Microcirculatory dysfunction in sepsis: a pathogenetic basis for therapy?

Sepsis is a frequent complication of multiple organ dysfunction syndrome an d remains a major problem of intensive care medicine. It is also a common f actor in the final cause of death in hospital populations. Clinical observa tions, assisted by invasive monitoring techniques as well as pathological-a natomical 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 endo toxins, have helped to shed light on the pathomechanisms leading to this dy sregulation in the peripheral circulation. Among these are activation of hu moral 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 tra nsport and utilization. In vitro studies have provided more insight into th e molecular mechanisms involved in this microcirculatory dysfunction, altho ugh much more attention must be directed towards microvascular endothelial cells and the role of heterogeneity of response in various vascular beds. T hese experimental data must in turn be validated by comparing with the huma n in situ situation, both clinical and morphological. This review aims at a critical appraisal of the clinical and experimental evidence for sepsis-in duced dysregulation of the microcirculation and how knowledge of the underl ying cellular and molecular pathology could be used to make therapy more ra tional and effective. To date, therapeutic approaches, such as anti-cytokin e and anti-oxidant regimens, which have been highly successful in experimen tal models, have failed to demonstrate clinical efficacy. Newer approaches, such as targeting the coagulation system, nitric oxide synthesis or intrac ellular signal transduction, are also discussed. The necessity to focus on the role of anti-inflammatory mediators, as well as the pathogenetic signif icance of important molecular groups, such as the heat shock proteins, whic h until now have been given scant attention, will be stressed. Copyright (C ) 2000 John Wiley & Sons, Ltd.