Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy?

Abstract

Sepsis is a frequent complication of multiple organ dysfunction syndrome and remains a major problem of intensive care medicine. It is also a common factor in the final cause of death in hospital populations. Clinical observations, assisted by invasive monitoring techniques as well as pathological–anatomical studies, clearly indicate that microcirculatory dysfunction lies at the centre of sepsis pathogenesis. Numerous animal models, from rodents to primates, many of which employ bacteria or their toxins, especially endotoxins, have helped to shed light on the pathomechanisms leading to this dysregulation in the peripheral circulation. Among these are activation of humoral and cellular inflammatory mediator systems, with special emphasis on neutrophil–endothelial interactions, affecting endothelial barrier function and vasoregulation and ultimately leading to severely perturbed oxygen transport and utilization. In vitro studies have provided more insight into the molecular mechanisms involved in this microcirculatory dysfunction, although much more attention must be directed towards microvascular endothelial cells and the role of heterogeneity of response in various vascular beds. These experimental data must in turn be validated by comparing with the human in situ situation, both clinical and morphological. This review aims at a critical appraisal of the clinical and experimental evidence for sepsis‐induced dysregulation of the microcirculation and how knowledge of the underlying cellular and molecular pathology could be used to make therapy more rational and effective. To date, therapeutic approaches, such as anti‐cytokine and anti‐oxidant regimens, which have been highly successful in experimental models, have failed to demonstrate clinical efficacy. Newer approaches, such as targeting the coagulation system, nitric oxide synthesis or intracellular signal transduction, are also discussed. The necessity to focus on the role of anti‐inflammatory mediators, as well as the pathogenetic significance of important molecular groups, such as the heat shock proteins, which until now have been given scant attention, will be stressed. Copyright © 2000 John Wiley & Sons, Ltd.

Cerebral microcirculation is impaired during sepsis: an experimental study

“…Microvascular perfusion is regulated by an intricate interplay of many neuroendocrine, paracrine and mechano-sensory pathways [35], adapting to the balance between local oxygen delivery and metabolic needs. Thus, one may imagine that mechanisms implicated in microvascular dysfunction in other organs may also be involved in brain microvascular dysfunction.…”

Role of vasodilator‐stimulated phosphoprotein in protein kinase A‐induced changes in endothelial junctional permeability

“…E ndothelial cells that line blood vessels are the primary determinants of vascular permeability [1], and structural and functional integrity of the endothelium is crucial in determining overall vascular permeability. Endothelial injury, such as occurs during leukocyte-endothelial interactions, may result in increased paracellular permeability, decreased barrier function, and subsequent intravascular loss of fluid and local tissue edema [2,3]. During transendothelial migration (TEM), polymorphonuclear leukocyte (PMN)-derived adenosine activates endothelial adenosine receptors and induces a cAMP-dependent sealing of endothelial monolayers [4,5].…”

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“…A review article from 2000 suggests that clinical and experimental evidence "clearly indicate that microcirculatory dysfunction lies at the centre of sepsis pathogenesis" [41]. …”