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Christopher G Ellis

Publications and source records attributed to Christopher G Ellis.

14 recordsLinked to original sources
PubMed2006

Effect of decreased O2 supply on skeletal muscle oxygenation and O2 consumption during sepsis: role of heterogeneous capillary spacing and blood flow.

One of the main aspects of the initial phase of the septic inflammatory response to a bacterial infection is abnormal microvascular perfusion, including decreased functional capillary density (FCD) and increased blood flow heterogeneity. On the other hand, one of the most important phenomena observed in the later stages of sepsis is an increased dependence of tissue O(2) utilization on the convective O(2) supply. This "pathological supply dependency" is associated with organ failure and poor clinical outcomes. Here, a detailed theoretical model of capillary-to-tissue O(2) transport during sepsis is used to examine the origins of abnormal supply dependency. With use of three-dimensional arrays of capillaries with heterogeneous spacing and blood flow, steady-state O(2) transport is simulated numerically during reductions in the O(2) supply. Increased supply dependency is shown to occur in sepsis for hypoxic (decreased hemoglobin O(2) saturation) and stagnant (decreased blood flow) hypoxia. For stagnant hypoxia, a reduction in FCD with decreasing blood flow is necessary to obtain the observed increase in supply dependency. Our results imply that supply dependency observed under normal conditions does not have its origin at the level of individual capillaries. In sepsis, however, diffusion limitation and shunting of O(2) by individual capillaries occur to a degree that is dependent on the heterogeneity of septic injury and the arrangement of capillary networks. Thus heterogeneous stoppage of individual capillaries is a likely factor in pathological supply dependency.

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PubMed2005

The microcirculation as a functional system.

This review examines experimental evidence that the microvascular dysfunction that occurs early in sepsis is the critical first stage in tissue hypoxia and organ failure. A functional microvasculature maintains tissue oxygenation despite limitations on oxygen delivery from blood to tissue imposed by diffusion; the density of perfused (functional) capillaries is high enough to ensure appropriate diffusion distances, and arterioles regulate the distribution of oxygen within the organ precisely to where it is needed. Key components of this regulatory system are the endothelium, which communicates and integrates signals along the microvascular network, and the erythrocytes, which directly monitor and regulate oxygen delivery. During hypovolemic shock, a functional microvasculature responds to diminish the impact of a decrease in oxygen supply on tissue perfusion. However, within hours of the onset of sepsis, a dysfunctional microcirculation is, due to a loss of functional capillary density and impaired regulation of oxygen delivery, unable to maintain capillary oxygen saturation levels and prevent the rapid onset of tissue hypoxia despite adequate oxygen supply to the organ. The mechanism(s) responsible for this dysfunctional microvasculature must be understood in order to develop appropriate management strategies for sepsis.

Animals↗
PubMed2005

A new video image analysis system to study red blood cell dynamics and oxygenation in capillary networks.

OBJECTIVE: The authors present a Measurement and Analysis System for Capillary Oxygen Transport (MASCOT) to study red blood cell (RBC) dynamics and oxygenation in capillary networks. The system enables analysis of capillaries to study geometry and morphology and provides values for capillary parameters such as diameter and segment length. It also serves as an analysis tool for capillary RBC flow characteristics, including RBC velocity, lineal density, and supply rate. Furthermore, the system provides a means of determining the oxygen saturation of hemoglobin contained within RBCs, by analysis of synchronized videotapes containing images at two wavelengths, enabling the quantification of the oxygen content of individual RBCs. METHODS: Video recordings of RBC flow at two wavelengths, 420 nm (isosbestic) and 436 nm (oxygen sensitive), are made using a dual camera video microscopy system. The 420-nm recording is used to generate images based on the variance of light intensity fluctuations that help to identify capillaries in a given field of view that are in sharp focus and exhibit flow of individual RBCs separated by plasma gaps. A region of interest enclosing the desired capillary is defined and a fixed number of successive video frames at the two wavelengths are captured. Next a difference image is created, which delineates the RBC column, whose width is used to estimate the internal diameter of the capillary. The 420-nm images are also used to identify the location and centroid of each RBC within the capillary. A space-time image is generated to compute the average RBC velocity. Lineal density is calculated as the number of RBCs per unit length of a capillary segment. The mean optical density (OD) of each RBC is calculated at both wavelengths, and the average SO(2) for each cell is determined from OD(436)/OD(420). RESULTS AND CONCLUSIONS: MASCOT is a robust and flexible system that requires simple hardware, including a SGI workstation fitted with an audio-visual module, a VCR, and an oscilloscope. Since the new system provides information on an individual cell basis from entire capillary segments, the authors believe that results obtained using MASCOT will be more accurate than those obtained from previous systems. Due to its flexibility and ease of extension to other applications, MASCOT has the potential to be applied widely as an analysis tool for capillary oxygen transport measurements.

Animals↗
PubMed2005

Automated method for tracking individual red blood cells within capillaries to compute velocity and oxygen saturation.

OBJECTIVE: The authors present a new method to track individual red blood cells (RBCs) as they move through capillaries. This method uses a recently developed Measurement and Analysis System for Capillary Oxygen Transport (MASCOT) and the concept of space-time images to track RBCs between consecutive frames of video recordings of the microcirculation. METHODS: A space-time image displays in a single static image for a single capillary the location of all RBCs as a function of time. Analysis is performed on video tapes of RBC flow through capillaries to obtain velocity of individual cells as they traverse the capillary of interest. A space-time image is generated to track RBCs from one frame to the next and their velocities are computed. Based on the optical density values of each cell obtained from synchronized videotapes at two wavelengths, the oxygen saturation of a cell can be determined. In this manner, oxygen saturation can be tracked for the same cells as they move through the capillary. RESULTS AND CONCLUSIONS: These measurements, taken together, allow one to determine how much and how fast oxygen is being delivered to the surrounding tissue. This method provides, for the first time, a way to track individual RBCs flowing through capillary networks and study their RBC dynamics and oxygenation.

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PubMed2004

Mapping of the functional microcirculation in vital organs using contrast-enhanced in vivo video microscopy.

A functional microcirculation is vital to the survival of mammalian tissues. In vivo video microscopy is often used in animal models to assess microvascular function, providing real-time observation of blood flow in normal and diseased tissues. To extend the capabilities of in vivo video microscopy, we have developed a contrast-enhanced system with postprocessing video analysis tools that permit quantitative assessment of microvascular geometry and function in vital organs and tissues. FITC-labeled dextran (250 kDa) was injected intravenously into anesthetized mice to provide intravascular fluorescence contrast with darker red blood cell (RBC) motion. Digitized video images of microcirculation in a variety of internal organs (e.g., lung, liver, ovary, and kidney) were processed using computer-based motion correction to remove background respiratory and cardiac movement. Stabilized videos were analyzed to generate a series of functional images revealing microhemodynamic parameters, such as plasma perfusion, RBC perfusion, and RBC supply rate. Fluorescence contrast revealed characteristic microvascular arrangements within different organs, and images generated from video sequences of liver metastases showed a marked reduction in the proportion of tumor vessels that were functional. Analysis of processed video sequences showed large reductions in vessel volume, length, and branch-point density, with a near doubling in vessel segment length. This study demonstrates that postprocessing of fluorescence contrast video sequences of the microcirculation can provide quantitative images useful for studies in a wide range of model systems.

Animals↗
PubMed2004

Effect of sepsis on skeletal muscle oxygen consumption and tissue oxygenation: interpreting capillary oxygen transport data using a mathematical model.

Inherent in the inflammatory response to sepsis is abnormal microvascular perfusion. Maldistribution of capillary red blood cell (RBC) flow in rat skeletal muscle has been characterized by increased 1) stopped-flow capillaries, 2) capillary oxygen extraction, and 3) ratio of fast-flow to normal-flow capillaries. On the basis of experimental data for functional capillary density (FCD), RBC velocity, and hemoglobin O2 saturation during sepsis, a mathematical model was used to calculate tissue O2 consumption (Vo2), tissue Po2 (Pt) profiles, and O2 delivery by fast-flow capillaries, which could not be measured experimentally. The model describes coupled capillary and tissue O2 transport using realistic blood and tissue biophysics and three-dimensional arrays of heterogeneously spaced capillaries and was solved numerically using a previously validated scheme. While total blood flow was maintained, capillary flow distribution was varied from 60/30/10% (normal/fast/stopped) in control to 33/33/33% (normal/fast/stopped) in average sepsis (AS) and 25/25/50% (normal/fast/stopped) in extreme sepsis (ES). Simulations found approximately two- and fourfold increases in tissue Vo2 in AS and ES, respectively. Average (minimum) Pt decreased from 43 (40) mmHg in control to 34 (27) and 26 (15) mmHg in AS and ES, respectively, and clustering fast-flow capillaries (increased flow heterogeneity) reduced minimum Pt to 14.5 mmHg. Thus, although fast capillaries prevented tissue dysoxia, they did not prevent increased hypoxia as the degree of microvascular injury increased. The model predicts that decreased FCD, increased fast flow, and increased Vo2 in sepsis expose skeletal muscle to significant regions of hypoxia, which could affect local cellular and organ function.

Animals↗
PubMed2004

In vivo videomicroscopy reveals differential effects of the vascular-targeting agent ZD6126 and the anti-angiogenic agent ZD6474 on vascular function in a liver metastasis model.

Metastases require a functional blood supply for progressive growth. Thus, therapies that target metastatic vasculature have potential clinical utility. The effects of the vascular-targeting agent (VTA), ZD6126, and the anti-angiogenic agent, ZD6474, on vascular development and function within metastases were compared in an experimental liver metastasis model. Ras-transformed PAP2 fibroblasts were injected into the mesenteric veins of SCID mice to produce a control liver metastasis burden of approximately 40% at 14 days. Mice given a single dose of ZD6126 (200 mg/kg, i.p.) on day 13 were examined 24 h later. Histology revealed a significant reduction in metastatic burden, associated with extensive tumor necrosis, increased tumor cell apoptosis and a reduction in tumor-associated vasculature. In vivo videomicroscopy (IVVM) revealed disrupted, non-functional vascular channels within metastases, with no blood flow. Mice given ZD6474 on days 4 to 10 (50 mg/kg daily, oral gavage) were examined on day 11. Histology revealed a lower metastatic burden, significant reductions in metastasis size and vasculature, and a significant increase in tumor cell apoptosis. IVVM revealed extensive reductions in vascularity and blood flow within metastases. Neither ZD6126 nor ZD6474 treatment affected surrounding normal liver tissue. This study shows that both agents can reduce experimental liver metastasis with no apparent effect on normal vasculature. However, these reductions were attained through distinct effects on the metastatic vasculature. Understanding differences in the modes of action of VTAs and anti-angiogenic agents will be important in optimizing their clinical application and in developing appropriate combination strategies.

Angiogenesis Inhibitors↗
PubMed2003

Effect of nitric oxide on capillary hemodynamics and cell injury in the pancreas during Pseudomonas pneumonia-induced sepsis.

Sepsis-induced nitric oxide (NO) overproduction has been implicated in a redistribution of flow from the pancreas making it vulnerable to ischemic injury in septic shock. To test this hypothesis in a remote injury model of normotensive sepsis, we induced Pseudomonas pneumonia in the rat and used intravital video microscopy (IVVM) of the pancreas to measure functional capillary density, capillary hemodynamics [red blood cell (RBC) velocity, lineal density, and supply rate], and lethal cellular damage (propidium iodine staining) at 6 and 24 h after the induction of pneumonia. With pneumonia, plasma nitrite/nitrate [NO2(-)/NO3(-)(NOx(-))] levels were doubled by 21 h (P < 0.05). To assess the effect of NO overproduction on microvascular perfusion, N6-(1-iminoethyl)-L-lysine (L-NIL) was administered to maintain NOx(-) levels at baseline. Pneumonia did cause a decrease in RBC velocity of 23% by 6 h, but by 24 h RBC velocity and supply rate had increased relative to sham by 22 and 38%, respectively (P < 0.05). L-NIL treatment demonstrated that this increase was due to NO overproduction. With pneumonia, there was no change in functional capillary density and only modest increases in cellular damage. We conclude that, in this normotensive pneumonia model of sepsis, NO overproduction was protective of microvascular perfusion in the pancreas.

Animals↗
PubMed2003

Bench-to-bedside review: microvascular dysfunction in sepsis--hemodynamics, oxygen transport, and nitric oxide.

The microcirculation is a complex and integrated system that supplies and distributes oxygen throughout the tissues. The red blood cell (RBC) facilitates convective oxygen transport via co-operative binding with hemoglobin. In the microcirculation oxygen diffuses from the RBC into neighboring tissues, where it is consumed by mitochondria. Evidence suggests that the RBC acts as deliverer of oxygen and 'sensor' of local oxygen gradients. Within vascular beds RBCs are distributed actively by arteriolar tone and passively by rheologic factors, including vessel geometry and RBC deformability. Microvascular oxygen transport is determined by microvascular geometry, hemodynamics, and RBC hemoglobin oxygen saturation. Sepsis causes abnormal microvascular oxygen transport as significant numbers of capillaries stop flowing and the microcirculation fails to compensate for decreased functional capillary density. The resulting maldistribution of RBC flow results in a mismatch of oxygen delivery with oxygen demand that affects both critical oxygen delivery and oxygen extraction ratio. Nitric oxide (NO) maintains microvascular homeostasis by regulating arteriolar tone, RBC deformability, leukocyte and platelet adhesion to endothelial cells, and blood volume. NO also regulates mitochondrial respiration. During sepsis, NO over-production mediates systemic hypotension and microvascular reactivity, and is seemingly protective of microvascular blood flow.

Hemodynamics↗
PubMed2003

A finite difference model of O2 transport in aortic valve cusps: importance of intrinsic microcirculation.

Recent studies have reported the presence of a microcirculation within the tissue of aortic valves. To test the hypothesis that this vascular bed is needed to satisfy the oxygen demands of the cusp tissue, a two-dimensional (2D) finite difference model of oxygen diffusion was developed. The in vivo environment was modeled for vascular and avascular cusps using thickness data from precise radiographic measurements of fresh porcine valves, and O2 diffusivity (DO2) and O2 consumption (VO2) values from experimental data. The location and density of the cusp vasculature were determined by the model to prevent oxygen levels from falling to zero. Validation of the model was performed by simulation of the experimental measurements of cusp DO2 and VO2. For a test cusp with uniform thickness, the model returned simulated DO2 and VO2 measurements within 1.43% and 0.18% difference of the true parameter values, respectively. For native cusps, the simulated DO2 measurements were sensitive to thickness variations (-38 to +21% difference), whereas the VO2 measurements were minimally affected (8% difference). An improved DO2 measurement technique was found to reduce these errors to <5% and is recommended for analysis of experimental data. In the avascular case, the model predicted large regions of hypoxic tissue, whereas in the vascular case, the model predicted vessel locations and densities similar to what was experimentally observed in porcine cusps. Overall, the in vivo model developed in this study confirmed the need for an intrinsic microcirculation in the thicker basal regions of aortic cusps.

Animals↗
PubMed2002

Effect of a maldistribution of microvascular blood flow on capillary O(2) extraction in sepsis.

Inherent in the remote organ injury caused by sepsis is a profound maldistribution of microvascular blood flow. Using a 24-h rat cecal ligation and perforation model of sepsis, we studied O(2) transport in individual capillaries of the extensor digitorum longus (EDL) skeletal muscle. We hypothesized that erythrocyte O(2) saturation (SO(2)) levels within normally flowing capillaries would provide evidence of either a mitochondrial failure (increased SO(2)) or an O(2) transport derangement (decreased SO(2)). Using a spectrophotometric functional imaging system, we found that sepsis caused 1) an increase in stopped flow capillaries (from 10 to 38%, P < 0.05), 2) an increase in the proportion of fast-flow to normal-flow capillaries (P < 0.05), and 3) a decrease in capillary venular-end SO(2) levels from 58.4 +/- 20.0 to 38.5 +/- 21.2%, whereas capillary arteriolar-end SO(2) levels remained unchanged compared with the sham group. Capillary O(2) extraction increased threefold (P < 0.05) and was directly related to the degree of stopped flow in the EDL. Thus impaired O(2) transport in early stage sepsis is likely the result of a microcirculatory dysfunction.

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PubMedDate not supplied

Flow visualization tools for image analysis of capillary networks.

OBJECTIVE: Video recordings of red blood cell (RBC) flow through capillary networks contain a considerable amount of information pertaining to oxygen transport through the microcirculation. Image analysis of these video recordings has been widely used to determine RBC dynamics (velocity, lineal density and supply rate) and oxygenation (Brunner et al., 2000; Ellis et al., 1990, 1992; Ellsworth et al., 1987; Klyscz et al., 1997; Pries 1988). However, not all capillaries in a given field of view are suitable for image analysis. Typically, capillary segments that are relatively straight and in sharp focus, and exhibit flow of individual RBCs that are well separated by plasma gaps, are good candidates for analysis. We have developed several image processing tools to aid in the selection of such capillaries for analysis and to obtain quick overviews of RBC flow through the microcirculation. METHODS: Burgess et al. (Microcirc. 2:75, 1995) and Burkell et al. (Annals Biomed. Eng. 24:1, 1996; J. Vasc. Res. 35:2, 1998) have previously introduced mean and variance images to aid in the selection of capillaries for analysis. We have extended their concept and developed similar two dimensional visualization techniques for studies of RBC flow through capillary networks. RESULTS: Five new methods of processing video data were developed. The minimum image highlights all capillaries containing RBCs in a given field of view. The maximum image identifies capillaries that exhibit high lineal density or stopped flow. The range image represents the difference between the maximum and minimum light intensity values that occur at a given pixel over a given time period, and helps to identify capillary segments that are in good focus and are perfused by RBCs and plasma. The difference image represents the cumulative sum of the square of differences in intensity values between consecutive frames and gives an indication of the frequency of passage of RBCs separated by plasma gaps. The transition image represents the number of times the intensity at a given pixel crosses a predefined threshold and indicates the number of RBCs (or trains of RBCs) that passes a given location during the observation period. CONCLUSIONS: The above flow visualization techniques are valuable tools to aid in the study of image focus, network geometry, RBC flow paths and dynamics, that can then be used in identifying capillaries for subsequent (separate) detailed analysis to provide quantitative information about RBC flow.

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