ObjectiveTo determine the incidence, cost, and outcome of severe sepsis in the United States.DesignObservational cohort study.SettingAll nonfederal hospitals (n = 847) in seven U.S. states.PatientsAll patients (n = 192,980) meeting criteria for severe sepsis based on the International Classification

Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.

Interleukin-1 in the pathogenesis and treatment of inflammatory diseases

Anti-Inflammatory Cytokines

Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.

Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases

The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome

Objective: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhlL-1ra) in the treatment of patients with severe sepsis. Design: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis. Setting: Ninety-one academic medical center intensive care units in North America and Europe. Patients: Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. Interventions: Patients were randomized to receive either rhlL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/ kg/hr) or placebo. Measurements and Main Results: The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhlL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhlL-1ra treatment in this study. Conclusions: A 72-hr, continuous intravenous infusion of rhlL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhlL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group

Objective: This study investigated whether treatment with the anti-tumor necrosis factor-or monoclonal antibody afelimomab would improve survival in septic patients with serum interleukin (IL)-6 concentrations of >1000 pg/ml, Design: Multicenter, double-blind, randomized, placebo-controlled study. Setting: Eighty-four intensive care units in academic medical centers in Europe and Israel. Patients: A total of 944 septic patients were screened and stratified by the results of a rapid qualitative immunostrip test for serum IL-6 concentrations. Patients with a positive test kit result indicating IL-6 concentrations of >1000 pg/mL were randomized to receive either afelimomab (n = 224) or placebo (n = 222), Patients with a negative IL-6 test (n = 498) were not randomized and were followed up for 28 days. Interventions: Treatment consisted of 15-min infusions of 1 mg/kg afelimomab or matching placebo every 8 hrs for 3 days. Standard surgical and intensive care therapy was otherwise delivered. Measurements and Main Results:The study was terminated prematurely after an interim analysis estimated that the primary efficacy end points would not be met. The 28-day mortality rate in the nonrandomized patients (39.6%, 197 of 498) was significantly lower (p <.001) than that found in the randomized patients (55.8%, 249 of 446). The mortality rates in the IL-6 test kit positive patients randomized to afelimomab and placebo were similar, 54.0% (121 of 224) vs, 57.7% (128 of 222), respectively. Treatment with afelimomab was not associated with any particular adverse events. Conclusions: The IL-6 immunostrip test identified two distinct sepsis populations with significantly different mortality rates. A small (3.7%) absolute reduction in mortality rate was found in the afelimomab-treated patients. The treatment difference did not reach statistical significance.

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study

Objective: To evaluate the safety of liposomal PGE1 (TLC C-53) in patients with acute respiratory distress syndrome (ARDS), and determine its efficacy in improving oxygenation and reducing ventilator dependency. Design: A multi-centre, randomized, double-blind, placebo-controlled clinical study. Setting: Thirty-one hospitals in six European countries. Patients: One hundred two patients with ARDS. Interventions: Patients were randomized in a 2:1 ratio to receive infusions of either the study drug TLC C-53 or placebo. Infusions were given over 60 min every 6 h for 7 days. The dose of study drug started at 0.6 µg/kg per h, rising over 24 h to a maximum dose of 1.8 µg/kg per h. Measurements and main results: Seventy patients received the study drug and 32 placebo. Sixty-nine patients (47 treatment, 22 placebo) completed the study protocol. Patients were monitored for changes in the PaO2/FIO2 ratio, changes in lung compliance, time to off-ventilator and 28-day mortality, in addition to basic haematological and haemodynamic parameters. There were no significant differences in demographics and baseline characteristics between the two groups. There were no differences in the time to off-ventilation (16 days with treatment, 16.6 days with placebo, p=0.94) or in 28-day mortality (30% with treatment, 28% with placebo, p=0.78). There was a difference in the time to achieve a PaO2/FIO2 ratio above 300 in favour of TLC C-53 (10.3 versus 26.5 days) but this was not statistically significant (p=0.23). Conclusions: TLC C-53 was generally well-tolerated but failed to reduce mortality or duration of mechanical ventilation.

/pdf/a-multi-centre-double-blind-placebo-controlled-study-of-50ubzysatg.pdf

Rainer Brase

Papers

Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group

Randomized, placebo-controlled trial of the anti-tumor necrosis factor antibody fragment afelimomab in hyperinflammatory response during severe sepsis: The RAMSES Study

A multi-centre, double-blind, placebo-controlled study of liposomal prostaglandin E1 (TLC C-53) in patients with acute respiratory distress syndrome.

A multicenter, double-blind, placebo-controlled. Study of liposomal prostaglandin El (TLC C-53) in patients with acute respiratory distress syndrome