Prevention of central venous catheter-associated thrombosis in critically ill children

项目总结 危重疾病、高凝状态和中心静脉导管的存在是最常见的两种情况。 儿童深静脉血栓形成的重要危险因素。导管相关性深静脉血栓形成 (CADVT)与重症监护病房住院时间的延长、护理成本的增加以及 肺栓塞和死亡的风险增加。然而，鉴于缺乏证据证明有益， 不建议在儿童中预防CADVT。提供预防措施的建议 在没有儿科证据的情况下，危重成人的抗血栓药物不应常规应用于儿童 因为成人和儿童的止血系统和合并症有很大不同。随机化 迫切需要对照试验来确定预防性抗凝是否可以安全地预防 危重患儿的CADVT。然而，实现这一目标所需的抗凝时间和水平是 不清楚。该R21应用的目标是评估早期预防的有效性，在标准剂量下， 在危重儿童中对抗CADVT，以确定是否应该在3期试验中进一步测试。我们将使用 依诺肝素是儿童的标准预防药物，通过调整抗Xa水平来实现这一目标。 目的1是获得早期预防对老年人CADVT发病率影响的初步证据。 病情危重的儿童。我们假设，在危重儿童中，在24小时后实施预防措施 与不插入导管相比，插入导管可降低超声诊断的CADVT的发生率 预防措施。CADVT的自然病史和先前的试验表明，需要进行预防 &lt；在插入导管24小时后，以防止CADVT。我们建议进行2b期试验，让儿童 使用新插入的中心静脉导管进入重症监护室的患者将被随机分配到标准 预防性剂量依诺肝素与不预防性比较。我们将使用贝叶斯决策理论范式来 决定是否继续使用标准剂量的依诺肝素进行早期预防的3期试验。 目的2是评价抗Xa水平导向的预防策略对凝血酶生成的影响 在危重儿童身上。我们假设，在危重儿童中，标准预防性剂量的 由抗Xa抗体水平调节的依诺肝素可将凝血酶的生成减少到700毫微米。 内源性凝血酶潜力。凝血酶的生成是最好的，它评估抗凝水平。 以内源性凝血酶潜力衡量。在非危重成人中，预防性剂量的依诺肝素被证明 防止血栓形成，降低内源性凝血酶潜力至700毫微米/分。我们提出了一个纵向的 在2b期试验中测量所有儿童在多个时间点的内源性凝血酶潜力的研究。 贝叶斯推理将用于通知第三阶段试验可能需要的剂量修改。 这项拟议的研究对当前预防儿童CADVT的范例提出了挑战。 我们的发现将为早期预防CADVT的儿科3期试验的成功和设计提供参考。

PROJECT SUMMARY Critical illness, a hypercoagulable state, and the presence of a central venous catheter are the 2 most important risk factors for deep venous thrombosis in children. Catheter-associated deep venous thrombosis (CADVT) is associated with increased length of stay in the intensive care unit, increased cost of care, and increased risks of pulmonary embolism and death. Yet, given the lack of evidence to demonstrate benefit, prophylaxis against CADVT is not recommended in children. The recommendation to provide prophylaxis against thrombosis in critically ill adults should not be routinely applied to children without pediatric evidence because the hemostatic system and co-morbidities vastly differ between adults and children. Randomized controlled trials are urgently needed to determine whether prophylactic anticoagulation can safely prevent CADVT in critically ill children. However, the timing and level of anticoagulation needed to achieve this are unclear. The goal of this R21 application is to assess the efficacy of early prophylaxis, at standard dose, against CADVT in critically ill children to determine if it should be further tested in a phase 3 trial. We will use enoxaparin, the standard prophylaxis in children, adjusted by anti-Xa level to achieve this goal. Aim 1 is to obtain preliminary evidence on the effect of early prophylaxis on the incidence of CADVT in critically ill children. We hypothesize that among critically ill children, prophylaxis administered <24 hours after insertion of the catheter decreases the incidence of ultrasound-diagnosed CADVT compared with no prophylaxis. The natural history of CADVT and prior trials suggest that prophylaxis needs to be administered <24 hours after the insertion of the catheter to prevent CADVT. We propose a phase 2b trial in which children admitted to the intensive care unit with a newly inserted central venous catheter will be randomized to standard prophylactic dose of enoxaparin vs. no prophylaxis. We will use Bayesian decision-theoretic paradigm to decide whether to proceed with a phase 3 trial of early prophylaxis with enoxaparin at standard dosing. Aim 2 is to evaluate the effect of an anti-Xa level-directed prophylactic strategy on thrombin generation in critically ill children. We hypothesize that among critically ill children, standard prophylactic dose of enoxaparin adjusted by anti-Xa level reduces thrombin generation to <700 nM.min, as measured by endogenous thrombin potential. Thrombin generation, which assesses the level of anticoagulation, is best measured by endogenous thrombin potential. In non-critically ill adults, prophylactic dose of enoxaparin proven to prevent thrombosis reduces endogenous thrombin potential to <700 nM.min. We propose a longitudinal study measuring endogenous thrombin potential at multiple time points in all children in the phase 2b trial. Bayesian inference will be used to inform of modifications in dosing that may be needed for a phase 3 trial. The proposed research challenges the current paradigm on prophylaxis against CADVT in children. Our findings will inform the success and design of a pediatric phase 3 trial of early prophylaxis against CADVT.