Division of Critical Care Medicine, Baystate Medical Center, Springfield, Massachusetts, USA.
Crit Care Med. 2010 Jan;38(1):72-83. doi: 10.1097/CCM.0b013e3181b07b78.
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.
Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial.
Adult intensive care units in the United States and Canada.
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%.
Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days.
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).
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.
内毒素是严重脓毒症患者促炎反应和全身凝血的有效刺激物。内毒素是革兰氏阴性菌的组成部分，通过髓样细胞中的 Toll 样受体 4 信号通路引发先天免疫反应。我们评估了两种剂量的埃替拉滨四钠（E5564）的安全性和耐受性，埃替拉滨四钠是一种合成的 Toll 样受体 4 拮抗剂，并探讨了它是否降低了严重脓毒症患者 28 天的死亡率。
前瞻性、随机、双盲、安慰剂对照、多中心、递增剂量 II 期试验。
美国和加拿大的成人重症监护病房。
严重脓毒症患者 12 小时内识别，急性生理学和慢性健康评估（APACHE）II 预测死亡率在 20%至 80%之间。
静脉内给予埃替拉滨四钠（45mg 或 105mg 总剂量）或安慰剂，每 12 小时给药一次，共 6 天。
接受埃替拉滨四钠 45mg 或 105mg 或安慰剂治疗的患者中，不良事件的发生率相似。对于改良意向治疗受试者，28 天全因死亡率分别为埃替拉滨四钠 105mg 组 26.6%、埃替拉滨四钠 45mg 组 32.0%和安慰剂组 33.3%。埃替拉滨四钠 105mg 组死亡率与安慰剂组无显著差异（p=0.335）。在预先指定的亚组中，按急性生理学和慢性健康评估（APACHE）II 评分四分位值最高的死亡风险受试者中，埃替拉滨四钠 105mg 组死亡率呈下降趋势（33.3%比安慰剂组 56.3%，p=0.105）。在埃替拉滨四钠 105mg 组中，APACHE II 评分最低四分位值的受试者中，死亡率呈上升趋势（12.0%比安慰剂组 0.0%，p=0.083）。
埃替拉滨四钠治疗似乎耐受性良好。在严重脓毒症和高死亡率预测风险的患者中，观察到 105mg 剂量死亡率下降的趋势，应进一步研究。
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