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Excerpt
During the last decade, enormous effort has been expended to unravel the complexities and intricacies surrounding the pathogenesis of sepsis and the systemic inflammatory response syndrome. Patterns of proinflammatory cytokine release, most notably tumor necrosis factor (TNF), interleukin-1, and interleukin-6, in critically ill septic patients have been thoroughly described [1-3]. Contrasts between these patterns and the patterns seen in other conditions, including burn injury, trauma/hemorrhage, and pancreatitis, were recently described by Bone [4]. In the last few years, the importance of balance between proinflammatory and anti-inflammatory cytokines in maintaining homeostasis in critically ill patients has come to the forefront [5]. The relationship between inflammation and activation of the coagulation cascade has also received considerable attention relative to the pathophysiology of sepsis. It is generally accepted that sepsis has the potential to induce increased procoagulant effects, decreased anticoagulation activity, and early increased fibrinolysis in these patients [6]. Central to these alterations are decreases in antithrombin III (ATIII) [7-9] and increases in plasminogen activator inhibitor 1 protein (PAI-1) [3,9,10]. The link between cytokine release and thrombotic disease in the septic patient was recently reviewed by Ten Cate et al. [11].
The importance of understanding the pathogenesis of sepsis and systemic inflammatory response syndrome relates most obviously to the development of treatment strategies designed to attenuate the deleterious effects of systemic inflammation and restore a homeostatic state. Additionally, knowledge of these events could prove to be of significant prognostic value. The vast majority of the research to date pertaining to sepsis, patterns of cytokine release, and development of hemostatic abnormalities has been conducted in critically ill patients. In this issue of Critical Care Medicine, Dr. Martinez and colleagues [12] describe a study investigating the relationship between TNF-alpha and various hemostatic markers and outcome in a cohort of septic patients at an early clinical stage. Specifically, they obtained serial measurements of TNF-alpha, fibrinogen, factor VII, ATIII, PAI-1, plasminogen, alpha 2-antiplasmin, tissue-type plasminogen activator (t-PA) activity, and platelet count in 43 adult emergency department patients who met the American College of Chest Physicians-Society of Critical Care Medicine criteria for sepsis without evidence of organ dysfunction or septic shock upon admission.
Dr. Martinez and colleagues found significantly decreased platelet counts and ATIII concentrations in septic patients compared with healthy volunteers, whereas fibrinogen, PAI-1, t-PA, fibrinopeptide A, and TNF-alpha concentrations were significantly increased. In septic patients who progressed to septic shock, admission values of ATIII were lower and TNF-alpha increased significantly over time compared with patients who did not develop septic shock. The ATIII concentration was the only admission variable that decreased significantly in nonsurvivors. However, when dichotomized to normal and abnormal ATIII activity, the ATIII did not prove superior to the Acute Physiology and Chronic Health Evaluation II score in predicting mortality. The current study [12] is consistent with previous studies [10,13] relative to normalization of ATIII over time correlating with survival. Interestingly, t-PA concentrations remained consistently elevated in both survivors and nonsurvivors. In contrast, previous studies [13] have shown t-PA to decrease over time in septic shock survivors. In addition, no difference was found in PAI-1 concentrations between survivors and nonsurvivors. Increased PAI-1 concentrations have been associated with increased mortality within the first 7 days of septic shock but not in deaths occurring after day 7 [10,14]. In the current study [12], the majority of the deaths occurred after day 7 of the study.
Several explanations can be offered to reconcile differences in the study by Dr. Martinez and colleagues [12] with previous investigations.
