Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe sepsis is a high prevalent disease at Intensive Care Units with no specific treatment till recently. Several clinical trials show low serum levels of activated protein C in this kind of patients. Recently, drotrecogin alfa (activated), a recombinant human activated protein C, has been approved in Spain for severe sepsis treatment in addition to the best patient care. Protein C (activated) has antithrombotic, profibrinolitic an antiinflamatory properties. So far, Prowess (phase 3 trial) is the most important clinical trial conducted with drotrecogin alfa (activated) at the moment. It demonstrates not only its efficacy and safety, but also a 19.4% reduction in the relative risk of death. Nevertheless, it is difficult to decide which patients would be candidate for this new therapy due to its lack of experience, high cost and the risk-benefit relationship. This review attempts to provide an overview about this new hospital drug.
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PMID:[Drotrecogin alfa (activated): specific treatment for serious sepsis]. 1577 3

Severe sepsis may be associated with depression of myocardial function, attributed to various inflammatory mediators. Myocardial dysfunction in sepsis is characterized by biventricular failure and complicates usual therapy with high-volume fluid resuscitation and vasopressors. However, in patients who survive septic shock, myocardial dysfunction can improve rapidly. We describe a young woman with septic shock due to Streptococcus pneumoniae, complicated by severe but reversible biventricular dysfunction.
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PMID:Sepsis and myocardial depression in a young woman. 1594 33

Sepsis, a systemic inflammatory syndrome, is a response to infection and when associated with multiple organ dysfunction is termed severe sepsis. It remains a leading cause of mortality in the critically ill. The response to the invading microorganisms may be considered as a balance between a pro-inflammatory and an anti-inflammatory reaction. While an inadequate pro-inflammatory reaction and a strong anti-inflammatory response could lead to overwhelming infection and the death of the patient, a strong and uncontrolled pro-inflammatory response, manifested by the release of pro-inflammatory mediators may lead to microvascular thrombosis and multiple organ failure. Endotoxin triggers sepsis via the release of various mediators such as tumour necrosis factor-alpha and interleukin-1 (IL-1). These cytokines activate the complement and coagulation systems, release adhesion molecules, prostaglandins, leukotrienes, reactive oxygen species and nitric oxide. Other mediators involved in the sepsis syndrome include IL-1, -6 and -8; arachidonic acid metabolites; platelet activating factor; histamine; bradykinin; angiotensin; complement components and vasoactive intestinal peptide. These pro-inflammatory responses are counteracted by IL-10. Most of the trials targeting the different mediators of the pro-inflammatory response have failed due to a lack of correct definition of sepsis. Understanding the exact pathophysiology of the disease will enable more advanced treatment options. Targeting the coagulation system with various anticoagulant agents including, activated protein C, and tissue factor pathway inhibitor (TFPI) is a rational approach. Many clinical trials have been conducted to evaluate these agents in severe sepsis. While trials on antithrombin and TFPI were not so successful, the double-blind, placebo-controlled, Phase III trial of recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) was successful, creating a significant decrease in mortality when compared to the placebo group. A better understanding of the pathophysiologic mechanism of severe sepsis will provide better treatment options, and combination antithrombotic treatment may provide a multipronged approach for the treatment of severe sepsis.
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PMID:Antithrombotic agents in the treatment of severe sepsis. 1598 40

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.
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PMID:Sepsis and coagulation. 1599 65

Severe sepsis is one of the most significant challenges in critical care. Despite all the developments achieved in infectious diseases and critical care, along with numerous attempts to develop treatments, the mortality rate of severe sepsis and septic shock remains unacceptably high. The pathophysiology of severe sepsis and septic shock is only partially understood. Circulating pro- inflammatory and anti-inflammatory mediators appear to participate in the complex cascade of events which leads to deranged microcirculatory function, as we know from the peak concentration hypothesis. Therapeutic trials targeting single pro-inflammatory and anti-inflammatory mediators failed to demonstrate any benefit, suggesting that the unselective removal of different mediators may be a more appropriate approach. In severe sepsis several blood purification techniques, such as continuous hemofiltration (CVVH), high volume hemofiltration (HVHF), pulse high volume hemofiltration (HVHF), plasma filtration, plasma dsorption, coupled plasma filtration adsorption (CPFA), have been proposed but such techniques appear to have both theorical as well as practical limitations. Plasma Filtration Adsorption Dialysis (PFAD) is a new extracorporeal treatment which combines different principles of blood purification in a single device. The core of this technique is a new dialyzer composed by three suitable compartments that provide specific functions. The association of multiple principles permits specific removal of molecules implicated in the pathophysiology of patient's disease and re-establishment of hydro-electrolyte, acid-base equilibrium, if renal dysfunction-failure is present. The final target of PFAD is to obtain complete purification by combining principles of physics and chemistry to remove hydrophilic and hydrophobic molecules with a very wide range of weights.
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PMID:Plasma filtration adsorption dialysis (PFAD): a new technology for blood purification. 1604 7

Severe sepsis in children or adults may cause a life-threatening coagulopathy, with widespread consumption of activated protein C (APC); recombinant human APC (rhAPC) is a promising candidate anticoagulant treatment. We investigated the effects of rhAPC and other anticoagulants on coagulation triggered by adding small quantities of lipidated tissue factor to human umbilical-cord plasma in vitro. rhAPC, unfractionated heparin (UH), and melagatran (a direct thrombin inhibitor) were studied individually, and in combinations of rhAPC with either UH or melagatran. rhAPC alone dose-dependently prolonged the activated partial-thromboplastin time (aPTT) but not the prothrombin time (PT), and dose-dependently suppressed two indices of thrombin generation, namely prothrombin fragment F 1.2 (F 1.2) generation and thrombin-antithrombin (TAT) complex formation. UH alone dose-dependently prolonged the aPTT but not the PT, while melagatran alone dose-dependently prolonged both the aPTT and the PT. Adding either UH or melagatran dose-dependently augmented the capacity of rhAPC to suppress F 1.2 generation (with addition of UH showing a greater effect) and TAT formation (with addition of melagatran showing a greater effect). Both the capacity of UH to prolong the aPTT and the capacity of melagatran to prolong the aPTT and the PT were augmented by adding rhAPC. In our in-vitro study, adding either UH or melagatran augmented the capacity of rhAPC to suppress thrombin generation in human umbilical-cord plasma, with the anticoagulant effect of melagatran being more predictable than that of UH. Hence, combining rhAPC with melagatran might be a valuable therapeutic option in patients with severe sepsis.
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PMID:Additive effects of anticoagulants: recombinant human activated protein C and heparin or melagatran, in tissue factor-activated umbilical-cord plasma. 1611 86

Severe sepsis with multiple organ dysfunctions is still the leading cause of death in non-cardiac intensive care units. The incidence is expected to rise in the future due to the growing number of older and immuno-compromized patients, the use of invasive procedures, and an increase in the percentage of aggressive or resistant microorganisms. Despite the enormous investment in critical care resources, mortality of severe sepsis remaines on a high level and ranges from 28 - 50 %. Based on the disappointing experiences with anti-inflammatory strategies, we now realize that sepsis is more than just inflammation. The new therapeutic approaches take account of this more sophisticated view of pathophysiologic changes, resulting in the modulation of the coagulation in combination with an improvement of the ICU-management of organ dysfunctions. This review discusses the therapeutic concepts, reported es exciting new interventions in the ICU setting to decrease the inacceptable high mortality in patients with severe sepsis.
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PMID:[Sepsis and multiple organ failure - update of current therapeutic concepts]. 1614 38

It has been hypothesized that the protein C pathway is a pivotal link between the inflammation and coagulation cascades. The demonstration that a survival benefit is associated with administration of drotrecogin alfa (activated) (recombinant human activated protein C [APC]) in severe sepsis patients has provided new insights into the protein C pathway. APC was originally identified based on its antithrombotic properties, which result from the inhibition of activated Factors V and VIII. In the early 1990s, any potential anti-inflammatory properties of APC were thought to relate primarily to its inhibition of thrombin generation. However, the mid-1990s saw the identification of the endothelial protein C receptor (EPCR), which has subsequently been shown to be neither endothelial specific nor protein C specific, but has a primary function as a cofactor for enhancing the generation of APC or behaving as an APC receptor. Thus, the potential biologic activities of APC can be classed into two categories related either to the limiting of thrombin generation or to cellular effects initiated by binding to the EPCR. Intracellular signaling initiated by binding of APC to its receptor appears to be mediated by interaction with an adjacent protease-activated receptor (PAR), or by indirect activation of the sphingosine 1-phosphate pathway. Based mostly on in vitro studies, binding of APC to its receptor on endothelial cells leads to a decrease in thrombin-induced endothelial permeability injury, while such binding on blood cells, epithelial cells, and neurons has been shown to inhibit chemotaxis, be anti-apoptotic, and be neuroprotective, respectively. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study, drotrecogin alfa (activated) was associated with improved cardiovascular function, respiratory function, and a prevention of hematologic dysfunction. This article discusses the way in which the interactions of APC may alter the microcirculation.
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PMID:New insights into the protein C pathway: potential implications for the biological activities of drotrecogin alfa (activated). 1616 74

Severe sepsis leading to shock is the principal cause of death in intensive care units. It is a systemic inflammatory response caused by excessive secretion of pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNFalpha) and reactive oxygen species (ROS), mainly induced by endotoxin (a major component of the Gram-negative bacterial outer membrane). Immune cells use ROS in order to support their functions and need adequate levels of antioxidant defenses to avoid harmful effects of an excessive ROS production. In addition, nitric oxide (NO) is thought to play a key role in the pathogenesis of sepsis and in the development of multiple organ failure. This article discusses the toxic effects of endotoxin, paying particular attention to cardiovascular damage. It continues by analysing the mechanism by which endotoxin is recognized by specific cells of the immune system, and the pathway leading to nuclear factor-kappaB (NF-kappaB) activation and pro-inflammatory gene transcription. In relation to this process, this review focuses on the involvement of reactive oxygen and nitrogen species. Finally, the protective role of antioxidants against homeostatic disturbances such as those caused by endotoxin toxicity, their potential clinical use and the effects on the redox state of the immune cells is discussed.
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PMID:Role of free radicals in sepsis: antioxidant therapy. 1617 50

Severe sepsis is more and more frequent, especially because of an increased rate of immunocompromised patients. Despite the improvement in the overall prognosis of HIV/AIDS patients and the improvement of global ICU care, the prognosis of HIV/ADS patients hospitalized in ICU with severe sepsis remained poor. This situation is partly due to the increased proportion of HIV/AIDS patients with limited access to health care and to a reluctance of ICU physicians in admitting HIV infected patients. However, medical literature suggests that ICU prognosis of immunocompromised (especially cancer) patients should be largely improved by early ICU admission and by an early institution of supportive techniques. This strategy should be used in HIV/AIDS patients with severe sepsis.
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PMID:Open the intensive care unit doors to HIV-infected patients with sepsis. 1628 60


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