Demetriades D, Smith J S, Jacobson L E, Moncure M, Minei J, Nelson B J, Scannon P J
Los Angeles County/USC Medical Center, California 90033, USA.
J Trauma. 1999 Apr;46(4):667-76; discussion 676-7. doi: 10.1097/00005373-199904000-00018.
Infection and organ failure are the most common causes of death or serious complication in trauma patients surviving initial resuscitation and operation. Of the many possible causes of these complications, bacterial translocation and release of harmful cytokines and oxygen free radicals may play an important role in the pathogenesis of the complications associated with traumatic hemorrhage. Recombinant human bactericidal/permeability-increasing protein (rBPI21) has antibacterial and antiendotoxin properties, reduces cytokine levels, and increases survival in animal models of hemorrhagic shock. The primary objective of this study was to evaluate the safety and efficacy of prophylactic rBPI21 infusion in patients with hemorrhage due to trauma.
This was a phase II, multicenter, randomized, double-blind, placebo-controlled trial. Patients who required at least 2 U of blood were randomized to receive rBPI21 (4 mg x kg(-1) x d(-1) for 2 consecutive days) or an equivalent volume of placebo by continuous infusion within 12 hours of injury. The primary efficacy end point was mortality or serious complication occurring during the first 15 days of the study. Safety was monitored clinically and by laboratory panels during the study period.
A total of 401 patients were treated (202 in the rBPI21 group and 199 in the placebo group). The composite end point rate of mortality or serious complication through day 15 was 46% in the placebo group and 39% in the rBPI21 group (hazard ratio = 0.79; p = 0.13). Secondary analysis, which adjusted for age, mechanism of injury, Injury Severity Score (1990 version), and units of blood received before study drug infusion showed similar results (hazard ratio = 0.79; p = 0.14). The proportion of patients who developed at least one serious organ dysfunction was 22% in the placebo group and 16% in the rBPI21 group (hazard ratio = 0.71; p = 0.14). The proportion of patients who developed either pneumonia or acute respiratory distress syndrome was 32% in the placebo group and 22% in the rBPI21 group (hazard ratio = 0.66; post hocp = 0.03). The beneficial trends of rBPI21 were observed in both blunt and penetrating trauma and were generally observed across different age groups, Injury Severity Scores, and units of blood transfused. No treatment difference was observed in mortality or resource utilization in this phase II study.
rBPI21 was well-tolerated and demonstrated a favorable trend in reducing the composite primary end point of mortality or serious complication through day 15, especially respiratory complications, in patients with hemorrhage due to trauma. A phase III study is currently in progress.
感染和器官衰竭是创伤患者在度过初始复苏和手术后死亡或发生严重并发症的最常见原因。在这些并发症的众多可能病因中，细菌移位以及有害细胞因子和氧自由基的释放可能在创伤性出血相关并发症的发病机制中起重要作用。重组人杀菌/通透性增加蛋白（rBPI21）具有抗菌和抗内毒素特性，可降低细胞因子水平，并提高失血性休克动物模型的存活率。本研究的主要目的是评估预防性输注rBPI21对创伤性出血患者的安全性和有效性。
这是一项II期、多中心、随机、双盲、安慰剂对照试验。需要至少输注2单位血液的患者在受伤后12小时内被随机分配接受rBPI21（连续2天，4mg·kg⁻¹·d⁻¹）或等量安慰剂持续输注。主要疗效终点是研究的前15天内发生的死亡或严重并发症。在研究期间通过临床和实验室指标监测安全性。
共治疗401例患者（rBPI21组202例，安慰剂组199例）。安慰剂组至第15天的死亡或严重并发症复合终点发生率为46%，rBPI21组为39%（风险比=0.79；p=0.13）。对年龄、损伤机制、损伤严重度评分（1990版）以及研究药物输注前接受的输血量进行校正后的二次分析显示了相似结果（风险比=0.79；p=0.14）。发生至少一种严重器官功能障碍的患者比例在安慰剂组为22%，在rBPI21组为16%（风险比=0.71；p=0.14）。发生肺炎或急性呼吸窘迫综合征的患者比例在安慰剂组为32%，在rBPI21组为22%（风险比=0.66；事后检验p=0.03）。在钝性创伤和穿透性创伤中均观察到rBPI21的有益趋势，并且在不同年龄组、损伤严重度评分和输血量中普遍观察到。在这项II期研究中，未观察到死亡率或资源利用方面的治疗差异。
rBPI21耐受性良好，在降低创伤性出血患者至第15天的死亡或严重并发症复合主要终点，尤其是呼吸并发症方面显示出有利趋势。目前正在进行III期研究。
