Preclinical and Clinical Investigations in Septic Shock

早期研究集中于败血性休克病理生理学（Am J Physiol 1988; Chest，1990）、内毒素血症的作用（J Clin Invest 1989; J Exp Med，1989; Chest.一九九一年; N Engl J Med，1993; Infect Immun 1996）和各种抗内毒素疗法（AntimicrobAgents Chemother 1989）的功效，包括脂质A类似物（J Clin Invest 1987; Pharm Res 1990）和抗体（JAMA，1993; J Infect Dis，1994）。 一氧化氮（NO）被认为是感染性休克的重要介质（Crit Care Med，1993; JAMA 1996）。发现非选择性NO合酶抑制剂有时是有毒的并且从未有益（J Exp Med 1992; Crit Care Med 1998; Am J Respir Crit Care Med 1998）。 用内毒素激发的正常志愿者显示释放增加量的NO。尽管布洛芬阻断内毒素诱导的NO产生增加，但血压不受影响，表明其他机制补偿维持血管舒张（J Pharmacol Exp Ther 1999）。 发现疾病的严重程度（死亡风险）会影响感染性休克中抗炎药的治疗效果（Am J Respir Crit Care Med 2002）。这一发现被FDA用于重新分析rhAPC（Xigris）的PROWESS试验，并导致最初仅批准用于高死亡风险的患者。在ADDRESS试验中证实了rhAPC在低死亡风险患者中缺乏疗效。 在犬感染性休克模型中，L-精氨酸（不含或含N-乙酰半胱氨酸）给药被发现是有害的（Crit Care Med 2006）。L-精氨酸是市场上用于重症患者的免疫营养配方的常见成分。 我们的犬败血性休克模型被重新开发，以更好地平衡动物福利和科学相关性。将脓毒症患者常规使用的特异性和支持性滴定治疗完全整合到模型中，以提供更真实的环境来评价脓毒症治疗（Am J Physiol Heart Circ Physiol 2007）。 死亡风险是否改变了氢化可的松的作用，在小鼠模型中进行了研究。大肠杆菌肺炎（重症监护医学2008）。 在金黄色葡萄球菌肺炎诱导的脓毒性休克的低动力犬模型中，主动脉内球囊反搏被证明可延长存活期（Crit Care Med 2009）。这一结果表明，左心室功能的反搏支持可能会提高与心输出量受损相关的感染性休克发作的生存率。10%至20%的成人和高达50%的感染性休克儿童出现低心排血量。 美国危重疾病和损伤试验组（USCIITG）的成立旨在创建一个临床研究框架，以减少研究障碍（http：www.massgeneral.org/research/researchlab.aspx? id=1262）。USCIITG为系统性审查和战略规划提供了年度场所，包括制定研究议程，并提高对急性护理研究价值的认识（Crit Care Med 2009）。 一项对感染性休克捆绑式护理的荟萃分析表明，在生存率和抗生素使用方面有一致和显著的改善。在各项研究中，其他束成分的使用变化不均匀，使得其对生存率的影响不确定（Crit Care Med 2010）。 p38抑制剂SB 203580在E.大肠杆菌肺炎（J Trauma 2010）。 炭疽致死毒素（LeTx）诱导的休克被发现有很大的不同，从LPS的挑战在大鼠。液体和血管加压药（脓毒性休克的标准方法）是有害的（Crit Care Med 2009）。值得注意的是，炭疽感染未能诱导NO合酶2，由于LeTx介导的细胞内炎症信号的截断。24小时水肿（ETx）和致死（LeTx）毒素输注96小时在镇静犬接受机械通气进行了研究。Etx的致死性远低于LeTx，但当加入等摩尔LeTx攻毒时，死亡率增加（J Infect Dis 2010）。 肝素在小鼠E.大肠杆菌肺炎未能改善肺损伤或存活率Crit Care Med 2011）。对已发表的动物研究进行的系统综述和荟萃回归分析表明，肝素可改善脂多糖或药物诱导感染的生存率，但不能改善单菌挑战。 同时激活盐皮质激素（MR）和糖皮质激素受体（GR）的糖皮质激素方案可持续逆转脓毒性休克中的血管加压素依赖性低血压，但对生存率的影响不同。在S.金黄色葡萄球菌肺炎诱导的感染性休克，MR和GR的选择性激动剂分别进行了检查。盐皮质激素仅在被动给药时有益，而糖皮质激素在接近感染发作时最有益（Crit Care Med 2012）。 葡萄球菌肠毒素B（SE B）可引发致死性超抗原介导的细胞因子风暴，这可能是导致S.金黄色葡萄球菌败血症，也构成了潜在的生物武器的威胁。使用雾化毒素，小鼠模型，SEB的全基因组效应正在研究中，以确定治疗靶点。这个项目揭示了一个强烈的，晚期干扰素反应，死亡之前，似乎是Toll样受体的独立。 淋巴细胞细胞因子的产生和细胞凋亡，有点矛盾，已与败血症的死亡。正在研究淋巴细胞活化和细胞凋亡的核受体调节，作为平息早期过度炎症的手段，同时在严重脓毒症后期保留免疫功能（FASEB J abstract，2011）。

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 various 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 lack of rhAPC efficacy in patients with a low risk of death was confirmed in the ADDRESS trial. The administration of L-arginine without or with N-acetylcysteine 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 that are marketed for use in critically ill patients. Our canine septic shock model was redeveloped to better balance animal welfare and scientific relevance. Both specific and supportive titrated therapies routinely used in septic patients were fully integrated into the model to provide a more realistic setting to evaluate therapies for sepsis (Am J Physiol Heart Circ Physiol 2007). Whether risk of death altered the effects of hydrocortisone was invested in a mouse model of E. coli pneumonia (Intensive Care Med 2008). Intra-aortic balloon counterpulsation was demonstrated to prolong survival in a hypodynamic canine model of Staphylococcus aureas pneumonia induced septic shock (Crit Care Med 2009). This result suggests that counterpulsation support of left ventricular function might improve survival in episodes of septic shock associated with compromised cardiac output. A 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 that will include framing the research agenda, and raising awareness for the value of acute care research (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. Fluids and vasopressors, standard approaches to septic shock, were harmful (Crit Care Med 2009). Notably, anthrax infection fails to induce NO synthase 2, due to a LeTx-mediated truncation of inflammatory signaling inside cells. Twenty-four hour edema (ETx) and lethal (LeTx) toxin infusions were investigated for 96 h in sedated canines receiving mechanical ventilation. 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. 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. 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). Staphylococcus enterotoxin B (SEB) can trigger a lethal super antigen-mediated cytokine storm that may contribute to the high mortality of S. aureas sepsis and also poses a threat as a potential bioweapon. Using an aerosolized-toxin, mouse model, the genome-wide effects of SEB are being examined in an effort to identify therapeutic targets. This project has revealed an intense, late interferon response that precedes death and appears to be Toll-like receptor independent. Both lymphocyte cytokine production and apoptosis, somewhat paradoxically, have been linked to death from sepsis. Nuclear receptor modulation of lymphocyte activation and apoptosis is being investigated as a means to quell early excessive inflammation, while preserving immune function later in severe sepsis (FASEB J abstract, 2011).