Levin M, Quint P A, Goldstein B, Barton P, Bradley J S, Shemie S D, Yeh T, Kim S S, Cafaro D P, Scannon P J, Giroir B P
Imperial College School of Medicine, Norfolk Place, London, UK.
Lancet. 2000 Sep 16;356(9234):961-7. doi: 10.1016/s0140-6736(00)02712-4.
Endotoxin is a primary trigger of the inflammatory processes that lead to shock, multiorgan failure, and purpura fulminans in meningococcal sepsis. Bactericidal/permeability-increasing protein (BPI) is a natural protein, stored within the neutrophil granules, that binds to and neutralises the effects of endotoxin in vitro, in laboratory animals, and in humans. To establish whether a recombinant 21-kDa modified fragment of human BPI (rBPI21), containing the active antimicrobial and endotoxin-neutralising moiety, would decrease death and long-term disability from meningococcal sepsis, we did a randomised, double-blind, placebo-controlled trial of rBPI21 in children with severe meningococcal sepsis.
We enrolled children (2 weeks to 18 years of age) presenting to 22 centres in the UK and the USA with a clinical picture suggestive of meningococcal sepsis, and with evidence of severe disease. Children were randomly assigned rBPI21 (2 mg/kg over 30 min followed by 2 mg/kg over 24 h) or placebo (0.2 mg/mL human albumin solution) in addition to conventional medical therapy. Primary outcome variables were mortality, amputations, and change in paediatric overall performance category (POPC) from before illness to day 60. Analysis was by intention to treat.
Of 1287 patients screened, 892 were excluded, including 57 patients who died or who met criteria for imminent death before receiving the study drug. 190 patients received rBPI21, and 203 placebo. 34 (8.7%) of 393 patients died during the study: 14 (7.4%) in the rBPI21 group and 20 (9.9%) in the placebo group (odds ratio 1.31 [95% CI 0.62-2.74], p=0.48). Compared with patients randomised to placebo, fewer patients treated with rBPI21 had multiple severe amputations (six of 190 [3.2%] vs 15 of 203 [7.4%], odds ratio 2.47 [0.94-6.51], p=0.067), and more had a functional outcome similar to that before illness (as measured by the POPC scale) at day 60 (136 of 176 [77.3%] vs 126 of 190 [66.3%], p=0.019).
Because most deaths occurred in the interval between identification of patients and study drug administration, the mortality rate in the placebo group was substantially lower than predicted. The trial was therefore underpowered to detect significant differences in mortality. However, patients receiving rBPI21 had a trend towards improved outcome in all primary outcome variables. Given the excellent severity match between placebo and rBPI21 groups at study entry, the results overall indicate that rBPI21 is beneficial in decreasing complications of meningococcal disease.
内毒素是导致脑膜炎球菌败血症患者发生休克、多器官功能衰竭及暴发性紫癜等炎症反应的主要诱因。杀菌/通透性增强蛋白（BPI）是一种天然蛋白质，储存于中性粒细胞颗粒内，在体外、实验动物及人体中均能结合并中和内毒素的作用。为确定含活性抗菌及内毒素中和部分的重组人BPI 21 kDa修饰片段（rBPI21）能否降低脑膜炎球菌败血症患儿的死亡率及长期残疾率，我们开展了一项针对重症脑膜炎球菌败血症患儿的rBPI21随机、双盲、安慰剂对照试验。
我们纳入了英国和美国22个中心出现提示脑膜炎球菌败血症临床表现且有重症疾病证据的儿童（2周龄至18岁）。除常规药物治疗外，儿童被随机分配接受rBPI21（30分钟内静脉输注2mg/kg，随后24小时内静脉输注2mg/kg）或安慰剂（0.2mg/mL人白蛋白溶液）。主要结局变量为死亡率、截肢情况以及从发病前至第60天小儿总体表现类别（POPC）的变化。分析采用意向性分析。
在1287例筛查患者中，892例被排除，其中包括57例在接受研究药物前死亡或符合濒死标准的患者。190例患者接受rBPI21治疗，203例接受安慰剂治疗。393例患者中有34例（8.7%）在研究期间死亡：rBPI21组14例（7.4%），安慰剂组20例（9.9%）（比值比1.31[95%CI 0.62 - 2.74]，p = 0.48）。与随机接受安慰剂治疗的患者相比，接受rBPI21治疗的患者发生多次严重截肢情况较少（190例中的6例[3.2%] vs 203例中的15例[7.4%]，比值比2.47[0.94 - 6.51]，p = 0.067），且在第60天时更多患者的功能结局与发病前相似（根据POPC量表测量）（176例中的136例[77.3%] vs 190例中的126例[66.3%]，p = 0.019）。
由于大多数死亡发生在识别患者与给予研究药物的间隔期，安慰剂组的死亡率远低于预期。因此该试验检测死亡率显著差异的效能不足。然而，接受rBPI21治疗的患者在所有主要结局变量上均有结局改善的趋势。鉴于安慰剂组和rBPI2治疗组在研究入组时病情严重程度匹配良好，总体结果表明rBPI21有助于降低脑膜炎球菌病的并发症。
