Long-Term Quality of Life Among Survivors of Severe Sepsis: Analyses of Two International Trials.

OBJECTIVES: To describe the quality of life among sepsis survivors. DESIGN: Secondary analyses of two international, randomized clinical trials (A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis [derivation cohort] and PROWESS-SHOCK [validation cohort]). SETTING: ICUs in North and South America, Europe, Africa, Asia, and Australia. PATIENTS: Adults with severe sepsis. We analyzed only patients who were functional and living at home without help before sepsis hospitalization (n = 1,143 and 987 from A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, respectively). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis and PROWESS-SHOCK, the average age of patients living at home independently was 63 and 61 years; 400 (34.9%) and 298 (30.2%) died by 6 months. In A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis, 580 patients had a quality of life measured using EQ-5D at 6 months. Of these, 41.6% could not live independently (22.7% were home but required help, 5.1% were in nursing home or rehabilitation facilities, and 5.3% were in acute care hospitals). Poor quality of life at 6 months, as evidenced by problems in mobility, usual activities, and self-care domains were reported in 37.4%, 43.7%, and 20.5%, respectively, and the high incidence of poor quality of life was also seen in patients in PROWESS-SHOCK. Over 45% of patients with mobility and self-care problems at 6 months in A Controlled Comparison of Eritoran and placebo in patients with Severe Sepsis died or reported persistent problems at 1 year. CONCLUSIONS: Among individuals enrolled in a clinical trial who lived independently prior to severe sepsis, one third had died and of those who survived, a further one third had not returned to independent living by 6 months. Both mortality and quality of life should be considered when designing new interventions and considering endpoints for sepsis trials.

Evaluating the efficacy and safety of two doses of the polyclonal anti-tumor necrosis factor-α fragment antibody AZD9773 in adult patients with severe sepsis and/or septic shock: randomized, double-blind, placebo-controlled phase IIb study*.

OBJECTIVE: This trial compared the efficacy/safety of two IV doses of AZD9773, a polyclonal antibody to tumor necrosis factor-α, in adult patients with severe sepsis/septic shock. DESIGN: Multicenter, randomized, double-blind, placebo-controlled phase IIb trial. SETTING: ICUs in seven countries (Australia, Belgium, Canada, Czech Republic, Finland, France, and Spain). PATIENTS: Patients 18 years old or older with severe sepsis and/or septic shock. Patients were required to have 1) objective clinical evidence of infection; 2) at least two of four systemic inflammatory response syndrome criteria; and 3) cardiovascular and/or respiratory sepsis-related failure. INTERVENTIONS: Patients were randomized 1:1:1 to a single loading infusion of AZD9773 250 U/kg followed by 50 U/kg every 12 hours (low dose, n = 100), a single loading infusion of AZD9773 500 U/kg followed by 100 U/kg every 12 hours (high dose, n = 100), or placebo (n = 100) for 5 days. Follow-up assessments were performed up to day 90. MEASUREMENTS AND MAIN RESULTS: Mean number of ventilator-free days (primary endpoint) did not differ between low-dose (19.7 d) or high-dose AZD9773 (17.3 d) and placebo (18.3 d) (one-sided p = 0.18 and 0.74, respectively). Mortality rates were comparable across treatment groups; relative risk of death versus placebo at day 29 was 0.80 for low-dose AZD9773 (one-sided p = 0.25) and 1.64 for high-dose AZD9773 (p = 0.97). Most patients experienced at least one treatment-emergent adverse event (87.8% in AZD9773-treated patients, 92.9% in placebo patients) although most were mild/moderate in nature. No differences in the incidence of adverse events or laboratory or vital sign abnormalities were observed between groups. CONCLUSIONS: AZD9773 rapidly and efficiently decreased plasma tumor necrosis factor-α concentration in patients with severe sepsis/septic shock, but this effect did not translate into clinical benefit.

A randomized, double-blind, placebo-controlled, Phase 2b study to evaluate the safety and efficacy of recombinant human soluble thrombomodulin, ART-123, in patients with sepsis and suspected disseminated intravascular coagulation.

OBJECTIVES: To determine the safety and efficacy of recombinant thrombomodulin (ART-123) in patients with suspected sepsis-associated disseminated intravascular coagulation. DESIGN: Phase 2b, international, multicenter, double-blind, randomized, placebo-controlled, parallel group, screening trial. SETTING: Two hundred and thirty-three ICUs in 17 countries. PATIENTS: All adult patients admitted with sepsis and suspected disseminated intravascular coagulation as assessed using a modified International Society on Thrombosis and Hemostasis score. INTERVENTIONS: Patients were randomized to receive IV ART-123 (0.06 mg/kg/d) for 6 days or placebo, in addition to standard of care. The primary endpoint was reduction in mortality. Secondary endpoints included reversal of overt disseminated intravascular coagulation and reduction in disease severity. MEASUREMENTS AND MAIN RESULTS: A total of 750 patients were randomized, nine of whom did not receive the allocated treatment so that 371 patients received ART-123 and 370 received placebo. There were no meaningful differences between the two groups in any of the baseline variables. Twenty-eight-day mortality was 17.8% in the ART-123 group and 21.6% in the placebo group (Cochran-Mantel-Haenszel two-sided p value of 0.273 in favor of ART-123, which met the predefined statistical test for evidence suggestive of efficacy). There were no statistically significant differences in event-free and alive days between the two groups. d-dimer, prothrombin fragment F1.2 and TATc concentrations were lower in the ART-123 group than in the placebo group. There were no differences between the two groups in organ function, inflammatory markers, bleeding or thrombotic events or in the development of new infections. In post hoc analyses, greatest benefit from ART-123 was seen in patients with at least one organ system dysfunction and an international normalized ratio greater than 1.4 at baseline. CONCLUSIONS: ART-123 is a safe intervention in critically ill patients with sepsis and suspected disseminated intravascular coagulation. The study provided evidence suggestive of efficacy supporting further development of this drug in sepsis-associated coagulopathy including disseminated intravascular coagulation. Future study should focus on using ART-123 in the subgroup of patients most likely to respond to this agent.

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

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.

Immune aspects of sepsis and hope for new therapeutics.

Marked alterations of the innate and adaptive immune response follow invasive infection and generalized inflammatory states. If left unchecked, this state of immune dysregulation contributes to a myriad of maladaptive cellular responses that culminate in multiple organ dysfunction, septic shock, and lethality. The molecular details of the cell-signaling networks that underlie the pathophysiology of systemic inflammation and sepsis are now increasingly well understood. While a vigorous and effective immune response to invasive pathogens is essential for microbial clearance and host survival, nonresolving, generalized inflammation can induce diffuse endovascular damage, increased capillary permeability, coagulopathy, and widespread tissue damage. Current evidence indicates that a state of relative immune suppression often accompanies sepsis and might provide novel therapeutic options in some patients. An expanding number of potential therapeutic options are now in clinical development to reestablish control and promote resolution over sepsis-induced systemic inflammation and organ dysfunction.

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.

RATIONALE: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS: A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.

Removal of clinically relevant SARS-CoV-2 variants by an affinity resin containing Galanthus nivalis agglutinin.

The Coronavirus -19 (COVID-19) pandemic due to the SARS-CoV-2 virus has now exceeded two years in duration. The pandemic has been characterized by the development of a succession of variants containing mutations in the spike protein affecting infectiousness, virulence and efficacy of vaccines and monoclonal antibodies. Resistance to vaccination and limitations in the current treatments available require the ongoing development of therapies especially for those with severe disease. The plant lectin Galanthus nivalis binds to mannose structures in the viral envelope. We hypothesized that viral binding should be unaffected by spike protein mutations. Known concentrations of seven clinically relevant SARS-CoV-2 variants were spiked in medium and passed three times over columns containing 1 gm of GNA affinity resin. Percent decrease in viral titer was compared with a control sample. Viral capture efficiency was found to range from 53 to 89% for all variants. Extrapolation indicated that an adult Aethlon Hemopurifier® would have more than sufficient binding capacity for viral loads observed in adult patients with severe COVID-19 infection.

Removal of COVID-19 Spike Protein, Whole Virus, Exosomes, and Exosomal MicroRNAs by the Hemopurifier® Lectin-Affinity Cartridge in Critically Ill Patients With COVID-19 Infection.

Coronavirus-19 (COVID-19) has rapidly spread throughout the world resulting in a significant amount of morbidity and mortality. Despite advances in therapy, social distancing, masks, and vaccination many places in the world continue to see an increase in the number of cases and deaths. Viremia is commonly present in severely ill patients with COVID-19 infections and is associated with organ dysfunction and poor outcomes. Exosomes released by activated cells have been implicated in the pathogenesis of COVID-19 infection. We report the experience of two cases of critically ill COVID-19 patients treated with the Hemopurifier; a lectin affinity cartridge designed to remove mannosylated viruses and exosomes. Both patients tolerated the Hemopurifier sessions without adverse effects. In the first patient removal of exosomes and exosomal microRNAs was associated with improved coagulopathy, oxygenation, and clinical recovery, while in a second patient removal of COVID-19 by the Hemopurifier cartridge was observed. The Hemopurifier is currently under further investigation in up to 40-patients in a safety and feasibility study in ICU patients with COVID-19 infection.

Phase 2 trial of eritoran tetrasodium (E5564), a toll-like receptor 4 antagonist, in patients with severe sepsis.

OBJECTIVES: Endotoxin is a potent stimulus of proinflammatory response and systemic coagulation in patients with severe sepsis. Endotoxin is a component of Gram-negative bacteria that triggers an innate immune response through Toll-like receptor 4 signaling pathways in myeloid cells. We evaluated safety and tolerability of two dose regimens of eritoran tetrasodium (E5564), a synthetic Toll-like receptor 4 antagonist, and explored whether it decreases 28-day mortality rate in subjects with severe sepsis. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial. SETTING: Adult intensive care units in the United States and Canada. PATIENTS: Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80%. INTERVENTIONS: Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days. MEASUREMENTS AND MAIN RESULTS: Prevalence of adverse events was similar among subjects treated with 45 mg or 105 mg of eritoran tetrasodium or with placebo. For modified intent-to-treat subjects, 28-day all-cause mortality rates were 26.6% (eritoran tetrasodium 105 mg), 32.0% (eritoran tetrasodium 45 mg), and 33.3% in the placebo group. Mortality rate in the eritoran tetrasodium 105-mg group was not significantly different from placebo (p = .335). In prespecified subgroups, subjects at highest risk of mortality by APACHE II score quartile had a trend toward lower mortality rate in the eritoran tetrasodium 105-mg group (33.3% vs. 56.3% placebo group, p = .105). A trend toward a higher mortality rate was observed in subjects in the lowest APACHE II score quartile for the eritoran 105-mg group (12.0% vs. 0.0% placebo group, p = .083). CONCLUSIONS: Eritoran tetrasodium treatment appears well tolerated. The observed trend toward a lower mortality rate at the 105-mg dose, in subjects with severe sepsis and high predicted risk of mortality, should be further investigated.

Activated protein C for H1N1 influenza? More work to do!

An animal model of H1N1 influenza demonstrates that this infection is associated with pulmonary and systemic activation of coagulation and impairment of fibrinolysis in addition to systemic inflammation and intense neutrophil influx into the lung. Activated protein C attenuates coagulation activation and restores fibrinolytic capacity but has little effect on inflammation or survival from this infection. This animal model points to a profound inflammatory state developing in H1N1 infection that impacts mortality. Additional modifications to the model and the type and amount of activated protein C dosing will provide the data to determine the possible use of activated protein C as a therapy in human H1N1 infection.

Time for Well-Powered Controlled Prospective Studies to Test a Causal Role for Herpes Viruses in Alzheimer's Disease Using Antiherpetic Drugs.

Twenty-six phase III studies on Alzheimer's disease are ongoing or have been completed in 2018. Most of these studies are targeting amyloid-beta, its production, polymerization, and/or multiple interactions. None of the amyloid-beta studies seem to affect positively the clinical outcome of patients with Alzheimer's disease thus far, no matter the advancement of disease. It is time to consider other hypotheses for the pathogenesis of Alzheimer's disease, including the potential role of human herpes viruses (HHV), and especially HHV1 (herpes simplex virus type 1), HHV3 (varicella zoster virus), HHV6A, and HHV7. With this perspective, we review the scientific evidence and make the case for appropriately powered, prospective, randomized, and controlled studies using an anti-HHV drug, to establish a causal role for HHV in Alzheimer's disease.

Year in review 2008: Critical Care--sepsis.

The present report highlights the most important papers appearing in Critical Care and other major journals about severe sepsis, the systemic inflammatory response and multiorgan dysfunction over the past year. A number of these clinical and laboratory studies will have a considerable impact on the sepsis research agenda for years to come. The steroid controversy, the debate over tight glycemic control, the colloid versus crystalloid issue, the value of selective decontamination of the digestive tract, the enlarging role of biomarkers, the value of genomics and rapid diagnostic techniques have all been prominently featured in recent publications. Basic research into novel predictive assays, genetic polymorphisms, and new molecular methods to risk-stratify and to determine treatment options for sepsis have occupied much of the Critical Care publications relating to sepsis pathophysiology in 2008. We will attempt to briefly summarize what we consider to be the most significant contributions to the sepsis literature over the last year, and their likely ramifications in the future, for critical care clinicians, clinical investigators and basic researchers alike.

A clinical evaluation committee assessment of recombinant human tissue factor pathway inhibitor (tifacogin) in patients with severe community-acquired pneumonia.

INTRODUCTION: The purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor (tifacogin) in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis. METHODS: A retrospective review of patients with suspected pneumonia was conducted by an independent clinical evaluation committee (CEC) blinded to treatment assignment. The CEC reanalyzed data from patients enrolled in an international multicenter clinical trial of sepsis who had a diagnosis of pneumonia as the probable source of sepsis. The primary efficacy measure was all-cause 28-day mortality. RESULTS: Of 847 patients identified on case report forms with a clinical diagnosis of pneumonia, 780 (92%) were confirmed by the CEC to have pneumonia. Of confirmed pneumonia cases, 496 (63.6%) met the definition for CAP. In the CEC CAP population, the mortality rates of the tifacogin and placebo groups were 70/251 (27.9%) and 80/245 (32.7%), respectively. The strongest signals were seen in patients with CAP not receiving concomitant heparin, having microbiologically confirmed infection, or having the combination of documented infection and no heparin. The reduction in mortality in this narrowly defined subgroup when treated with tifacogin compared with placebo was statistically significant (17/58 [29.3%] with tifacogin and 28/54 [51.9%] with placebo; unadjusted P value of less than 0.02). CONCLUSIONS: Tifacogin administration did not significantly reduce mortality in any severe CAP patient. Exploratory analyses showed an improved survival in patients who did not receive concomitant heparin with microbiologically confirmed infections. These data support the rationale of an ongoing phase III study exploring the potential benefit of tifacogin in severe CAP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00084071.

Decreased protein C, protein S, and antithrombin levels are predictive of poor outcome in Gram-negative sepsis caused by Burkholderia pseudomallei.

BACKGROUND: Acute septicemic melioidosis is associated with systemic release of endotoxin and the proinflammatory cytokines tumor necrosis factor (TNF)-alpha, interleukin-1, and interleukin-6. Excessive release of these cytokines may lead to endothelial injury, depletion of naturally occurring endothelial modulators, microvascular thrombosis, organ failure, and death. METHOD: Plasma samples drawn at baseline and after initial antimicrobial therapy in 30 patients with suspected acute severe melioidosis were assayed for D-dimer levels, protein C and protein S antigen levels, and antithrombin functional activities. RESULTS: Both baseline and continued deficiencies of protein C, protein S, and antithrombin were statistically associated with a poor outcome by logistic regression. Baseline D-dimer levels were significantly higher in fatal cases than survivors and correlated inversely with protein C and antithrombin, suggesting both increased fibrin deposition and fibrinolysis. CONCLUSION: The inflammatory response to systemic Burkholderia pseudomallei infection leads to depletion of the natural endothelial modulators protein C, protein S, and antithrombin. Both baseline and continued deficiency of these endothelial modulators is predictive of poor outcome in melioidosis.

Tissue factor pathway inhibitor and antithrombin trial results.

The endogenous plasma anticoagulant proteins tissue factor pathway inhibitor (TFPI) and antithrombin (AT) have both been extensively studied in large, multinational phase III clinical trials in patients with severe sepsis. The TFPI and AT trials failed to result in significant reductions in the 28-day, all-cause mortality rates in their respective study populations. However, there appear to be definable patient populations within each study that may have benefited from TFPI or AT. Drug-drug interactions and dosing issues were observed in both trials. The similarities and differences of each anticoagulant and the lessons learned from the recent phase III clinical trials are examined in this review.

What's new in antibiotics?

Antibiotics are important agents in dermatologic practice. New drugs have expanded the therapeutic approach to uncomplicated skin infections and complicated infections involving deeper soft tissue or infections that require surgical intervention. This article reviews new antibiotics of dermatologic importance, including daptomycin (cyclic lipopeptide), linezolid (oxazolidinone), quinupristin-dalfopristin (streptogramins), moxifloxacin and gatifloxacin (fluoroquinolones), and dalbavancin and oritavancin, which are presently under investigation.

Use of corticosteroids in the sepsis syndrome: what do we know now?

Several lines of evidence support the use of corticosteroids as adjunctive therapy for sepsis. In human trials, high-dose, short-course corticosteroid therapy for sepsis has not shown benefit, but prolonged use of low doses has shown benefit in patients with vasopressor-dependent septic shock. The Corticosteroid Therapy of Septic Shock (CORTICUS) trial is addressing the remaining questions regarding the ideal target population for corticosteroid therapy, as well as the best definition of relative adrenal insufficiency in the critically ill.

Systemic host responses in severe sepsis analyzed by causative microorganism and treatment effects of drotrecogin alfa (activated).

Clinical trials with novel therapeutic agents for severe sepsis have suggested that patients might respond differently depending on causative microorganism. Data from a large, placebo-controlled trial of recombinant human drotrecogin alfa (activated) (DrotAA) were analyzed by type of causative microorganism for treatment-associated differences in mortality, coagulopathy, and inflammatory response. Compared with placebo, mortality rates associated with DrotAA were consistently reduced for each microorganism group (gram-positive bacteria, gram-negative bacteria, mixed bacteria, fungi, other, and unknown microbial etiology), with a stratified relative risk (RR) of 0.80 (95% confidence interval [CI], 0.69-0.94). The greatest reduction in the mortality rate was for Streptococcus pneumoniae infection (RR, 0.56; 95% CI, 0.35-0.88). Levels of coagulation and inflammation biomarkers varied with different pathogens at study entry. Results demonstrate that DrotAA, administered as an adjunct to standard anti-infective therapy, can improve the rate of survival for patients who develop severe sepsis regardless of causative microorganism.