de Kleijn Ester D, de Groot Ronald, Hack C Erik, Mulder Paul G H, Engl Werner, Moritz Berta, Joosten Koen F M, Hazelzet Jan A
Department of Pediatrics, Sophia Children's Hospital, Erasmus Medical Center, Rotterdam, the Netherlands.
Crit Care Med. 2003 Jun;31(6):1839-47. doi: 10.1097/01.CCM.0000072121.61120.D8.
Meningococcal septic shock in children results in high mortality and morbidity, and decreased protein C levels in these patients are associated with a poor outcome. We carried out a randomized, double-blinded, placebo-controlled study by supplying protein C concentrate. This phase 2 study was designed to assess the activation process of protein C and to study the dosing regimen of protein C concentrate in children with purpura fulminans and meningococcal septic shock in the perspective of a possible phase 3 trial.
Forty children were randomized to receive placebo or protein C concentrate (200 IU/kg, 400 IU/kg, or 600 IU/kg), for a maximum of 7 days. Clinical and laboratory data, including plasma levels of protein C and activated protein C (APC), were collected at various time points. All patients received standard therapy for septic shock, including antibiotics, inotropic/vasoactive drugs, and blood products.
Increased APC levels relative to baseline were observed for the 27 of 28 patients treated with protein C concentrate, and the areas under the curve of protein C and APC were correlated with the dosage of protein C concentrate administered. Activation of coagulation, as evidenced by d-dimer levels, as well as the ratio of thrombin vs. APC normalized significantly faster with increasing dosages of protein C concentrate. No adverse reactions related to protein C concentrate were observed. Nine of the 40 (23%) patients died, and five survivors required amputations, with no differences in these rates among the randomized groups. Baseline APC levels were positively correlated with sequential organ failure assessment and pediatric risk of mortality scores and with d-dimers, tumor necrosis factor-alpha, interleukin-1, interleukin-6, interleukin-8, plasminogen activator inhibitor-1, TAT complexes, and PAP complexes.
Treatment with protein C concentrate is safe in children with purpura fulminans and meningococcal septic shock and leads to dose-related increases of plasma APC and resolution of coagulation imbalances.
儿童脑膜炎球菌性感染性休克导致高死亡率和高发病率，这些患者蛋白C水平降低与不良预后相关。我们通过提供蛋白C浓缩物进行了一项随机、双盲、安慰剂对照研究。这项2期研究旨在评估蛋白C的激活过程，并从可能开展的3期试验角度研究蛋白C浓缩物在暴发性紫癜和脑膜炎球菌性感染性休克患儿中的给药方案。
40名儿童被随机分为接受安慰剂或蛋白C浓缩物（200 IU/kg、400 IU/kg或600 IU/kg），最长治疗7天。在不同时间点收集临床和实验室数据，包括血浆蛋白C和活化蛋白C（APC）水平。所有患者均接受感染性休克的标准治疗，包括抗生素、血管活性药物和血液制品。
在接受蛋白C浓缩物治疗的28名患者中的27名中观察到APC水平相对于基线升高，蛋白C和APC的曲线下面积与给予的蛋白C浓缩物剂量相关。随着蛋白C浓缩物剂量增加，凝血激活（以D-二聚体水平为证）以及凝血酶与APC的比率显著更快恢复正常。未观察到与蛋白C浓缩物相关的不良反应。40名患者中有9名（23%）死亡，5名幸存者需要截肢，随机分组之间这些比率无差异。基线APC水平与序贯器官衰竭评估、儿科死亡风险评分以及D-二聚体、肿瘤坏死因子-α、白细胞介素-1、白细胞介素-6、白细胞介素-8、纤溶酶原激活物抑制剂-1、凝血酶-抗凝血酶复合物和纤溶酶-抗纤溶酶复合物呈正相关。
蛋白C浓缩物治疗对暴发性紫癜和脑膜炎球菌性感染性休克患儿是安全的，并导致血浆APC剂量相关增加以及凝血失衡的缓解。
