Sepsis and immune response

BACKGROUND: Sepsis and secondary multiple organ failure in critically ill patients are the major cause of death, but the pathogenesis of sepsis is not clear, especially the dysfunction of the immune system. In this paper, we review the response and regulation of the immune system and the functions of a variety of inflammatory mediators in sepsis.DATA SOURCES: Studies were identified by searching MEDLINE and PubMed for articles using the keywords "sepsis", "immune response", and "inflammatory mediator" up to October 2010. Additional papers were identified by a manual search of the references from the key articles.RESULTS: This systematic review was conducted of: 1) the immune response; 2) immune regulation; 3) inflammatory mediators; 4) high-mobility group box 1 protein; 5) the complement system; and 6) the autonomic nervous system. There are no therapeutic approaches available for sepsis that target inflammatory response; the mortality of sepsis has not been significantly reduced.CONCLUSIONS: Sepsis is complex and dynamic, and it has a group of heterogeneous syndromes. Since different patients with sepsis have different etiology, susceptibility, and responses, treatment should be prescribed individually.     

Sepsis mortality prediction based on predisposition,infection and response

Objective To empirically test, based on a large multicenter, multinational database, whether a modified PIRO (predisposition, insult, response, and organ dysfunction) concept could be applied to predict mortality in patients with infection and sepsis. Design Substudy of a multicenter multinational cohort study (SAPS 3). Patients A total of 2,628 patients with signs of infection or sepsis who stayed in the ICU for > 48 h. Three boxes of variables were defined, according to the PIRO concept. Box 1 (Predisposition) contained information about the patient's condition before ICU admission. Box 2 (Injury) contained information about the infection at ICU admission. Box 3 (Response) was defined as the response to the infection, expressed as a Sequential Organ Failure Assessment score after 48 h. Interventions None. Main measurements and results Most of the infections were community acquired (59.6%); 32.5% were hospital acquired. The median age of the patients was 65 (50–75) years, and 41.1% were female. About 22% (n = 576) of the patients presented with infection only, 36.3% (n = 953) with signs of sepsis, 23.6% (n = 619) with severe sepsis, and 18.3% (n = 480) with septic shock. Hospital mortality was 40.6% overall, greater in those with septic shock (52.5%) than in those with infection (34.7%). Several factors related to predisposition, infection and response were associated with hospital mortality. Conclusion The proposed three-level system, by using objectively defined criteria for risk of mortality in sepsis, could be used by physicians to stratify patients at ICU admission or shortly thereafter, contributing to a better selection of management according to the risk of death. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Sepsis and the kidney

Acute renal failure (ARF) secondary to sepsis is a highly prevalent diagnosis in the ICU setting and continues to be associated with a high rate of morbidity and mortality. The pathophysiology of sepsis-induced acute renal failure involves ischemic or toxic injury to the renal tubular epithelia, resulting in necrosis or apoptosis, and clinically is characterized as acute tubular necrosis. The management of sepsis-induced ARF includes both conventional intermittent hemodialysis and continuous renal replacement therapies. Experimental therapies to improve outcomes in sepsis-associated ARF include the provision of plasmapheresis and adsorption therapies, and the recent development and deployment of a renal tubule assist device.     

Sepsis and the dendritic cell

Sepsis is a syndrome of significant morbidity and mortality. Unlike the advances made in other diseases processes, improvements in outcome from sepsis, severe sepsis, and septic shock have been modest. Current research has altered our understanding of sepsis pathogenesis such that present models and definitions are still evolving. One relatively novel cell type, the dendritic cell, is the subject of much current investigation in sepsis. Although our present understanding of dendritic cell biology is incomplete, growing evidence supports the importance of this antigen-presenting cell in the normal and maladaptive responses to microbial invasion and tissue injury. A better understanding of this cell's basic biology as well as its potential as a therapeutic target will undoubtedly play increasing roles in the development of new strategies for the treatment of the septic patient.     

Sepsis and the broken endothelium

The study by Yang and colleagues examined 81 patients with septic shock due to pneumonia, along with 20 patients with pneumonia without organ dysfunction. Their major findings were that circulating levels of soluble vascular endothelial cell growth factor receptor-1 (sVEGFR-1) and urokinase-type plasminogen activator (uPA) were associated with organ dysfunction and mortality, whereas vascular endothelial cell growth factor (VEGF) levels had no such predictive power. Yang and colleagues are to be complimented for a well-conducted study of a reasonably (and helpfully!) homogeneous population of patients with sepsis that carefully and comprehensively analyzed the relationship between sVEGFR-1, uPA, VEGF and clinical outcome. The study serves not only to provide evidence in support of new diagnostic biomarker targets in sepsis, but also to augment the growing evidence of an important role of the endothelium in sepsis in general, and the VEGF signaling axis in particular.     

Sepsis and the trauma patient

Conventional therapy for septic shock concentrates on correcting circulatory perfusion defects by optimizing hemodynamic parameters and oxygen delivery to the periphery. In the face of ongoing sepsis, the central abnormality of nutrient acquisition and energy production at the cellular level remains and the patient often progresses to MSOF despite our best efforts. Currently, surgical drainage and antibiotic therapy are the mainstays for eradication of infection. In the future, as we understand more of the mediators and metabolic consequences of septic shock, we anticipate that a more specific, directed therapy will be developed to reduce the high mortality rate.     

Sepsis

OBJECTIVES: To review infection and sepsis in patients with cancer and to provide an overview of controversies and research-based practices of infectious complications and management strategies. DATA SOURCES: Research studies, review articles, web sites, and consensus documents. CONCLUSIONS: Traditional assumptions about infection and its optimal management are redefined by research regarding transfusion and catheter-related infections, prophylactic antibiotic administration, use of growth factors, and antimicrobial therapy regimens. IMPLICATIONS FOR NURSING PRACTICE: Infection is still the most common source of morbidity and mortality among cancer patients. The importance of recognizing high-risk patients, implementing infection prevention practices, and prompt intervention for infection symptoms has been established.     

Sepsis and coagulation

The host response to infection is a highly complex yet well-orchestrated process that involves an elaborate array of soluble mediators and cells. Normally, the host response prevails in containing and eliminating the pathogenic threat. When excessive or sustained, however, the host response may "turn on its bearer" and lead to organ dysfunction. Severe sepsis is invariably associated with activation of primary and secondary hemostasis. This article describes sepsis-associated changes in coagulation, discusses the putative role for these changes in pathogenesis of the sepsis syndrome, and outlines current diagnostic and therapeutic strategies.     

Sepsis and coagulation

PURPOSE OF REVIEW: There is considerable evidence that dysregulation of the coagulation and fibrinolytic systems plays a major role in the pathophysiology of severe sepsis, with a special focus on the protein C system. Conversely, there is an approval for use of recombinant human activated protein C in the more severe patients. This review highlights recent findings about the biology of the protein C system and of other important coagulation components such as tissue factor, platelets, and protein S, with an effort to link fundamental data and recent clinical findings. RECENT FINDINGS: There is a better comprehension of the biology of the thrombomodulin-protein C-endothelial protein C receptor complex, and mainly of its cellular effects via the protease activated receptor 1 receptor and of its implication in the generation of anticoagulant microparticles. The implications of other important agents such as platelets and von Willebrand factor, tissue factor, and protein S are also becoming increasingly evident, both from experimental and clinical studies. From a clinical point of view, the more immediately promising approach could be the ability to identify the fraction of severe sepsis patients exhibiting an impaired ability to activate protein C, raising the possibility to select the better candidates for activated protein C infusion. SUMMARY: The comprehension of the protein C pathway is undoubtedly progressing both in experimental and clinical settings. In parallel, some promising other coagulant pathways are also under investigation in the sepsis context, with a hope for major clinical implications in the future.