Microvascular dysfunction in sepsis

Sepsis causes microvascular dysfunction. Increased heterogeneity of capillary blood flow results in local tissue hypoxia, which can cause local tissue inflammation, impaired oxygen extraction, and, ultimately, organ dysfunction. Microvascular dysfunction is clinically relevant because it is a marker for mortality: it improves rapidly in survivors of sepsis but fails to improve in nonsurvivors. This, along with the fact that resuscitation of mean arterial pressure and cardiac output alone fails to improve microvascular function, means that microvascular resuscitation is therefore a therapeutic goal. In animal studies of sepsis, volume resuscitation improves microvascular permeability and tissue oxygenation, and leads to improved organ function, including a reduction in myocardial dysfunction. Microvascular resuscitation strategies include hemodynamic resuscitation using the linked combination of volume resuscitation, judicious vasopressor use, and inotropes and vasodilators. Alternative vasoactive agents, such as vasopressin, may improve microcirculatory function to a greater degree than conventional vasopressors. Successful modulation of inflammation has a positive impact on endothelial function. Finally, targeted treatment of the endothelium, using activated protein C, also improves microvascular function and ultimately increases survival. Thus, attention must be paid to the microcirculation in patients with sepsis, and therapeutic strategies should be employed to resuscitate the microcirculation in order to avoid organ dysfunction and to reduce mortality. Introduction Impaired microvascular function is increasingly recognized as a key characteristic contributing to organ dysfunction and death in patients with sepsis. In fact, impaired oxygen extraction in patients who have sepsis was recognized more than 40 years ago, although it is only more recently that there has been consensus among investigators that microvascular dysfunction is a central feature of sepsis, accounting for many characteristics of the pathogenesis of septic organ dysfunction [1-5]. Indeed, a key observation is that therapeutic modalities that may improve microvascular function are also associated with decreased organ dysfunction and improved outcome in patients with sepsis [6-8]. Furthermore, since normal endothelial function underlies normal microvascular function, there is an increasing interest in endothelial function during sepsis [9-12]. It is therefore vital to understand as much as possible about the microcirculation and endothelium in sepsis in order to identify therapeutic strategies for resuscitating the microcirculation and thus improving outcome. Microvascular dysfunction in sepsis The clinical observations of cyanosis with mottled skin, and evidence of tissue hypoxia (e.g. elevated lactate levels) despite high cardiac output, are common and longrecognized in patients with septic shock. Taken together with reports of abnormal sublingual perfusion in septic patients [13-15], these simple observations suggest that microvascular dysfunction occurs and leads to impaired tissue oxygen transport. Recently, microvascular function has been examined more vigorously in experimental models of sepsis where increased heterogeneity of microvascular perfusion is a hallmark of sepsis. Ellis and colleagues [16,17] demonstrated that microvascular dysfunction occurs in the skeletal muscle microcirculation in septic rats following cecal ligation and puncture. In this rat model, the authors reported an increase in stopped-flow capillaries that was consistent with other reports [18], as well as an increase in the proportion of fast-flow to normal-flow capillaries and a decrease in capillary venular-end erythrocyte hemoglobin oxygen saturation levels, while capillary arteriolar-end erythrocyte hemoglobin oxygen saturation remained unchanged. Capillary oxygen extraction was found to increase threefold and be directly related to the degree of stopped flow. The authors concluded that the septic microcirculation could no longer regulate flow to regions of higher oxygen demand. Review Microvascular resuscitation as a therapeutic goal in severe sepsis Ryon M Bateman and Keith R Walley The James Hogg Imaging, Cell Analysis, and Phenotyping Toward Understanding Responsive, Reparative, Remodelling, and Recombinant Events Centre for Cardiovascular and Pulmonary Research, University of British Columbia, Vancouver, Canada Corresponding author: Keith R Walley, [email protected] Published online: 25 August 2005 Critical Care 2005, 9(suppl 4):S27-S32 (DOI 10.1186/cc3756) This article is online at http://ccforum.com/supplements/9/S4/S27 © 2005 BioMed Central Ltd