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)

The primary goal of the intensive care clinician can be said to be to optimize global DO2. This approach is the primary means by which the greatest killers of the critically ill patient (sepsis, SIRS, multiple organ dysfunction syndrome) may be addressed at present. Optimizing DO2 means delivering just enough to meet the patient's needs, because therapeutic measures taken to increase DO2 are all associated with some degree of risk. When used correctly, the PAC can allow the clinician to determine if DO2 is optimal and, if not, what steps might be best suited to improve on it. Newer generations of PACs are becoming available and can provide valuable additional insights into a patient's cardiovascular status. Nearly all attempts to increase DO2 address one or more of a relatively short list of variables. The specific endpoints of therapy need to be tailored to the individual patient but include clinical, metabolic, organ function, and hemodynamic markers. As clinicians expand our understanding of the key elements found in survivors of critical illness, it is hoped that this knowledge translates into better outcomes.
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PMID:Cardiac output, wedge pressure, and oxygen delivery. 1172 33

The dendritic cell (DC) is the most potent APC of the immune system, capable of stimulating naive T cells to proliferate and differentiate into effector T cells. Recombinant adenovirus (Adv) readily transduces DCs in vitro allowing directed delivery of transgenes that modify DC function and immune responses. In this study we demonstrate that footpad injection of a recombinant Adv readily targets transduction of myeloid and lymphoid DCs in the draining popliteal lymph node, but not in other lymphoid organs. Popliteal DCs transduced with an empty recombinant Adv undergo maturation, as determined by high MHC class II and CD86 expression. However, transduction with vectors expressing human IL-10 limit DC maturation and associated T cell activation in the draining lymph node. The extent of IL-10 expression is dose dependent; transduction with low particle numbers (10(5)) yields only local expression, while transduction with higher particle numbers (10(7) and 10(10)) leads additionally to IL-10 appearance in the circulation. Furthermore, local DC expression of human IL-10 following in vivo transduction with low particle numbers (10(5)) significantly improves survival following cecal ligation and puncture, suggesting that compartmental modulation of DC function profoundly alters the sepsis-induced immune response.
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PMID:Increased survival in sepsis by in vivo adenovirus-induced expression of IL-10 in dendritic cells. 1190 99

Following an interpretative philosophy, dyna-mic and faithful to the complexity theory, a clinical pathway is outlined close to the reality, at the patient bedside, that is comprehensive of the diagnostic process in its temporal dynamism, of the therapeutic process in its specificity (antibiotic therapy, surgical souce control), in the use of organs supportive therapy (haemodynamic, respiratory, renal, etc.) and in the use of adjunctive and immunomodulatory therapies (APC, AT, etc.). The importance of the contextual activation of microbiological, immunological and coagulative monitorings is underlined. Through a critical review of the more recent literature, a strict relationship, in sepsis and septic shock, between inflammation and coagulation is described, that allowed the activated protein C (drotrecogin alpha activated) success, in terms of reduction of the absolute and relative mortality. This therapeutic success is contextualized into two other important therapeutic successes, recently obtained in severe sepsis and septic shock, based on the medical evidence, one using low doses of corticosteroids and the other using the early (6 h) goal directed haemodynamic therapy to restore a balance between oxygen delivery and oxygen demand. Once systemic inflammation is complicated by organ failure, there are few options. Treatment with activated protein C lowers the risk of death but is associated with an increased risk of bleeding and is likely to be expensive. The strategies described by the groups of Rivers and Annane offer the opportunity for good therapeutic results, by preventing the progression or even the development of sepsis and its complications: septic shock and multiple organ dysfunction.
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PMID:Critical points for sepsis management at the patient bedside. 1267 62

Inflammatory and procoagulant host responses are closely related in sepsis. The protein C pathway serves as a regulatory pathway with anti-inflammatory and anticoagulant properties. Recently, recombinant human activated protein C (rhAPC) was shown to reduce mortality in severe sepsis. Nevertheless, the effects of rhAPC in humans are still ill defined. The infusion of low endotoxin doses into humans provides a standardized model to study inflammatory and hemostatic mechanisms. Thus, we investigated whether rhAPC acts as an anticoagulant or anti-inflammatory drug in human endotoxemia. There were 24 volunteers randomized to receive either 24 microg/kg per hour rhAPC or placebo intravenously for 8 hours. Lipopolysaccharide (LPS, 2 ng/kg) was administered 2 hours after starting the infusions. rhAPC decreased basal tissue factor (TF)-mRNA expression, and thrombin formation and action. In contrast, rhAPC did not significantly blunt LPS-induced thrombin generation. Consistently, rhAPC did not reduce LPS-induced levels of TF-mRNA or D-dimer and had no effect on fibrinolytic activity or inflammation. Finally, endogenous APC formation was enhanced during endotoxemia and appeared to be associated with inflammation rather than thrombin formation. In conclusion, even low-grade endotoxemia induces significant protein C activation. Infusion of rhAPC decreases "spontaneous" activation of coagulation but does not blunt LPS-induced, TF-mediated coagulation in healthy volunteers, which is in contrast to a number of anticoagulants.
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PMID:Recombinant human activated protein C (rhAPC; drotrecogin alfa [activated]) has minimal effect on markers of coagulation, fibrinolysis, and inflammation in acute human endotoxemia. 1275 Jan 66

Dendritic cells are a phenotypically diverse group of APC that have unique capabilities to regulate the activity and survival of B and T cells. Although proper function of dendritic cells is essential to host control of invading pathogens, few studies have examined the impact of sepsis on dendritic cells. The purpose of this study was to determine the effect of sepsis on splenic interdigitating dendritic cells (IDCs) and follicular dendritic cells (FDCs) using a clinically relevant animal model. Immunohistochemical staining for FDCs showed that sepsis induced an initial marked expansion in FDCs that peaked at 36 h after onset. The FDCs expanded to fill the entire lymphoid zone otherwise occupied by B cells. Between 36 and 48 h after sepsis, there was a profound caspase 3 mediated apoptosis induced depletion of FDCs such that only a small contingent of cells remained. In contrast to the initial increase in FDCs, IDC numbers were decreased to approximately 50% of control by 12 h after onset of sepsis. IDC death occurred by caspase 3-mediated apoptosis. Such profound apoptosis induced loss of FDCs and IDCs may significantly compromise B and T cell function and impair the ability of the host to survive sepsis.
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PMID:Sepsis induces apoptosis and profound depletion of splenic interdigitating and follicular dendritic cells. 1284 61

Sepsis is an infection-induced inflammatory syndrome that results in a complex network of adaptive and maladaptive alterations in homeostatic mechanisms. Severe sepsis, defined as sepsis associated with acute organ failure, is a serious disease with a mortality rate of 30-50%. The coagulation system, through complex interactions, has an important role in the final outcome of the sepsis-induced inflammatory cascade. A fine and delicate balance that normally exists between anticoagulant mechanisms and the procoagulant response is altered in sepsis. Activated protein C, an endogenous vitamin K-dependent anticoagulant, plays a major role in the down-regulation of the procoagulant arm. It also possesses anti-inflammatory properties. Endothelial damage during sepsis impairs the endothelium-dependent activation of protein C, thus shifting the balance towards thrombosis. This shift may contribute to the development of sepsis-related multi-organ failure. Evidence suggesting that activation of the coagulation system may contribute to sepsis-related morbidity and mortality has led to extensive research attempting to correct the hemostatic defects seen in septic patients. Indeed, a recent randomized controlled trial demonstrated a reduction in overall mortality in patients with severe sepsis treated with APC. In this review we discuss the pathogenesis of the coagulopathy of sepsis, as well as the new therapeutic approaches aimed at correcting the defects in the coagulation system.
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PMID:The coagulopathy of sepsis: pathophysiology and management. 1290 Dec 50

The present study was performed to compare the anti-coagulant efficiency of recombinant human activated protein C (rhAPC) in cord with that in adult plasma. RhAPC is a promising candidate to improve the outcome of severe sepsis. However, different anticoagulant efficiency of rhAPC in cord compared with adult plasma has to be expected due to physiological low plasma levels of tissue factor pathway inhibitor (TFPI) and antithrombin (AT) present in neonates, two inhibitors known to markedly influence the anticoagulant action of APC. Clot formation was induced in our experiments by addition of high (30 micro M) or low (20 pM) amounts of lipidated tissue factor (TF). High amounts of TF are conventionally applied in standard clotting assays, whereas plasma activation with low amounts of TF probably better matches the conditions in vivo. We demonstrate that under low coagulant challenge increasing amounts of rhAPC (0.1-0.5 micro g/ml final plasma concentration) dose-dependently prolonged clotting time and suppressed thrombin potential and prothrombin fragment 1+2 generation in both cord and adult plasma. The same was true for experiments performed under high coagulant challenge when 4-16 micro g/ml of rhAPC were added. Whereby, cord plasma was significantly more susceptible to addition of rhAPC in the presence of high amounts of TF and adult plasma was significantly more susceptible to addition of rhAPC in the presence of low amounts of TF. We demonstrate that increased anticoagulant efficiency of rhAPC in adult plasma under low coagulant challenge is attributable to the physiological high levels of TFPI and AT present in adults.
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PMID:The anticoagulant action of recombinant human activated protein C (rhAPC, Drotrecogin alpha activated): comparison between cord and adult plasma. 1511 51

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

The protein C pathway serves as a modulating system with both anti-inflammatory and anticoagulant properties and is intimately involved in the pathophysiology of inflammation and sepsis. Treatment with recombinant human activated protein C (rhAPC) can reduce the mortality of severe sepsis. We investigated whether an elevation of plasma protein C levels to supra-normal levels by infusion of a protein C zymogen concentrate has an effect on coagulation, protein C activation or inflammation in a human endotoxemia model. Eleven healthy male volunteers were enrolled in a double-blind, placebo-controlled two-way cross-over trial. Ten minutes after infusion of 2ng/kg endotoxin each volunteer received either placebo or a plasma-derived protein C zymogen concentrate (Ceprotin, Baxter) (150 U/kg as a slow bolus infusion followed by 30 U/kg/h continuous infusion until 4 hours after LPS-infusion). Protein C antigen and activity increased 4- to 5-fold after infusion of the concentrate. APC was generated during endotoxin-induced inflammation in the placebo (1.6 fold increase) and the protein C period (4.0-fold increase). The increase of APC levels correlated with the TNF-alpha and IL-6 release in both periods (r = 0.65-0.68; p < 0.05) and paralleled the protein C antigen and activity levels in the period with supranormal protein C levels. Supra normal protein C levels resulted in slightly, although non-significant, lower tissue factor mRNA expression and thrombin generation (TAT, F1+2). Systemic inflammation (TNF-alpha, IL-6) was not influenced by protein C zymogen concentrate administration. Infusion of protein C zymogen was safe and no adverse effects occurred. The increase of protein C levels several fold above the normal range resulted in a proportional increase of the APC levels, but had no major anticoagulant, anti-inflammatory or profibrinolytic effects. Low grade endotoxemia itself induces significant protein C activation, which correlates with the TNF release.
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PMID:The effects of supra-normal protein C levels on markers of coagulation, fibrinolysis and inflammation in a human model of endotoxemia. 1673 92

A 64-year-old male with an APC resistance (factor V mutation Leiden) and interrupted oral anticoagulation due to an erosive gastritis, was admitted to hospital for increasing dyspnoea. Transthoracic echocardiography revealed a floating thrombus via an open foramen ovale in both atria reaching both ventricles. Sonography showed multiple stage thrombosis of the left leg reaching to the V. femoralis superficialis. A few months previously, peripheral pulmonary artery embolization has been confirmed by scintigraphy. The patient was transferred to our hospital and underwent emergency surgery for closure of the atrial septum defect and thrombus removal. On the 4th postoperative day, the patient was transferred to the normal ward, however, on the 10th postoperative day, the patient developed a symptomatic transitory psychotic syndrome and became hypotensive before he was transferred to the ICU. Due to impaired oxygenation and the patient's history, a new pulmonary artery embolization was suspected. After ICU admission, the patient required increasing norepinephrine support and rapidly developed septic fever. However, serum procalcitonin was elevated and a computed tomography (skull, chest and abdomen) was performed for a focus search. Pulmonary artery embolism could be ruled out but an oval structure near to the ampulla recti (ca. 30 x 20 mm) was identified as an abscess and immediate abscess incision was performed. After surgery, the further course was characterized by a steep fall in vasopressor support and body temperature. The patient was transferred to the normal ward on the 2nd postoperative day. This case shows that procalcitonin allows early and reliable diagnosis of sepsis in patients with undefined shock.
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PMID:[Procalcitonin as an early marker of sepsis]. 1656 89


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