Clinical trials in severe sepsis with drotrecogin alfa (activated)

Drotecogin alfa (activated; DrotAA) was approved in 2001 by the US Food and Drug Administration for the treatment of patients with severe sepsis who are at high risk for death. The European Agency for the Evaluation of Medical Products also recommended that DrotAA could be administered to patients with severe sepsis and multiple organ dysfunction when added to the best standard care. Following the initial publication of the PROWESS (Protein C Worldwide Evaluation in Severe Sepsis) findings, multiple subgroup analyses supported the need for additional studies to explore the various hypotheses raised by this study. This review discusses all large clinical trials exploring the efficacy and safety of DrotAA and proposes recommendations for the use of DrotAA in severe sepsis

Clinical review: Drotrecogin alfa (activated) as adjunctive therapy for severe sepsis – practical aspects at the bedside and patient identification

Administration of drotrecogin alfa (activated) has been demonstrated to reduce mortality in patients with severe sepsis who are at high risk for death or who have multiple organ dysfunction. This benefit was associated with an increased incidence of bleeding events, but the latter were mainly procedure related. Drug infusion interruptions should be instituted, in accordance with recent recommendations. Monitoring coagulation parameters may help in identifying patients at higher risk for bleeding but it is not indicated to adjust drug dosage. Acute renal failure and hemodialysis are not contraindications to this therapy, and no drug dosage adjustment is indicated. Finally, the type and source of infection, and its anticipated natural history, may determine whether drotrecogin alfa (activated) is indicated as well as the timing of its administration

Toll-like Receptor 4 Modulation as a Strategy to Treat Sepsis

Despite a decrease in mortality over the last decade, sepsis remains the tenth leading causes of death in western countries and one of the most common cause of death in intensive care units. The recent discovery of Toll-like receptors and their downstream signalling pathways allowed us to better understand the pathophysiology of sepsis-related disorders. Particular attention has been paid to Toll-like receptor 4, the receptor for Gram-negative bacteria outer membrane lipopolysaccharide or endotoxin. Since most of the clinical trial targeting single inflammatory cytokine in the treatment of sepsis failed, therapeutic targeting of Toll-like receptor 4, because of its central role, looks promising. The purpose of this paper is to focus on the recent data of various drugs targeting TLR4 expression and pathway and their potential role as adjunctive therapy in severe sepsis and septic shock

L’objet et l’acteur au corps à corps : une enveloppe corporelle commune dans la pratique d’Ilka Schönbein

Le présent article se donne pour objet d’interroger le rapport entre l'objet et le corps du manipulateur au sein des spectacles d'Ilka Schönbein. Celle-ci qualifie sa technique de « masque de corps » : masques ou prothèses portant l’empreinte de son visage, de ses membres, de son torse, la plupart réalisés par moulage. Le corps d’Ilka Schönbein dessine alors l’espace de jeu de la marionnette, il constitue l’espace « vivant » de la marionnette. La main n’est plus seulement le nœud entre le corps et la marionnette. Le corps se fait corps-castelet chez Ilka Schönbein. Dans sa pratique, l’objet marionnettique est à la fois une marionnette dotée d’une identité propre et une déformation du corps de la manipulatrice. Dans ce corps à corps, entre la marionnette et la marionnettiste, l’acteur constitue avec l’objet un seul organisme : il s’agissait de mettre au jour le corps produit par cette union. La métamorphose suppose que tout est mouvant. À l’aide de l’objet-prothèse, Ilka Schönbein crée une dynamique du corps : un corps en perpétuelle autoconstruction et autodestruction interne. Le corps réel ici ne change pas, l’imaginaire seul le réinvente. Le corps produit par Ilka Schönbein est celui d’un être qui s’oppose à une définition monolithique de son identité, qui accepte les multiplicités dont il est composé : on passe ainsi du corps objectif à un corps habité

Influence of enrollment sequence effect on observed outcomes in the ADDRESS and PROWESS studies of drotrecogin alfa (activated) in patients with severe sepsis

INTRODUCTION: We performed a study to determine whether an enrollment sequence effect noted in the PROWESS (recombinant human activated Protein C Worldwide Evaluation in Severe Sepsis) trial exists in the ADDRESS (Administration of Drotrecogin Alfa [Activated] [DrotAA] in Early Stage Severe Sepsis) trial. METHODS: We evaluated prospectively defined subgroups from two large phase 3 clinical trials: ADDRESS, which included 516 sites in 34 countries, and PROWESS, which included 164 sites in 11 countries. ADDRESS consisted of patients with severe sepsis at low risk of death not indicated for treatment with DrotAA. PROWESS consisted of patients with severe sepsis with one or more organ dysfunctions. DrotAA (24 microg/kg per hour) or placebo was infused for 96 hours. RESULTS: In ADDRESS and PROWESS, there was a statistically significant interaction between the DrotAA treatment effect and the sequence in which patients were enrolled. In both trials, higher mortality was associated with DrotAA use in the subgroup of patients enrolled first at study sites. Compared with placebo, PROWESS mortality was lower with DrotAA treatment for the second and subsequent patients enrolled, whereas in ADDRESS, mortality remained higher for the second patient enrolled but thereafter was lower for DrotAA-treated patients. Comparison of patients enrolled first with subsequent patients enrolled indicated that the characteristics of patients changed. Subsequently enrolled patients were treated earlier, were less likely to suffer nonserious bleeds (ADDRESS), and experienced fewer protocol violations (PROWESS). CONCLUSIONS: Analyses suggest that an enrollment sequence effect was present in the ADDRESS and PROWESS trials. Analysis of this effect on outcomes suggests that it is most apparent in patients at lower risk of death. In PROWESS, this effect appeared to be associated with a reduction of the DrotAA treatment effect for the first patients enrolled at each site. In ADDRESS, this effect may have contributed to early termination of the study. The finding of an enrollment sequence effect in two separate trials suggests that trial designs, site selection and training, data collection and monitoring, and statistical analysis plans may need to be adjusted for these potentially confounding events. TRIAL REGISTRATION: ADDRESS trial registration number: NCT00568737. PROWESS was completed before trial registration was required