RESULTS Absolute mortality in severe sepsis decreased from 35.0% (95% CI, 33.2%-36.8%; 949/2708) to 18.4% (95% CI, 17.8%-19.0%; 2300/12 512; P < .001), representing an overall decrease of 16.7% (95% CI, 14.8%-18.6%), an annual rate of absolute decrease of 1.3%, and a relative risk reduction of 47.5% (95% CI, 44.1%-50.8%). After adjusted analysis, mortality decreased throughout the study period with an odds ratio (OR) of 0.49 (95% CI, 0.46-0.52) in 2012, using the year 2000 as the reference (P < .001). The annual decline in mortality did not differ significantly between patients with severe sepsis and those with all other diagnoses (OR, 0.94 [95% CI, 0.94-0.95] vs 0.94 [95% CI, 0.94-0.94]; P = .37). The annual increase in rates of discharge to home was significantly greater in patients with severe sepsis compared with all other diagnoses (OR, 1.03 [95% CI, 1.02-1.03] vs 1.01 [95% CI, 1.01-1.01]; P < .001). Conversely, the annual increase in the rate of patients discharged to rehabilitation facilities was significantly less in severe sepsis compared with all other diagnoses (OR, 1.08 [95% CI, 1.07-1.09] vs 1.09 [95% CI, 1.09-1.10]; P < .001). In the absence of comorbidities and older age, mortality was less than 5%.

https://jamanetwork.com/journals/jama/articlepdf/1850096/joi140034.pdf

Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012

A better understanding of the inflammatory, procoagulant, and immunosuppressive aspects of sepsis has contributed to rational therapeutic plans. This review considers optimal management of sepsis from the point of early, goal-directed therapy, lung-protective ventilation, antibiotics, and additional therapies, such as activated protein C, as well as the use of corticosteroids, vasopressin, and intensive insulin.

Management of sepsis.

BACKGROUND The consensus definition of severe sepsis requires suspected or proven infection, organ failure, and signs that meet two or more criteria for the systemic inflammatory response syndrome (SIRS). We aimed to test the sensitivity, face validity, and construct validity of this approach. METHODS We studied data from patients from 172 intensive care units in Australia and New Zealand from 2000 through 2013. We identified patients with infection and organ failure and categorized them according to whether they had signs meeting two or more SIRS criteria (SIRS-positive severe sepsis) or less than two SIRS criteria (SIRSnegative severe sepsis). We compared their characteristics and outcomes and assessed them for the presence of a step increase in the risk of death at a threshold of two SIRS criteria. RESULTS Of 1,171,797 patients, a total of 109,663 had infection and organ failure. Among these, 96,385 patients (87.9%) had SIRS-positive severe sepsis and 13,278 (12.1%) had SIRS-negative severe sepsis. Over a period of 14 years, these groups had similar characteristics and changes in mortality (SIRS-positive group: from 36.1% [829 of 2296 patients] to 18.3% [2037 of 11,119], P<0.001; SIRS-negative group: from 27.7% [100 of 361] to 9.3% [122 of 1315], P<0.001). Moreover, this pattern remained similar after adjustment for baseline characteristics (odds ratio in the SIRS-positive group, 0.96; 95% confidence interval [CI], 0.96 to 0.97; odds ratio in the SIRSnegative group, 0.96; 95% CI, 0.94 to 0.98; P = 0.12 for between-group difference). In the adjusted analysis, mortality increased linearly with each additional SIRS criterion (odds ratio for each additional criterion, 1.13; 95% CI, 1.11 to 1.15; P<0.001) without any transitional increase in risk at a threshold of two SIRS criteria. CONCLUSIONS The need for two or more SIRS criteria to define severe sepsis excluded one in eight otherwise similar patients with infection, organ failure, and substantial mortality and failed to define a transition point in the risk of death. (Funded by the Australian and New Zealand Intensive Care Research Centre.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1415236

Systemic Inflammatory Response Syndrome Criteria in Defining Severe Sepsis

For more than two decades, sepsis was defined as a microbial infection that produces fever (or hypothermia), tachycardia, tachypnoea and blood leukocyte changes. Sepsis is now increasingly being considered a dysregulated systemic inflammatory and immune response to microbial invasion that produces organ injury for which mortality rates are declining to 15-25%. Septic shock remains defined as sepsis with hyperlactataemia and concurrent hypotension requiring vasopressor therapy, with in-hospital mortality rates approaching 30-50%. With earlier recognition and more compliance to best practices, sepsis has become less of an immediate life-threatening disorder and more of a long-term chronic critical illness, often associated with prolonged inflammation, immune suppression, organ injury and lean tissue wasting. Furthermore, patients who survive sepsis have continuing risk of mortality after discharge, as well as long-term cognitive and functional deficits. Earlier recognition and improved implementation of best practices have reduced in-hospital mortality, but results from the use of immunomodulatory agents to date have been disappointing. Similarly, no biomarker can definitely diagnose sepsis or predict its clinical outcome. Because of its complexity, improvements in sepsis outcomes are likely to continue to be slow and incremental.

Sepsis and septic shock

Infectious diseases are a leading cause of death worldwide. Sepsis is a severe clinical syndrome related to the host response to infection. The severity of infections is due to an activation cascade that will lead to an autoamplifying cytokine production: the cytokine storm. Cytokines are a broad category of relatively small proteins (<40 kDa) that are produced and released with the aim of cell signaling. Our understanding of the processes that trigger this tremendous amount of cytokine production has made dramatic progress over the last decades, but unfortunately, these findings could not translate yet into effective treatments; so far, all clinical trials targeting cytokine production or effects failed. This review aims to summarize the pathophysiology of the cytokine storm; to describe the type, effects, and kinetics of cytokine production; and to discuss the therapeutic challenges of targeting cytokines. New promising therapeutic strategies focusing on the endothelium, as a source and a target of cytokines, are described.

Cytokine storm and sepsis disease pathogenesis

Importance Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. Objective To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. Design, Setting, and Participants We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. Interventions Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. Main Outcome Measures The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. Results Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, −1.1; 95% CI, −5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. Conclusions and Relevance Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. Trial Registration clinicaltrials.gov Identifier: NCT00334828

https://jamanetwork.com/journals/jama/articlepdf/1669798/jce130005_1154_1162.pdf

Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

Steven M. Opal, MDPierre-Francois Laterre, MDBruno Francois, MDSteven P. LaRosa, MDDerek C. Angus, MD, MPHJean-Paul Mira, MD, PhDXavier Wittebole, MDThierry Dugernier, MDDominique Perrotin, MDMark Tidswell, MDLuis Jauregui, MDKenneth Krell, MDJan Pachl, MDTakeshi Takahashi, MDClaus Peckelsen, MDEdward Cordasco, DOChia-Sheng Chang, MDSandra Oeyen, MDNaoki Aikawa, MD, PhDTatsuya Maruyama, MD, PhDRoland Schein, MDAndre C. Kalil, MD, MPHMarc Van Nuffelen, MDMelvyn Lynn, PhDDaniel P. Rossignol, PhDJogadish Gogate, PhDMary B. Roberts, MSJanice L. Wheeler, BS, RNJean-Louis Vincent, MD, PhDfor the ACCESS Study Group

https://biblio.ugent.be/publication/4222072/file/4222102.pdf

Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis

Objective: Platelet-activating factor (PAF) and structurally-related oxidized phospholipids are proinflammatory mediators in systemic inflammatory states such as severe sepsis. The enzyme platelet-activating factor acetylhydrolase (PAF-AH) rapidly degrades PAF and oxidized phospholipids into inactive metabolites. Reduced PAF-AH activity has been observed in patients with severe sepsis and may contribute to their systemic inflammatory response and organ dysfunction. A previous clinical trial with recombinant human PAF-AH (rPAF-AH, Pafase) suggested that this treatment may decrease 28-day all-cause mortality in patients with severe sepsis. The current study was undertaken to confirm this result. Design: A prospective, randomized, double-blind, placebo-controlled, multicenter, international trial. Setting: One hundred forty-six intensive care units from nine countries. Patients: Approximately 2,522 patients were planned to be enrolled less than or equal to 12 hrs after the onset of severe sepsis. Eligible patients were randomized to receive either rPAF-AH 1.0 mg/kg or placebo administered intravenously once daily for five consecutive days. Measurements and Main Results: The study was terminated based on the recommendation of an independent data and safety monitoring committee after the second of three planned interim analyses, and the enrollment of 1,425 patients. rPAF-AH treatment was well tolerated among the 1,261 patients included in the interim analysis (643 rPAF-AH and 618 placebo), but did not decrease 28-day all-cause mortality compared with placebo (25% for rPAF-AH vs. 24% for placebo; relative risk, 1.03; 95% confidence interval, 0.85-1.25; p = .80). There were no statistically significant differences between treatment groups in any of the secondary efficacy end points. The overall incidence of adverse events was similar among rPAF-AH and placebo-treated patients, and no rPAF-AH-treated patients developed antibodies to PAF-AH. Conclusions: rPAF-AH was well tolerated and not antigenic, but did not decrease 28-day all-cause mortality in patients with severe sepsis.

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial

Luis Jauregui

Papers

Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis

Recombinant human platelet-activating factor acetylhydrolase for treatment of severe sepsis: Results of a phase III, multicenter, randomized, double-blind, placebo-controlled, clinical trial