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Current and new therapies for the critically injured microcirculation

Abstract : For the past 20 years, the microcirculation has been regarded as cornerstone in the development of organ failure in critically ill patients. Eventually, the microcirculation became a therapeutic target. Due to the complexity of the microarchitecture of this functional system, varying across organs, one therapy cannot “fit all”. The alterations observed in the critically injured microcirculation involve: (i) the container defined by the different layers of the vascular wall including the endothelial cells and a protective gel called the glycocalyx spread on the surface, where contact with blood is made, (ii) the contents representing the flowing plasma and the different elements of blood and (iii) the extraluminal surrounding tissue. The microcirculation can be injured in various ways, with different levels of injury to these constitutive elements. Thus, to appropriately resuscitate the injured microcirculation, the choice of the optimal therapy or bundle of therapies should be rationalized with a meticulous analysis of the damages suffered by the microcirculation. The evaluation of the microcirculation should be multivariate. In this thesis, the research was mainly focused on the kidney. The first part is dedicated to the review of the structural and functional mechanisms of the renal microcirculation in both healthy and septic states. The second part tries to identify the respective roles of each of the components of the microcirculation in critical conditions especially the glycocalyx and plasma viscosity. The vascular barrier permeability was investigated in hemorrhagic shock and hemodilution models in rodents. The main findings suggest that a gradation in the level of injury to the vascular barrier permeability exist.The last part of the thesis investigated how current and older therapies can modulate microcirculation in terms of oxygenation, inflammation and microcirculatory flow within the kidney. Among therapies investigated, N-acetylcysteine was efficient at limiting inflammation and increasing oxygenation within the kidney. A new generation of hemoglobin-based oxygen carrier showed some efficacy in murine endotoxemic model. Overall, these different findings coalesce to show the importance of having a multivariate analysis of the microcirculation, as each of the therapies acts on a specific aspect of it. Hopefully, this research helped pave the way for a more personalized medicine for the patients.
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Submitted on : Thursday, September 17, 2020 - 2:47:04 PM
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  • HAL Id : tel-02941976, version 1


Philippe Guerci. Current and new therapies for the critically injured microcirculation. Human health and pathology. Université de Lorraine; Universiteit van Amsterdam, 2020. English. ⟨NNT : 2020LORR0053⟩. ⟨tel-02941976⟩



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