-6 were altered by directional oscillatory shear index (DOSI, a measure of the biaxiality of oscillatory shear), but not shear magnitude. The significance of DOSI was further reinforced by the strength of its interactions with other atherogenic factors. Hence, directionality of shear appears to be an important factor in regulating gene expression and provides a potential explanation of the propensity for increased vascular lesions in regions in the arteries with oscillating biaxial flow.

Peristalsis with Oscillating Flow Resistance: A Mechanism for Periarterial Clearance of Amyloid Beta from the Brain.

Alzheimer's disease is characterized by accumulation of amyloid-ß (Aß) in the brain and in the walls of cerebral arteries. The focus of this work is on clearance of Aß along artery walls, the failure of which may explain the accumulation of Aß in Alzheimer's disease. Periarterial basement membranes form continuous channels from cerebral capillaries to major arteries on the surface of the brain. Arterial pressure pulses drive peristaltic flow in the basement membranes in the same direction as blood flow. Here we forward the hypothesis that flexible structures within the basement membrane, if oriented such they present greater resistance to forward than retrograde flow, may cause net reverse flow, advecting Aß along with it. A solution was obtained for peristaltic flow with low Reynolds number, long wavelength compared to channel height and small channel height compared to vessel radius in a Darcy-Brinkman medium representing a square array of cylinders. Results show that retrograde flow is promoted by high cylinder volume fraction and low peristaltic amplitude. A decrease in cylinder concentration and/or an increase in amplitude, both of which may occur during ageing, can reduce retrograde flow or even cause a transition from retrograde to forward flow. Such changes may explain the accumulation of Aß in the brain and in artery walls in Alzheimer's disease.

In vitro validation of flow measurement with phase contrast MRI at 3 tesla using stereoscopic particle image velocimetry and stereoscopic particle image velocimetry-based computational fluid dynamics.

PURPOSE: To validate conventional phase-contrast MRI (PC-MRI) measurements of steady and pulsatile flows through stenotic phantoms with various degrees of narrowing at Reynolds numbers mimicking flows in the human iliac artery using stereoscopic particle image velocimetry (SPIV) as gold standard. MATERIALS AND METHODS: A series of detailed experiments are reported for validation of MR measurements of steady and pulsatile flows with SPIV and CFD on three different stenotic models with 50%, 74%, and 87% area occlusions at three sites: two diameters proximal to the stenosis, at the throat, and two diameters distal to the stenosis. RESULTS: Agreement between conventional spin-warp PC-MRI with Cartesian read-out and SPIV was demonstrated for both steady and pulsatile flows with mean Reynolds numbers of 130, 160, and 190 at the inlet by evaluating the linear regression between the two methods. The analysis revealed a correlation coefficient of > 0.99 and > 0.96 for steady and pulsatile flows, respectively. Additionally, it was found that the most accurate measures of flow by the sequence were at the throat of the stenosis (error < 5% for both steady and pulsatile mean flows). The flow rate error distal to the stenosis was primarily found to be a function of narrowing severity including dependence on proper Venc selection. CONCLUSION: SPIV and CFD provide excellent approaches to in vitro validation of new or existing PC-MRI flow measurement techniques.

Testing of models of flow-induced hemolysis in blood flow through hypodermic needles.

Hemolysis caused by flow in hypodermic needles interferes with a number of tests on blood samples drawn by venipuncture, including assays for metabolites, electrolytes, and enzymes, causes discomfort during dialysis sessions, and limits transfusion flow rates. To evaluate design modifications to address this problem, as well as hemolysis issues in other cardiovascular devices, computational fluid dynamics (CFD)-based prediction of hemolysis has potential for reducing the time and expense for testing of prototypes. In this project, three CFD-integrated blood damage models were applied to flow-induced hemolysis in 16-G needles and compared with experimental results, which demonstrated that a modified needle with chamfered entrance increased hemolysis, while a rounded entrance decreased hemolysis, compared with a standard needle with sharp entrance. After CFD simulation of the steady-state velocity field, the time histories of scalar stress along a grid of streamlines were calculated. A strain-based cell membrane failure model and two empirical power-law blood damage models were used to predict hemolysis on each streamline. Total hemolysis was calculated by weighting the predicted hemolysis along each streamline by the flow rate along each streamline. The results showed that only the strain-based blood damage model correctly predicted increased hemolysis in the beveled needle and decreased hemolysis in the rounded needle, while the power-law models predicted the opposite trends.

Maximizing information from space data resources: a case for expanding integration across research disciplines.

Regulatory systems are affected in space by exposure to weightlessness, high-energy radiation or other spaceflight-induced changes. The impact of spaceflight occurs across multiple scales and systems. Exploring such interactions and interdependencies via an integrative approach provides new opportunities for elucidating these complex responses. This paper argues the case for increased emphasis on integration, systematically archiving, and the coordination of past, present and future space and ground-based analogue experiments. We also discuss possible mechanisms for such integration across disciplines and missions. This article then introduces several discipline-specific reviews that show how such integration can be implemented. Areas explored include: adaptation of the central nervous system to space; cerebral autoregulation and weightlessness; modelling of the cardiovascular system in space exploration; human metabolic response to spaceflight; and exercise, artificial gravity, and physiologic countermeasures for spaceflight. In summary, spaceflight physiology research needs a conceptual framework that extends problem solving beyond disciplinary barriers. Administrative commitment and a high degree of cooperation among investigators are needed to further such a process. Well-designed interdisciplinary research can expand opportunities for broad interpretation of results across multiple physiological systems, which may have applications on Earth.

Effects of biaxial oscillatory shear stress on endothelial cell proliferation and morphology.

Wall shear stress (WSS) on anchored cells affects their responses, including cell proliferation and morphology. In this study, the effects of the directionality of pulsatile WSS on endothelial cell proliferation and morphology were investigated for cells grown in a Petri dish orbiting on a shaker platform. Time and location dependent WSS was determined by computational fluid dynamics (CFD). At low orbital speed (50 rpm), WSS was shown to be uniform (0-1 dyne/cm(2)) across the bottom of the dish, while at higher orbital speed (100 and 150 rpm), WSS remained fairly uniform near the center and fluctuated significantly (0-9 dyne/cm(2)) near the side walls of the dish. Since WSS on the bottom of the dish is two-dimensional, a new directional oscillatory shear index (DOSI) was developed to quantify the directionality of oscillating shear. DOSI approached zero for biaxial oscillatory shear of equal magnitudes near the center and approached one for uniaxial pulsatile shear near the wall, where large tangential WSS dominated a much smaller radial component. Near the center (low DOSI), more, smaller and less elongated cells grew, whereas larger cells with greater elongation were observed in the more uniaxial oscillatory shear (high DOSI) near the periphery of the dish. Further, cells aligned with the direction of the largest component of shear but were randomly oriented in low magnitude biaxial shear. Statistical analyses of the individual and interacting effects of multiple factors (DOSI, shear magnitudes and orbital speeds) showed that DOSI significantly affected all the responses, indicating that directionality is an important determinant of cellular responses.

Spatial and temporal resolution of shear in an orbiting petri dish.

It is well documented that physiological and morphological properties of anchored cells are influenced by fluid shear stress. Common orbital shakers provide a means of simultaneously applying shear stress to cells for tens to hundreds of cases by loading the shaker with multiple dishes. However, the complex flow in orbiting dishes is amenable to analytical solution for resolving shear created by the fluid motion only for simplified conditions. The only existing quantification of shear in this flow is an equation that estimates a constant scalar value of shear for the entire surface of the dish. In practice, wall shear stress (WSS) will be oscillatory rather than steady due to the travelling waveform and will vary across the surface of the dish at any instant in time. This article presents a computational model that provides complete spatial and temporal resolution of WSS over the bottom surface of a dish throughout the orbital cycle. The model is reasonably well validated by the analytical solution, with resultant WSS magnitudes that are within 0.99 ± 0.42 dyne/cm(2) . The model results were compared to tangential WSS magnitudes obtained using one-dimensional optical velocimetry at discreet locations on the bottom of an orbiting dish. The experimental minimum and maximum WSS at 1 mm from the center of the dish were 6 and 7 dyne/cm(2) , respectively, whereas WSS generated from the computational model ranged from 0.5 to 8.5 dyne/cm(2) . The experimental minimum and maximum WSS at 12 mm from the center of the dish were 6 and 16 dyne/cm(2) , respectively, whereas WSS generated from the computational model ranged from 0.5 to 14 dyne/cm(2) . Discrepancies between the experimental and computational data may be attributed to a sparse sampling rate for the experimental probe, a sharp gradient at the sample area which could cause the unidirectional probe to be inaccurate if its location were not precise, and too few particles to track and a scattering of the signal by the free surface when the liquid is shallow.

Modelling of cardiovascular response to graded orthostatic stress: role of capillary filtration.

BACKGROUND: Of the many possible factors that may contribute to orthostatic intolerance, the loss of circulating blood because of capillary filtration is one of the few that can explain the gradual decline of arterial pressure during stand tests. This study used a computer model to investigate the relative importance of haemodynamic parameters, including capillary filtration, as potential contributors to orthostatic intolerance. Simulated orthostatic tolerance times were compared to previous experiments combining head-up tilt and lower body negative pressure graded orthostatic stress, which provided haemodynamic data, in particular haematocrit measurements that allowed subject-specific modelling of capillary transport. MATERIALS AND METHODS: The cardiovascular system was simulated using a seven-compartment model with measured heart rate, stroke volume, total peripheral resistance, mean arterial pressure and haematocrit data for 12 subjects. Simulations were controlled by decreasing the total blood volume at the measured rates of capillary filtration until cerebral pressure dropped below a threshold for consciousness. Predicted times to syncope were compared to actual times to presyncope, and sensitivity of arterial pressure and cardiac output to independent system parameters were determined. RESULTS: There was no statistical difference in modelled times to syncope and actual times to presyncope. Both arterial pressure and cardiac output were most sensitive to total blood volume and least sensitive to caudal compliance parameters. CONCLUSIONS: The feasibility of subject-specific simulations of cardiovascular response to orthostatic stress was demonstrated, providing stronger evidence that capillary filtration is a prominent mechanism in causing orthostatic intolerance. These results may have clinical and spaceflight applications.