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1 Departments of Mathematical Sciences and Biomedical Engineering, New Jersey Institute of Technology, Newark, New Jersey, USA
2 iCAPTURE, University of British, Vancouver, British Columbia, Canada
3 CentreDepartment of Medical Biophysics, Columbia University of Western Ontario, London, Ontario, Canada
* To whom correspondence should be addressed. E-mail: dgoldman{at}oak.njit.edu.
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 O2 utilization on the convective O2 supply. This "pathological supply dependency" is associated with organ failure and poor clinical outcomes. Here, a detailed theoretical model of capillary-tissue O2 transport during sepsis is used to examine the origins of abnormal supply dependency. Using three-dimensional arrays of capillaries with heterogeneous spacing and blood flow, steady-state O2 transport is simulated numerically during reductions in the O2 supply. Increased supply dependency is shown to occur in sepsis for both hypoxic hypoxia (decreased hemoglobin O2 saturation) and stagnant hypoxia (decreased blood flow). For stagnant hypoxia, it is found that 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. However, in sepsis diffusion limitation and shunting of O2 by individual capillaries occur to a degree 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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