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      Practical aspects of treatment with drotrecogin alfa (activated)

      review-article

      1 , , 1

      Critical Care

      BioMed Central

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          Abstract

          In November 2001, drotrecogin alfa (activated) was approved by the US Food and Drug Administration; in August 2002 it was approved by the European Medicines Agency. Since the approval of drotrecogin alfa (activated), however, critical care physicians have been faced with several challenges, namely its costs, selection of patients who are more likely to benefit from it, and the decision regarding when to start drotrecogin alfa (activated) treatment. There are also operational issues such as how to manage the infusion to deliver an effective treatment while minimizing the risk for bleeding, particularly in patients with deranged clotting, at around the time of surgery or during renal replacement therapy. While addressing these issues, this review remains practical but evidence based as much as possible.

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          Most cited references 53

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          Septic shock.

          Septic shock, the most severe complication of sepsis, is a deadly disease. In recent years, exciting advances have been made in the understanding of its pathophysiology and treatment. Pathogens, via their microbial-associated molecular patterns, trigger sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. Proinflammatory mediators that contribute to eradication of invading microorganisms are produced, and anti-inflammatory mediators control this response. The inflammatory response leads to damage to host tissue, and the anti-inflammatory response causes leucocyte reprogramming and changes in immune status. The time-window for interventions is short, and treatment must promptly control the source of infection and restore haemodynamic homoeostasis. Further research is needed to establish which fluids and vasopressors are best. Some patients with septic shock might benefit from drugs such as corticosteroids or activated protein C. Other therapeutic strategies are under investigation, including those that target late proinflammatory mediators, endothelium, or the neuroendocrine system.
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            Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study.

            To examine the incidence of infections and to describe them and their outcome in intensive care unit (ICU) patients. International prospective cohort study in which all patients admitted to the 28 participating units in eight countries between May 1997 and May 1998 were followed until hospital discharge. A total of 14,364 patients were admitted to the ICUs, 6011 of whom stayed less than 24 h and 8353 more than 24 h. Overall 3034 infectious episodes were recorded at ICU admission (crude incidence: 21.1%). In ICU patients hospitalised longer than 24 h there were 1581 infectious episodes (crude incidence: 18.9%) including 713 (45%) in patients already infected at ICU admission. These rates varied between ICUs. Respiratory, digestive, urinary tracts, and primary bloodstream infections represented about 80% of all sites. Hospital-acquired and ICU-acquired infections were documented more frequently microbiologically than community-acquired infections (71% and 86%, respectively vs. 55%). About 28% of infections were associated with sepsis, 24% with severe sepsis and 30% with septic shock, and 18% were not classified. Crude hospital mortality rates ranged from 16.9% in non-infected patients to 53.6% in patients with hospital-acquired infections at the time of ICU admission and acquiring infection during the ICU stay. The crude incidence of ICU infections remains high, although the rate varies between ICUs and patient subsets, illustrating the added burden of nosocomial infections in the use of ICU resources.
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              Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation.

              Disseminated intravascular coagulation (DIC) is a serious condition associated with sepsis. Clinical management of DIC is hampered by lack of clear diagnostic criteria. The International Society on Thrombosis and Haemostasis (ISTH) has proposed a diagnostic scoring algorithm for overt DIC based on routine laboratory tests. The objective was to assess a modified version of the ISTH scoring system and determine the effect of drotrecogin alfa (activated) (DrotAA, recombinant human activated protein C) on patients with DIC. The large database from the PROWESS clinical trial in severe sepsis was retrospectively used to assess a modified ISTH scoring system. Baseline characteristics and treatment effects of DrotAA were evaluated. At baseline, 29% (454/1568) of patients had overt DIC. Overt DIC was a strong predictor of mortality, independent of APACHE II score and age. Placebo-treated patients with overt DIC had higher mortality than patients without (43 vs. 27%). DrotAA-treated patients with overt DIC had a trend towards greater relative risk reduction in mortality than patients without (29 vs. 18%, P = 0.261) but both groups had greater relative risk reduction than placebo-treated patients. Serious bleeding rates during DrotAA infusion in patients with and without overt DIC were slightly increased (P = 0.498), compared with placebo, while clinically overt thrombotic events during the 28-day period were slightly reduced (P = 0.144). Modified ISTH overt DIC scoring may be useful as an independent assessment for identifying severe sepsis patients at high risk of death with a favorable risk/benefit profile for DrotAA treatment. Patients without overt DIC also received significant treatment benefit.
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                Author and article information

                Journal
                Crit Care
                Critical Care
                BioMed Central
                1364-8535
                1466-609X
                2007
                19 December 2007
                : 11
                : Suppl 5
                : S7
                Affiliations
                [1 ]Adult Intensive Care Unit, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK
                Article
                cc6158
                10.1186/cc6158
                2230611
                18269694
                Copyright © 2007 BioMed Central Ltd
                Categories
                Review

                Emergency medicine & Trauma

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