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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 common, frequently fatal, and expensive. Many factors related to the pathogenesis of severe sepsis have made it difficult to effectively design clinical trials for the management of this disease. Hence, multiple trials of compounds for the treatment of severe sepsis have yielded largely negative results, except in small subsets of patients. This review provides a synopsis of the complex nature of sepsis and the problems associated with sepsis trials. Emphasis is placed on the difficulties in evaluating investigational agents in patients with severe sepsis because of the heterogeneity of the disorder, lack of correlation between animal and human models, the complexity of the insult and the host reaction, and the interaction between inflammation and coagulation in severe sepsis. Additionally, positive results from trials of steroids, intensive insulin therapy, and activated protein C (drotrecogin alfa [activated]) will be discussed. Because drotrecogin alfa (activated) is the only Food and Drug Administration-approved therapy for severe sepsis, the Phase 3 Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial results will be discussed in detail to help define a model for further clinical trials on severe sepsis.
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PMID:Clinical trial design and outcomes in patients with severe sepsis. 1475 95

Severe sepsis syndrome has important consequences to healthcare systems as the incidence is increasing, there is significant attributed morbidity and mortality and there is a substantial cost for in-hospital and post-discharge care. Current treatment includes the use of antimicrobials, local source control and aggressive physiological support, usually in an intensive care unit setting. Drotrecogin-alpha (activated) or recombinant human activated protein C (rhAPC) is the only biological agent approved for use in severe sepsis syndrome that has demonstrated efficacy in reducing 28-day all-cause mortality and new data suggests a trend towards longer term survival. However, given the evidence of a variable effect on survival rates in patient subgroups and its acquisition cost, controversy has arisen concerning its appropriate use. This review discusses the epidemiology of sepsis, preclinical and clinical evidence supporting the use of rhAPC use, controversies about the evidence of efficacy in severe sepsis syndrome and cost-effectiveness data.
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PMID:The epidemiology of severe sepsis syndrome and its treatment with recombinant human activated protein C. 1452 88

Sepsis is a complex syndrome that can lead to multiple organ failure and death. Severe sepsis has been associated with mortality rates ranging from 28% to 50% and is the most common cause of death in the noncardiac intensive care unit. Despite advances in both antibiotic therapy and supportive care, the mortality rate due to severe sepsis has remained fundamentally unchanged in the past several decades. With increased understanding of the pathophysiology of sepsis, particularly the intricate interplay between activation of coagulation and inflammation, novel therapeutic agents that may improve clinical outcomes are being researched and developed. The epidemiology, pathophysiology, and treatment of severe sepsis are reviewed. Also discussed are the recently published results from a multicenter, randomized, placebo-controlled phase 3 clinical trial of drotrecogin alfa (activated), a recombinant form of human activated protein C, in patients with severe sepsis. The nursing implications of this new approved therapy are discussed.
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PMID:Role of activated protein C in the pathophysiology of severe sepsis. 1461 57

Despite spectacular advances in life-support technology, the management of patients with severe sepsis continues to be a significant health care challenge because of the associated major morbidity, high mortality, and health economic implications. Severe sepsis with associated multisystem organ dysfunction (MOD) is the leading cause of death in the intensive care unit. Recent understanding of the pathophysiology now demonstrates that the syndrome of severe sepsis after a major physiologic insult is characterized by the activation of multiple overlapping and interacting cascades leading to systemic inflammation, a procoagulant state, and decreased fibrinolysis, which if unchecked leads to the progressive functional deterioration of multiple interdependent organs. This review will highlight the epidemiology, current understanding of the pathophysiology, management, and prevention of the syndrome of severe sepsis with MOD.
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PMID:State-of-the-art therapy for severe sepsis and multisystem organ dysfunction. 1468 22

Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPARalpha and PPARdelta, and TRalpha and TRbeta in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPARgamma coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase Ibeta, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXRalpha, -beta, and -gamma, PPARalpha and -delta, and TRalpha and -beta, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.
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PMID:Altered expression of nuclear hormone receptors and coactivators in mouse heart during the acute-phase response. 1470 65

A 64-year-old man and a 52-year-old woman in shock with multiple organ failure and worsening of sepsis related organ failure assessment SOFA scores in the early days of care were treated with recombinant human activated protein C (rhAPC). In the woman sepsis was associated with reversible heart failure, with decreased ejection fraction, biventricular dilatation, and a sharp increase of troponin I, observations that have been linked to a higher rate of multiorgan failure and higher mortality. The man began to improve after 24 hours and the woman after 48 hours of rhAPC treatment, with both continuing to improve after withdrawal of treatment. Severe sepsis remains a therapeutic challenge. Among the many treatments based on the physiopathology of the disease, so far only rhAPC seems to improve outcome and reduce mortality.
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PMID:[Two cases of severe sepsis successfully treated with activated protein C]. 1473 82

Regarding the definition. Severe sepsis associates an explosive inflammatory reaction and organ failure. It is secondary to bacterial, fungal or viral infection. It can be at the origin of acute circulatory failure (state of septic shock). Response of the organism to infection. The presence of certain components of the membrane of pathogenic agents induces the release of various mediators in cascade, notably cytokines. Toll-like receptors (10 cloned in humans) intervene in the detection of microbes and in the inherent and subsequently adaptive immune response. Immune paralysis. The release of pro-inflammatory mediators characterizes the initial phase of sepsis. Persistence of the latter provokes acquired immunodepression, related to an anti-inflammatory profile, and hence to a delayed decrease in hypersensitivity, an incapacity to cope with the infection and the onset of nosocomial infections. The role of the mediators. During sepsis, the cytokines are predominantly pro-inflammatory (TNF-alpha and notably IL-1beta) whereas others, produced concomitantly or subsequently, are predominantly anti-inflammatory (IL-10 in particular). In fact, the majority of the cytokines have multiple and intrinsic effects, they mediate immune defense but also pathological manifestations. Many other mediators intervene: coagulation or complement systems, contact system, breakdown products of the phospholipid membrane, arachidonic acid metabolites, free radicals and nitrous oxide. Endocrine and metabolic dysregulations. The concept of relative adrenal insufficiency and peripheral syndrome of resistance to glycocorticosteroids have led to hormone replacement therapy during septic shock. Acute insulin resistance has also been described. The role of the endothelium and coagulation. The endothelium plays a key part in the onset of vascular insufficiency during sepsis due to abnormalities in vasomotricity and thrombomodulation. The anticoagulant regulating system is perturbed; there is a decrease in protein C with inactivation of its active form, which has pro-fibrinolytic properties, and a decrease in antithrombin III. Regarding myocardial dysfunction During septic shock there is often severe left ventricular systolic dysfunction, sometimes also involving the right ventricle, largely under-diagnosed despite its severe prognosis, and associated with reduced or even collapsed heart rate.
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PMID:[Physiopathology of severe sepsis]. 1502 17

Consensual and precise definitions. Sepsis is composed of a suspected or documented infection associated with at least 2 SIRS criteria (systemic inflammatory response syndrome). Severe sepsis is sepsis with arterial hypotension and failure of one or several organs following the reduction in tIssue perfusion. Septic shock is a severe sepsis, the hypotension of which is refractory to volemic expansion. From an epidemiological point of view. Over the past two decades, its incidence is on the increase. Mortality varies from 25 to 80% of cases and sepsis remains the first cause of death in intensive care. The elements of diagnosis. The initial clinical signs are those of an infection and the port of entry and microbiological proof must be systematically researched before the appearance of a drop in blood pressure with hemodynamic impact on the various organs and hence their possible failure. The biological abnormalities observed depend on the deficient organ(s); hyperlactatemia is a good marker of visceral hypoperfusion. The sepsis risk factors. Any situation enhancing immunodepression is a risk factor for sepsis. Factors of virulence of the micro-organisms also intervene and, in cases of fungal infection, inherent risk factors. Genetic susceptibility probably intervenes, genetic variability playing either a protective or a deleterious role (the interest of Toll-like receptors).
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PMID:[Diagnosis of sepsis, severe sepsis and septic shock]. 1502 18

Severe sepsis and septic shock are among the most common causes of death in noncoronary intensive care units. The incidence of sepsis has been increasing over the past two decades, and is predicted to continue to rise over the next 20 years. While our understanding of the complex pathophysiologic alterations that occur in severe sepsis and septic shock has increased greatly asa result of recent clinical and preclinical studies, mortality associated with the disorder remains unacceptably high. Despite these new insights, the cornerstone of therapy continues to be early recognition, prompt initiation of effective antibiotic therapy, and source control, and goal-directed hemodynamic, ventilatory,and metabolic support as necessary. To date, attempts to reduce mortality with innovative, predominantly anti-inflammatory therapeutic strategies have been extremely disappointing. Observations of improved outcomes with physiologic doses of corticosteroid replacement therapy and activated protein C (drotrecogin alfa[activated]) have provided new adjuvant therapies for severe sepsis and septic shock in selected patients. This article reviews the components of sepsis management and discusses the available evidence in support of these recommendations. In addition, there is a discussion of some promising new strategies.
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PMID:Optimum treatment of severe sepsis and septic shock: evidence in support of the recommendations. 1513 67

Drotrecogin alfa (activated) [Xigris] (DAA), the recombinant form of human activated protein C, is approved as an adjunctive therapy for patients with severe sepsis (sepsis associated with > or = 1 organ system failure [OSF]). In the international, randomised, double-blind, placebo-controlled PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) study, the absolute reduction in 28-day all-cause mortality with intravenous DAA 24 micro g/kg/h for 96 hours plus conventional care versus conventional care alone was 6.1%. Although lacking statistical power, a prospectively planned subgroup analysis of this study suggested that the absolute reduction in mortality increased in patients with a baseline APACHE (Acute Physiology and Chronic Health Evaluation) II score of > or = 25 or > or = 2 OSFs, with no clear treatment effect in patients with an APACHE II score of < or = 24 or 1 OSF. Three fully published cost-effectiveness/cost-utility models of DAA plus conventional care relative to conventional care alone adopted a national healthcare payer's and/or societal perspective in North America. The base-case (baseline) discounted incremental cost per life-year gained (LYG) with DAA for all patients with severe sepsis was $US15,801-33,300 (year of costing 2000-2002). The results were more favourable for patients with an APACHE II score of > or = 25 ($US10,833-19,723 per LYG), but considerably worse for patients with an APACHE II score of < or = 24 based on a post hoc reanalysis by the US FDA. Among several fully or partly published cost-effectiveness/cost-utility models that adopted a national healthcare payer's perspective in continental Western European countries, the base-case (baseline) undiscounted incremental cost per LYG was broadly similar and more favourable for patients with > or = 2 OSFs (9660-11,300 euros; year of costing/publication 1998/1999, 2000, 2002 or 2003) than for all patients with severe sepsis (13,436-15,071 euros) in those studies that reported both analyses. The DAA acquisition cost accounts for up to 95% of the additional cost of using the drug. In conclusion, DAA is a major advance in the treatment of severe sepsis, based on the significant mortality reduction observed in the PROWESS study. From a hospital/hospital pharmacy perspective, the drug is associated with a high acquisition cost and a small increase in other short-term costs. From a societal or national healthcare payer's perspective, however, its administration to patients who meet the PROWESS study inclusion criteria, especially individuals with more severe disease (e.g APACHE II score of > or =25 and/or > or = 2 OSFs), has a lifetime cost-effectiveness profile that compares well to that of many widely accepted therapies.
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PMID:Drotrecogin alfa (activated): a pharmacoeconomic review of its use in severe sepsis. 1513 83


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