Preclinical and Clinical Investigations in Septic Shock

早期的研究集中在比较革兰氏阳性和革兰氏阴性生物的病理生理学，内毒素血症的作用，以及抗内毒素治疗的疗效，如类脂A类似物和抗体。 一氧化氮被认为是感染性休克的重要介质。非选择性一氧化氮合酶抑制剂有时是有毒的，永远不会有益。 研究发现，受到内毒素攻击的正常志愿者会释放更多的一氧化氮。虽然布洛芬阻止了内毒素诱导的一氧化氮产生的增加，但血压没有受到影响，这表明其他机制补偿了维持血管扩张的作用。 疾病的严重程度(死亡风险)被发现影响败血症休克的抗炎药的疗效。FDA利用这一发现重新分析了重组人APC(Xgris)的PROWESS试验，并导致最初只批准了死亡风险较高的患者。ADDRESS试验证实，在低死亡风险的患者中，重组人APC缺乏疗效。 在感染性休克的犬模型中，L精氨酸单独或与N-乙酰半胱氨酸合用被发现是有害的。L精氨酸是市场上用于危重患者的免疫营养配方中的常见成分。 在金黄色葡萄球菌肺炎感染性休克的低动力犬模型中，主动脉内球囊反搏被发现可以延长存活时间。这一结果表明，在感染性休克相关的心输出量受损的情况下，左心功能的反搏支持可能会提高存活率。感染性休克的成年人和儿童中有10%到20%的人和高达50%的儿童出现低心输出量。 关于下丘脑-垂体-肾上腺轴的研究以及糖皮质激素和盐皮质激素对感染性休克的小鼠和犬模型的潜在益处正在进行中。这些实验的目的是确定剂量和时间问题，以及细胞水平上的糖皮质激素和盐皮质激素的影响。脓毒症的炎症反应的核受体反式抑制这一更普遍的话题正在体外和体内进行探索。

Early studies focused on pathophysiology comparing gram positive and gram negative organisms, the role of endotoxemia, and the efficacy of anti-endotoxin therapies such as lipid A analogs and antibodies. Nitric oxide was examined as an important mediator of septic shock. Non-selective nitric oxide synthase inhibitors were sometimes toxic and never beneficial. Normal volunteers challenged with endotoxin were found to release increased amounts of nitric oxide. Although ibuprofen blocked endotoxin-induced increases in nitric oxide production, blood pressure was unaffected, suggesting that other mechanisms compensated to maintain vasodilation. Severity of illness (risk of death) was found to influence the therapeutic efficacy of anti-inflammatory agents in septic shock. 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. L-arginine is a common component of immunonutrition formulas that are marketed for use in critically ill patients. Intra-aortic balloon counterpulsation was found to prolong survival in a hypodynamic canine model of Staphylococcus aureas pneumonia induced septic shock. 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. An investigation of the hypothalamic-pituitary-adrenal axis and potential benefits of glucocorticoids and mineralocorticoids is ongoing in mouse and canine models of septic shock. These experiments are aimed at defining issues of dose and timing as well as glucocorticoid and mineralicorticoid effects at the cellular level. The more general topic of nuclear receptor transrepression of inflammatory responses to sepsis is being explored both in vitro and in vivo.