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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sepsis remains a major cause of death in hospitalized patients. Despite a massive research effort over the past 2 decades to identify innovative therapies for sepsis, current treatment strategies consist primarily of antiinfective agents and a variety of supportive measures. Activated protein C, an endogenous protein that inhibits thrombosis and inflammation while promoting fibrinolysis, plays an important role in the pathogenesis of sepsis. Recombinant human activated protein C, drotrecogin alfa (activated), when compared with placebo in a randomized, double-blind study of 1690 patients with severe sepsis (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis [PROWESS] trial), decreased the relative risk of death at 28 days by 19.4% (95% confidence interval 6.6-30.5%, p=0.005), although there was a trend for more serious bleeding (3.5% vs 2.0%, p=0.06) with its use. Drotrecogin alfa is the first antisepsis drug found to have a mortality benefit. It should be administered only to patients with severe sepsis who meet the PROWESS study inclusion criteria and should be avoided when risk factors for bleeding are present. Ongoing research will help determine the cost-effectiveness of drotrecogin alfa, as well as its role in critically ill populations not studied in the PROWESS trial.
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PMID:Recombinant human activated protein C, drotrecogin alfa (activated): a novel therapy for severe sepsis. 1171 12

Effective therapies for sepsis are being devised, after many failures. However, instead of a "one therapy for all" approach, management of sepsis will involve a menu of treatments, depending on the presence of inflammatory markers, the severity of disease, and other factors. This article looks at promising new therapies, including recombinant human activated protein C (rhAPC; drotrecogin alfa, Xigris), recently approved by the US Food and Drug Administration.
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PMID:Sepsis: menu of new approaches replaces one therapy for all. 1181 22

Drotrecogin alfa (activated), recombinant human activated protein C, inhibits coagulation and inflammation and promotes fibrinolysis in patients with severe sepsis. 850 patients with severe sepsis treated with intravenous drotrecogin alfa (activated) 24 microg/kg/h for 96 hours had a significantly greater reduction in 28-day all-cause mortality (24.7%) than 840 placebo recipients (30.8%) in a randomised, double-blind, placebo-controlled study. The drug was associated with a 19.4% reduction in the relative risk of death at 28 days compared with placebo. Baseline characteristics of and pre-existing conditions in patients with sepsis appeared to have no effect on the efficacy of drotrecogin alfa (activated). A significantly greater reduction in median percentage change from baseline plasma D-dimer levels (a coagulation marker) was seen with drotrecogin alfa (activated) treatment than with placebo on study days 1 to 7 in patients with severe sepsis. On study days 1, 4, 5, 6 and 7, a significantly greater median reduction in interleukin-6 levels (an inflammation marker) from baseline was seen with drotrecogin alfa (activated) treatment than placebo. Drotrecogin alfa (activated) was associated with an increased incidence of serious bleeding events during the infusion period [2.4% vs 1.0% with placebo; p = 0.024] and the 28-day study period (3.5 vs 2.0%; p = 0.06) of the efficacy trial. This increase was primarily related to procedure-related events; there were no significant differences between the treatment groups in nonprocedure-related serious bleeding events. The most frequent site of bleeding was the gastrointestinal tract. With the exception of bleeding events, there were no clinically significant differences between treatment groups in the efficacy trial in the incidence of adverse events. Of the 210 deaths in patients with severe sepsis treated with drotrecogin alfa (activated) 24 microg/kg/h in the efficacy trial, four deaths due to haemorrhage and one due to cerebral oedema were possibly related to the study drug.
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PMID:Drotrecogin alfa (activated). 1189 30

Severe sepsis is a common and frequently fatal condition. Evidence showing a link between the coagulation system and the inflammatory response to sepsis led to the development of drotrecogin alfa (activated) as an agent in the treatment of sepsis. This recombinant form of the natural protein, activated protein C (Xigris, Eli Lilly Co.), has been shown to significantly reduce mortality in a large randomised, controlled Phase III study involving 1690 patients. The exact mode of action of drotrecogin alfa (activated) remains uncertain, although it clearly combines anticoagulant and anti-inflammatory properties. Although associated with an increased risk of bleeding, this is usually procedure-related rather than spontaneous. Although costly, this is a drug that effectively reduces mortality rates in patients with severe sepsis.
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PMID:Drotrecogin alfa: a new approach in the treatment of severe sepsis. 1217 9

An impaired function of the protein C pathway plays a central role in the pathogenesis of sepsis. Administration of human recombinant activated protein C (Xigris) may restore the dysfunctional anticoagulant mechanism and prevent amplification and propagation of thrombin generation and formation of microvascular thrombosis but may simultaneously modulate the systemic pro-inflammatory response. Experimental studies indicated that the administration of activated protein C could block the derangement of coagulation, inhibit inflammatory effects and preserve organ function. Randomised controlled clinical studies in patients with severe sepsis confirmed these beneficial effects and demonstrated that administration of recombinant human activated protein C resulted in a reduction of mortality in patients with severe sepsis.
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PMID:Recombinant human activated protein C (Xigris). 1229 18

The protein C pathway, which plays an important role in maintaining normal hemostasis and is a critical link between the inflammatory and procoagulant host responses to infection, is involved in modulating the coagulation and inflammation associated with severe sepsis. Recombinant human activated protein C (APC), or drotrecogin alfa (activated), shares the intrinsic pharmacologic activity of endogenous APC. In the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, drotrecogin alfa (activated) decreased absolute mortality by 6% and relative risk of mortality by 19% compared with placebo. Drotrecogin alfa (activated) is an important advancement in the treatment of adult patients with severe sepsis.
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PMID:Pharmacology, clinical efficacy, and safety of drotrecogin alfa (activated). 1249 25

Drotrecogin alfa (activated) pharmacokinetics have been reported in healthy volunteers and in patients with severe sepsis. Clearance is rapid and appears to increase with weight; consequently, drotrecogin alfa (activated) is dosed on a weight basis. Drotrecogin alfa (activated) promotes fibrinolysis and inhibits thrombin production to produce an anticoagulant effect. The primary adverse events are related to its pharmacologic activity, with serious bleeding reported in 3.5% of patients receiving the drug in a multicenter phase III trial compared with 2.0% for patients receiving placebo. Monitoring parameters correspond with bleeding and should include international normalized ratio, platelet count, hematocrit, and overt signs of bleeding. Because of the protein nature of drotrecogin alfa (activated), pharmacists should be aware of the proper preparation and stability issues in order to afford efficient, cost-effective administration. As further data on drotrecogin alfa (activated) therapy become available, dosing and monitoring strategies may be altered to optimize the clinical benefits.
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PMID:Pharmacokinetics and clinical use of drotrecogin alfa (activated) in patients with severe sepsis. 1249 26

Drotrecogin alfa (activated) is a new agent that may substantially affect the treatment of patients with severe sepsis. Despite its therapeutic promise, treatment with drotrecogin alfa (activated) represents a new challenge for many clinicians and health care centers. Specifically, optimizing the appropriate role for drotrecogin alfa (activated) requires balancing numerous issues, including its efficacy in high-risk patients with its potential for indiscriminate administration. One common approach to minimizing indiscriminate administration of drotrecogin alfa (activated) and maximizing its efficacy while minimizing its toxicity is for hospitals to develop therapeutic guidelines that define how the agent should be used. We outline factors that should be considered when developing drotrecogin alfa (activated) therapy guidelines and address realistic questions that routinely arise in clinical practice regarding the implementation of such guidelines and the administration of this product. In general, the guidelines must facilitate optimization of drug therapy and not be viewed as hurdles to drug therapy Developing clear guidelines that are based on evidence, outlining a specific process to facilitate optimal therapy, and educating all parties involved are paramount to ensuring that the benefits of therapy are maximized.
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PMID:Strategies to optimize drotrecogin alfa (activated) use: guidelines and therapeutic controversies. 1249 29

Selecting patients for drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN) therapy outside of a clinical trial setting requires knowledge of the rationale that led the Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) investigators to select the various entry criteria for the trial. Enrollment criteria for the study included a known or suspected infection, presence of at least 3 systemic inflammatory response syndrome (SIRS) criteria, and dysfunction of > or =1 organ or system. The infection criteria used in PROWESS were designed to be straightforward and were based on common clinical and radiological data. Although previous definitions of sepsis required only 2 SIRS criteria, the PROWESS trial investigators required the presence of > or =3 SIRS criteria to improve the sensitivity and specificity of these criteria for the diagnosis of sepsis. Acute organ dysfunction, the diagnostic criterion for severe sepsis, was used to define the study population because it identifies patients at significant risk of death. Characteristics of drotrecogin alfa (activated)-treated patients, including infection, modified SIRS criteria, and organ dysfunction, were similar to those of the placebo group and the general sepsis population. Proper clinical judgment and use of the these inclusion criteria as a guide will help clinicians select and treat sepsis patients with drotrecogin alfa (activated).
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PMID:Selecting patients with severe sepsis for drotrecogin alfa (activated) therapy. 1252 13

Historically, clinical trials evaluating treatment of patients with severe sepsis have failed to show a reduction of mortality. However, retrospective analyses of some of these trials showed benefits in certain patient subgroups. Conversely, the recent Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial, which evaluated the safety and efficacy of drotrecogin alfa (activated) (Xigris; Eli Lilly and Company, Indianapolis, IN), a recombinant form of human activated protein C, in adult patients with severe sepsis, is notable in that it is the first trial to show a reduction in 28-day all-cause mortality in the intent-to-treat population compared with the placebo group. When assessing a new intervention, patient exclusion criteria are important considerations in evaluating the evidence from a controlled clinical trial. Appropriate patient selection will be a key factor in the use of this newly approved therapeutic agent to treat severe sepsis. A review of the exclusion criteria used in the PROWESS trial should provide clinicians with a way of differentiating those patients in the critical care setting who will benefit most from treatment with drotrecogin alfa (activated) from those who should not be treated.
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PMID:Identifying patients with severe sepsis who should not be treated with drotrecogin alfa (activated). 1252 14


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