Division of Critical Care Medicine, Phoenix Children's Hospital, Phoenix, AZ, USA.
Pediatr Crit Care Med. 2012 Nov;13(6):639-45. doi: 10.1097/PCC.0b013e318250ad48.
REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE), a phase III trial of drotrecogin alfa (activated) in pediatric severe sepsis, examined biomarker changes in inflammation and coagulation. This report describes biomarker profiles in early severe sepsis and the pharmacodynamic assessment of drotrecogin alfa (activated) in RESOLVE.
Serial measurements of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tissue necrosis factor-α, procalcitonin, D-dimer, and thrombin-antithrombin complex were performed at baseline and daily over the first five study days. Protein C levels were performed at baseline and at the end of the 96-hr study drug infusion. Analysis of variance-based log-transformed data compared the treatment groups for each measured variable.
: One hundred four pediatric intensive care units in 18 countries.
Four hundred seventy-seven children between 38 wks corrected gestational age and 17 yrs with sepsis-induced cardiovascular and respiratory dysfunction.
Drotrecogin alfa (activated).
Pharmacodynamic activity of drotrecogin alfa (activated) compared with placebo was observed with reduction of D-dimer on day 1 (p < .01) and thrombin-antithrombin complex on days 1-4 (p < .05). There were no significant changes by treatment in multiple cytokines or procalcitonin. In the overall population, a median protein C difference was not observed (p > .05) with drotrecogin alfa (activated) administration compared with placebo, although a difference (median percentage change from baseline) in favor of drotrecogin alfa (activated) was observed in patients >1 yr old (p = .0449).
While children in the RESOLVE trial were similar to adults in that they showed a relationship between severity of coagulation and inflammation abnormalities and mortality, their pharmacodynamic response to drotrecogin alfa (activated) differed with respect to changes in protein C activity and systemic inflammation.
研究严重脓毒症和儿童器官功能障碍：全球视角（RESOLVE），一项儿科严重脓毒症中使用活化的打洛替戈汀的 III 期试验，研究了炎症和凝血的生物标志物变化。本报告描述了早期严重脓毒症中的生物标志物特征，以及 RESOLVE 中活化的打洛替戈汀的药效学评估。
在基线和研究药物输注的前 5 天每天进行白细胞介素-1β、白细胞介素-6、白细胞介素-8、白细胞介素-10、肿瘤坏死因子-α、降钙素原、D-二聚体和凝血酶-抗凝血酶复合物的连续测量。蛋白 C 水平在基线和 96 小时研究药物输注结束时进行测量。基于方差分析的对数转换数据比较了治疗组的每个测量变量。
18 个国家的 104 个儿科重症监护病房。
477 名胎龄 38 周纠正至 17 岁的伴有脓毒症引起的心血管和呼吸功能障碍的儿童。
打洛替戈汀（活化）。
与安慰剂相比，观察到活化的打洛替戈汀的药效学活性，表现在第 1 天 D-二聚体降低（p <.01）和第 1-4 天凝血酶-抗凝血酶复合物降低（p <.05）。治疗组在多种细胞因子或降钙素原方面没有显著变化。在整个人群中，与安慰剂相比，未观察到活化的打洛替戈汀给药后蛋白 C 的中位数差异（p >.05），尽管在>1 岁的患者中观察到有利于活化的打洛替戈汀的差异（从基线的中位数百分比变化）（p =.0449）。
虽然 RESOLVE 试验中的儿童与成人相似，即他们表现出凝血和炎症异常与死亡率之间的关系，但他们对活化的打洛替戈汀的药效学反应在蛋白 C 活性和全身炎症方面有所不同。
