Antithrombin III Supplementation for Infants Undergoing Cardiac Surgery With Cardiopulmonary Bypass.
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 1
- 主要终点
- The primary hypothesis is that treatment with ATIII before bypass will decrease the activation of inflammation during CPB as measured by plasma neutrophil elastase.
研究概览
简要总结
The purpose of this study is to discern whether supplementation of Antithrombin III will decrease coagulation and inflammation associated with cardiopulmonary bypass in infants undergoing cardiac surgery.
详细描述
Cardiopulmonary bypass (CPB) and cardiovascular surgery initiate diffuse activation of coagulation, inflammation and fibrinolysis that often has deleterious effects on patient outcomes, including bleeding, transfusion, myocardial dysfunction, renal failure, pulmonary dysfunction, prolonged intubation, ICU and hospital length of stay, stroke and neurocognitive dysfunction, and mortality.Pediatric patients are especially at risk for hematologic derangement related to CPB. Not only are infants and children subject to the same diffuse activations of coagulation, inflammation, and fibrinolysis as adults, but their size, immaturity, and circulatory abnormalities secondary to congenital heart disease increase the risk of loss of hematologic homeostasis. Since an infant's blood volume is much smaller than that of the prime in the CPB pump, hemodilution alone produces impaired hemostasis related to thrombocytopenia and coagulation factor dilution The incidence of each of these complications is variable and depends on the diagnosis, operation, time on CPB and other factors.
Adequate anticoagulation during cardiopulmonary bypass (CPB) is essential to preserve the hemostatic system and ensure hemostasis after surgery. Heparin has long been the mainstay of anticoagulation for CPB, due to its ease of use, familiarity, and reversibility. For heparin to exert its anticoagulant effect, it must bind with an intrinsic cofactor, antithrombin III (ATIII) to inhibit enzymes of the intrinsic and final common coagulation pathways. It has been established that neonates have significantly decreased levels of ATIII relative to adults, and that this relative deficiency continues at least until 6 months of age. Children with congenital heart disease have further decreases in ATIII and other abnormalities of coagulation which may contribute to adverse outcomes. Given this ATIII deficiency, it is not surprising that heparin anticoagulation does not fully suppress coagulation during CPB. Neonates anticoagulated for CPB with heparin have ongoing activation of humoral and cellular coagulation with associated activation of inflammation and fibrinolysis. Improved anticoagulation may reduce activation of these cascades and improve outcomes. In addition, infants are at high risk for post cardiac surgery intervascular thrombosis. Baseline ATIII deficiency, and consumption of ATIII during bypass may contribute to a postoperative prothrombotic state esulting in this often fatal complication. ATIII supplementation may decrease this risk.
ATIII is available as a lyophilized product derived from pooled human plasma. Treatment with ATIII has been shown to improve the anticoagulant effects of heparin and attenuate activation of hemostasis and inflammation during adult CPB, and to decrease the incidence of thrombosis associated with central venous cannulation in children. The incidence of central venous thrombosis in infants undergoing cardiac surgery has been reported as 5.8 - 22% in neonates, with a resultant mortality of 20%.
The biologic half-life of antithrombin in healthy adult volunteers is 2.5 - 3.8 days. Pharmacokinetic data in neonates is not available, but biologic activity should certainly persist through the 2 highest risk periods:
CPB, where activation of coagulation produces activation of inflammation, both cellular and humoral, and fibrinolysis.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 1 Day 至 180 Days（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects will be included if they are presenting for elective cardiac surgery using cardiopulmonary bypass and are 180 days of age or less.
排除标准
- •Sensitivity to ATIII product (Thrombate, Grifols, Los Angeles, CA)
- •Known inherited or acquired coagulation defect
- •Current or prior treatment with pro-or anticoagulant medication within past 30 days (except aspirin or a single dose of heparin, e.g. for catheterization)
- •Known central venous thrombosis
- •Recent (30 days) transfusion with hemostatic blood products (fresh-frozen plasma, platelets, cryoprecipitate, whole blood)
- •wt less than 3000g
研究组 & 干预措施
Placebo
placebo (normal saline)
干预措施: Antithrombin III (Drug)
Antithrombin III
Product- Antithrombin III is derived from pooled human plasma
ATIII will be dosed using the formula recommended by the manufacturer:
(goal activity - baseline activity) x weight (kg) x .714 (Assume: start with 35% activity [7], goal 120% activity[18], so dose = 120-35 x wt (kg) x .714, e.g. 5 kg infant: 85 x 5 x .714 = 303 units)
a.
干预措施: Placebo (Drug)
结局指标
主要结局
The primary hypothesis is that treatment with ATIII before bypass will decrease the activation of inflammation during CPB as measured by plasma neutrophil elastase.
时间窗: Expected average of 24 months
Patients treated with ATIII as standard of care (good clinical practice) will remain in the study and be analyzed by their intention to treat group. Review of our clinical experience shows that treatment with ATIII for heparin resistance occurs in 2-3% of cases. If there are more than two patients so treated, we will also perform an "as-treated" analysis.
次要结局
- prothrombin fragment 1.2(expected average of 24 months)
- interleukin-6(Expected average of 24 months)
- 24 hour blood loss(24 hours post surgery)
- ICU length of stay(Expected average of 3 days)
- p-selectin(expected average of 24 months)
- Hospital length of stay(Expected average of 3 weeks)
研究者
Michael Eaton
Principal Investigator
University of Rochester