Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Laboratory of Experimental Intensive Care and Anesthesiology, Department of Trauma Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands; Department of Trauma Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
Department of Pulmonary Diseases, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
Br J Anaesth. 2021 May;126(5):958-966. doi: 10.1016/j.bja.2021.01.032. Epub 2021 Mar 6.
Trauma-induced shock is associated with endothelial dysfunction. We examined whether the tyrosine kinase inhibitor bosutinib as an adjunct therapy to a balanced blood component resuscitation strategy reduces trauma-induced endothelial permeability, thereby improving shock reversal and limiting transfusion requirements and organ failure in a rat polytrauma transfusion model.
Male Sprague-Dawley rats (n=13 per group) were traumatised and exsanguinated until a MAP of 40 mm Hg was reached, then randomised to two groups: red blood cells, plasma and platelets in a 1:1:1 ratio with either bosutinib or vehicle. Controls were randomised to sham (median laparotomy, no trauma) with bosutinib or vehicle. Organs were harvested for histology and wet/dry (W/D) weight ratio.
Traumatic injury resulted in shock, with higher lactate levels compared with controls. In trauma-induced shock, the resuscitation volume needed to obtain a MAP of 60 mm Hg was lower in bosutinib-treated animals (2.8 [2.7-3.2] ml kg) compared with vehicle (6.1 [5.1-7.2] ml kg, P<0.001). Lactate levels in the bosutinib group were 2.9 [1.7-4.8] mM compared with 6.2 [3.1-14.1] mM in the vehicle group (P=0.06). Bosutinib compared with vehicle reduced lung vascular leakage (W/D ratio of 5.1 [4.6-5.3] vs 5.7 [5.4-6.0] (P=0.046) and lung injury scores (P=0.027).
Bosutinib as an adjunct therapy to a balanced transfusion strategy reduced resuscitation volume, improved shock reversal, and reduced vascular leak and organ injury in a rat polytrauma model.
创伤性休克与血管内皮功能障碍有关。我们研究了酪氨酸激酶抑制剂波舒替尼作为平衡血液成分复苏策略的辅助治疗是否可以降低创伤引起的内皮通透性，从而改善休克逆转并限制输血需求和多创伤输血模型中的器官衰竭。
雄性 Sprague-Dawley 大鼠（每组 13 只）接受创伤和放血，直至平均动脉压达到 40mmHg，然后随机分为两组：红细胞、血浆和血小板 1:1:1 比例，分别给予波舒替尼或载体。对照组随机分为假手术（中位数剖腹术，无创伤），给予波舒替尼或载体。采集器官进行组织学和湿/干（W/D）重量比检查。
创伤性损伤导致休克，与对照组相比，乳酸水平更高。在创伤性休克中，给予波舒替尼的动物需要复苏的容量才能达到 60mmHg 的平均动脉压较低（2.8[2.7-3.2]ml/kg），而给予载体的动物需要复苏的容量较高（6.1[5.1-7.2]ml/kg，P<0.001）。与载体组相比，波舒替尼组的乳酸水平为 2.9[1.7-4.8]mM，而载体组为 6.2[3.1-14.1]mM（P=0.06）。与载体相比，波舒替尼组肺血管渗漏（W/D 比 5.1[4.6-5.3]vs 5.7[5.4-6.0]（P=0.046）和肺损伤评分（P=0.027）降低。
波舒替尼作为平衡输血策略的辅助治疗可减少复苏容量，改善休克逆转，并降低大鼠多创伤模型中的血管渗漏和器官损伤。
