Preclinical and Clinical Investigations in Septic Shock

感染性休克的临床前和临床研究

• 批准号: 8952819
• 负责人: ROBERT L DANNER
• 金额: --
• 依托单位: CLINICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8952819
• 关键词: Academic Medical Centers; Admission activity; Adrenal Cortex Hormones; Adrenal Glands; Adult; Affect; Agonist; Aldosterone; American; Animal Model; Animals; Anthrax disease; Anti-Inflammatory Agents; Antibiotics; Antibodies; Antigens; Arginine; Blood Pressure; Canis familiaris; Cardiac; Caring; Cell Culture System; Cells; Cessation of life; Chest; Child; Clinical Research; Clinical Trials; Cohort Studies; Colistin; Counterpulsation; Critical Illness; Databases; Dose; Edema; Endocrinology; Endotoxemia; Endotoxins; Enterotoxins; Escherichia coli; Exotoxins; Extreme drug resistant tuberculosis; Fibrosis; Functional disorder; Gene Expression; Glucocorticoid Receptor; Glucocorticoids; Heart; Heparin; Home environment; Hospitalization; Hospitals; Hydrocortisone; Hypotension; Hypothalamic structure; Ibuprofen; Infection; Inflammatory; Injury; Intensive Care; Interferons; Intravenous; Investigation; Journals; Lilly brand of drotrecogin alfa activated; Lipid A; Lipopolysaccharides; Low Cardiac Output; MAPK14 gene; Marketing; Measurement; Mediating; Mediator of activation protein; Meta-Analysis; Mineralocorticoids; Modeling; Mus; Natural Immunity; Nitric Oxide; Nitric Oxide Synthase; Organ; Outcome; Pathogenesis; Patients; Physiology; Pituitary Gland; Pneumonia; Population; Probability; Production; Public Health; Publishing; Rattus; Regimen; Regression Analysis; Research; Risk; Role; SB 203580; Sepsis; Septic Shock; Severity of illness; Shock; Signal Transduction; Staphylococcal Enterotoxin B; Staphylococcus aureus; Strategic Planning; Stress; Syndrome; Testing; Time; TimeLine; Toxic Shock Syndrome; Toxin; Trauma; Treatment Efficacy; Vasoconstrictor Agents; Vasodilation; aerosolized; analog; anthrax lethal factor; carbapenem resistance; cost; cytokine; drug resistant bacteria; healthy volunteer; high risk; hypothalamic-pituitary-adrenal axis; improved; inhibitor/antagonist; lung injury; mortality; mouse model; novel therapeutics; outcome forecast; pre-clinical; response; septic; systematic review; trend; volunteer

Early studies focused on septic shock pathophysiology (Am J Physiol 1988; Chest, 1990), the role of endotoxemia (J Clin Invest 1989; J Exp Med, 1989; Chest. 1991; N Engl J Med, 1993; Infect Immun 1996), and the efficacy of anti-endotoxin therapies (Antimicrob Agents Chemother 1989) including lipid A analogs (J Clin Invest 1987; Pharm Res 1990) and antibodies (JAMA, 1993; J Infect Dis, 1994). Nitric oxide (NO) was examined as an important mediator of septic shock (Crit Care Med, 1993; JAMA 1996). Non-selective NO synthase inhibitors were found to be sometimes toxic and never beneficial (J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998). Normal volunteers challenged with endotoxin were shown to release increased amounts of NO. Although ibuprofen blocked endotoxin-induced increases in NO production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation (J Pharmacol Exp Ther 1999). Severity of illness (risk of death) was found to influence the therapeutic efficacy of anti-inflammatory agents in septic shock (Am J Respir Crit Care Med 2002). This finding was used by the FDA to re-analyze the PROWESS trial of rhAPC (Xigris) and led to initial approval only for patients with a high risk of death. The administration of L-arginine in a canine model of septic shock was found to be harmful (Crit Care Med 2006). L-arginine is a common component of immunonutrition formulas marketed for use in critically ill patients. Our canine septic shock model was redeveloped to incorporate specific and supportive titrated therapies routinely used in septic patients (Am J Physiol Heart Circ Physiol 2007). Intra-aortic balloon counterpulsation was demonstrated to prolong survival in a hypodynamic canine model of Staphylococcus aureus pneumonia induced septic shock (Crit Care Med 2009). Importantly, low cardiac output is seen in 10 to 20 percent of adults and up to 50 percent of children with septic shock. The U.S. Critical Illness and Injury Trials Group (USCIITG) was founded to create a clinical research framework that can reduce the barriers to investigation (http://www.massgeneral.org/research/researchlab.aspx?id=1262). USCIITG provides an annual venue for systematic review and strategic planning (Crit Care Med 2009). A meta-analysis of bundled care for septic shock demonstrated consistent and significant improvement in survival and antibiotic use. Use of other bundle components changed heterogeneously across studies, making their impact on survival uncertain (Crit Care Med 2010). SB203580, a p38 inhibitor, improved cardiac function but worsened lung injury and survival during E. coli pneumonia in mice (J Trauma 2010). Anthrax lethal toxin (LeTx)-induced shock was found to differ substantially from LPS challenge in rats Crit Care Med 2009). Notably, anthrax infection fails to induce NO synthase 2, due to a LeTx-mediated truncation of inflammatory signaling inside cells. In canines, anthrax edema toxin (ETx) was much less lethal than LeTx, but increased mortality when added to equimolar LeTx challenges (J Infect Dis 2010). Heparin in a mouse model of E. coli pneumonia failed to improve lung injury or survival (Crit Care Med 2011). A systematic review and meta-regression analysis of published animal studies showed that heparin improved survival with lipopolysaccharide or surgically-induced infection, but not monobacterial challenges. Staphylococcal exotoxins including enterotoxin B (SEB) can trigger a lethal super antigen-mediated cytokine storm. These exotoxins contribute to the high mortality of S. aureus sepsis and also pose a threat as potential bioweapons. Using an aerosolized-toxin, mouse model, global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death (PLoS One 2014). These results suggest that therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes. Corticosteroid regimens that activate both mineralocorticoid (MR) and glucocorticoid receptors (GR) consistently reverse vasopressor-dependent hypotension in septic shock, but have variable effects on survival. The relationship between hydrocortisone efficacy and risk of death was first investigated in a mouse model of E. coli pneumonia (Intensive Care Med 2008). . In a canine model of S. aureus pneumonia-induced septic shock, selective agonists of MR and GR were examined separately. Mineralocorticoid was only beneficial if given prophylactically, while glucocorticoid was most beneficial when given close to the onset of infection (Crit Care Med 2012). Stress dose corticosteroids were only beneficial in cases of sepsis with high risk for death and even short courses may interfere with host mechanisms of bacterial clearance (Intensive Care Med 2012). Hypothalamic-pituitary-adrenal (HPA) function was characterized serially over five days in 101 canines with severe Staphylococcus aureus pneumonia. During septic shock, only serial measurements and provocative testing over a well-defined timeline was able to demonstrate a strong relationship between HPA axis function and prognosis. HPA axis unresponsiveness and high aldosterone levels identified a septic shock subpopulation with poor outcomes that may have the greatest potential to benefit from new therapies (American Journal of Physiology - Endocrinology and Metabolism 2014, in press). While carbapenem resistance increases the risk of death from gram-negative infections, the trend in mortality over time is unknown. A retrospective cohort study was conducted at 40 academic medical centers using a discharge database to identify non-cystic fibrosis, adult hospital admissions (2006-12) who received intravenous colistin for >3 consecutive days or died on therapy (termed colistin-cases). Colistin tracking identified a severely ill population with a high probability of having culture-confirmed CRGNIs, particularly those caused by extensively drug-resistant bacteria. While colistin-cases nearly trebled over 7 years, more patients are surviving hospitalization and going home (Clin Infect Dis 2014, in press).