An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): Protocol for a randomized controlled trial

Background

Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients.

This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg^-1.min^-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients will be recruited from approximately 25 ICUs in the United Kingdom.

This trial will test the efficacy of levosimendan to reduce acute organ dysfunction in adult patients who have septic shock and evaluate its biological mechanisms of action.

Forgoing primacy: Damaging democratic policing in the West Bank

Since the Oslo Accords were signed between Israel and the Palestinian Liberation Organization (PLO) in September 1993, the international community has supported civil policing programmes. It has done so as part of its development commitments to Palestinian state-building. Such programmes were, until the outbreak of the second Intifada in 2000, largely regarded as successful in terms of supporting the establishment of a Palestinian civil police (PCP). Such programmes were essentially Western imported models which loosely mixed community and public order policing approaches. With re-engagement in the Palestinian security sector (PSS) in the West Bank in 2007, the international community has once again sought to play a major role in PSS reform. This role includes supporting rehabilitation and retraining of the PCP as a principal institution of state-building. Such activities alongside the so-called transformation efforts within the wider realm of the PSS have re-established as their goal law and order. Within the transformation agenda, there are inherent demands with respect to Israel and the Palestinian National Authority's security and counterterrorism agendas. This analysis examines these activities, and accompanying political intent to contend that such approaches are undermining principles of democratic policing including civil police primacy (CPP). CPP reinforces police universality and means supporting rule of law by putting security under governmental control with proper mechanisms of accountability. This article argues that support to the security sector in the West Bank has increasingly only paid lip service or sought to subvert normative approaches to democratic policing.

Metaphor and Matter(s) Arising: Gongorine Metaphor and the Cultivation of the Imagination

This article focuses on the concept of metaphor as metaphorai, as varied means of transfer and transport, specifically on Góngora's innovative development of the metaphor as a vehicle for experiential transformation and epistemological exploration; ultimately emphasizing a hitherto neglected valorization of affect in the liberation of the imagination. Although Góngora's use of metaphor became a major source of controversy in the debate unleashed by the Polifemo and Soledades during his lifetime, the Generation of 1927 looked to Gongorine metaphor as model and inspiration for their cultivation of imaginary worlds through poetry. By examining the models and concepts that nourished Góngora's innovative engagement with metaphor, shaped readers' responses to the poet's imaginary worlds of metaphor, triggered the recovery and reframing of Gongorine metaphor as springboard for the poetic imagination in the twentieth century, and sheds light on the power of Góngora's metaphor to transform and transmute the world through the exercise of the imagination.