Impact of Immunomodulating Therapy on Morbidity in Patients with Severe Sepsis

Abstract

We assessed the impact, over a 28-d period, of therapy with the tumor necrosis factor (TNF) neutralizing receptor fusion protein (p55-IgG) on the incidence of end-organ failures in patients with severe sepsis or early septic shock in a subgroup of 165 patients recruited into a randomized, multicenter clinical trial to receive placebo (n = 78) or a single infusion of p55-IgG, 0.083 mg/kg (n = 87). At study entry, distribution of organ dysfunctions and other baseline characteristics were similar for the two study groups. Treatment with p55-IgG was associated with a trend toward reduced 28-d mortality (p = 0.07), a decreased incidence of new organ dysfunctions (relative risk [RR], 0.57; 95% confidence interval [95% CI] 0.29 to 1.10, p = 0.10), and a decreased overall incidence-density of organ failures (RR 0.65; 95% CI 0.60 to 0.71, p = 0.0001). Patients treated with p55-IgG had more organ failure-free days after study entry than those who received placebo. Average intensive care unit (ICU) stay was 2.6 d shorter (95% CI 0.2 to 5.0) for patients who received p55-IgG than for those who received placebo. For those patients who survived, this difference was 4.1 d (95% CI 1.6 to 6.6). Duration of ventilatory support was 3.2 d shorter (95% CI 0.1 to 6.3) among 28-d survivors who received p55-IgG, compared with placebo. In conclusion, in the population of septic patients studied, treatment with p55-IgG was associated with a trend toward shorter need for mechanical ventilatory support, a decreased length of stay (LOS), and a decreased incidence and duration of organ failure.

Expression of non-signaling membrane-anchored death receptors protects murine livers in different models of hepatitis

“…Most of the strategies developed to counteract apoptosis rely on the administration of soluble antagonists, for example, antibodies or soluble decoy receptors. 14,15 For example, systemic administration of anti-TNF-␣ antibody or soluble TNFR attenuated rheumatoid arthritis symptoms 34 ; however, because such molecules neutralize apoptosis ligands throughout the body, they can have harmful side effects by interrupting physiological processes, as demonstrated by tuberculosis reactivation after anti-TNF-␣ therapy. 18,35 Also, on binding to transmembrane death ligands, these soluble antagonists may induce macrophage apoptosis by reverse signaling.…”

The Systemic Mediator-Associated Response Test Identifies Patients in Failed Sepsis Clinical Trials Among Whom Novel Drugs Reduce Mortality

“…All three studies failed to reduce septic mortality. Similarly, severity of illness scores, including APACHE II scoring, 5,18 and/or the presence of DIC 11 or ARDS, 23 while attractive as single, commonly understood screening measurements, also have not panned out as patient identification tools for predicting anti-TNF and antiendotoxin treatment responses. Even though APACHE II was an independent variable in SMART survival models for both the E5 and TNFMAb populations, and DIC, and ARDS figured in the E5 SMART modeling, they contributed only to building the tools that identified individual septic pathophysiology.…”

Epidemiology and Prognostic Determinants of Bloodstream Infections in Surgical Intensive Care

“…2,18,19 In brief, organ failures assessed at baseline and during the 28 days after BSI were characterized as follows: (1) renal-serum creatinine level greater than 3.0 mg/dL (Ͼ265 µmol/L) or, in the case of preexisting renal dysfunction, a doubling of previous serum creatinine values; (2) hepatic-acute elevation of total bilirubin concentration to greater than 3.0 mg/dL (Ͼ51 µmol/L) and elevation of the alanine aminotransferase or aspartate aminotransferase level to 3 times the upper limit of normal in the absence of primary liver disease; (3) hematologic-disseminated intravascular coagulation defined as prothrombin time and partial thromboplastin time more than 2 times the normal range, platelet count of less than 100ϫ10 3 /µL or less than half of a previous count, and fibrin degradation products greater than 10 µg/mL; (4) central nervous system-Glasgow Coma Scale score of less than 10 or a decrease in the score of at least 3 if primary central nervous system injury is present; (5) acute lung injury-acute-onset respiratory failure with bilateral diffuse chest infiltrates, a PaO 2 / fraction of inspired oxygen ratio of 300 mm Hg or less, a left filling pressure of 18 mm Hg or less, and presence of a known risk factor for acute lung injury; (6) acute respiratory distress syndrome-acute-onset respiratory failure with bilateral diffuse chest infiltrates, a PaO 2 /fraction of inspired oxygen ratio of 200 mm Hg or less, a left filling pressure of 18 mm Hg or less, and presence of a known risk factor for acute respiratory distress syndrome; (7) shock-arterial systolic blood pressure less than 90 mm Hg or a decrease of more than 40 mm Hg during more than 30 minutes, refractory to fluid repletion, and vasopressors required for 2 hours or more to sustain a blood pressure of more than 90 mm Hg; and (8) Polymicrobial bacteremia was defined as either growth of 2 or more different species of microorganisms in the same blood culture or growth of different species in 2 or more separate blood cultures within the same episode. 20 Breakthrough bacteremia was defined as BSI that occurred in patients treated for longer than 24 hours with appropriate antibiotics.…”