Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Department of Integrated Neurovascular Biology, INSERM U1083, CNRS UMR 6214, LUNAM University, Université d'Angers, Angers, France.
Departments of Cardiothoracic Anesthesiology and Intensive Care Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands.
Br J Anaesth. 2018 Jun;120(6):1165-1175. doi: 10.1016/j.bja.2017.11.095. Epub 2018 Jan 17.
Cardiopulmonary bypass during cardiac surgery leads to impaired microcirculatory perfusion. We hypothesized that vascular leakage is an important contributor to microcirculatory dysfunction. Imatinib, a tyrosine kinase inhibitor, has been shown to reduce vascular leakage in septic mice. We investigated whether prevention of vascular leakage using imatinib preserves microcirculatory perfusion and reduces organ injury markers in a rat model of cardiopulmonary bypass.
Male Wistar rats underwent cardiopulmonary bypass after treatment with imatinib or vehicle (n=8 per group). Cremaster muscle microcirculatory perfusion and quadriceps microvascular oxygen saturation were measured using intravital microscopy and reflectance spectroscopy. Evans Blue extravasation was determined in separate experiments. Organ injury markers were determined in plasma, intestine, kidney, and lungs.
The onset of cardiopulmonary bypass decreased the number of perfused microvessels by 40% in the control group [9.4 (8.6-10.6) to 5.7 (4.8-6.2) per microscope field; P<0.001 vs baseline], whereas this reduction was not seen in the imatinib group. In the control group, the number of perfused capillaries remained low throughout the experiment, whilst perfusion remained normal after imatinib administration. Microvascular oxygen saturation was less impaired after imatinib treatment compared with controls. Imatinib reduced vascular leakage and decreased fluid resuscitation compared with control [3 (3-6) vs 12 ml (7-16); P=0.024]. Plasma neutrophil-gelatinase-associated-lipocalin concentrations were reduced by imatinib.
Prevention of endothelial barrier dysfunction using imatinib preserved microcirculatory perfusion and oxygenation during and after cardiopulmonary bypass. Moreover, imatinib-induced protection of endothelial barrier integrity reduced fluid-resuscitation requirements and attenuated renal and pulmonary injury markers.
心脏手术中的体外循环会导致微血管灌注受损。我们假设血管渗漏是导致微循环功能障碍的一个重要因素。伊马替尼是一种酪氨酸激酶抑制剂，已被证明可减少脓毒症小鼠的血管渗漏。我们研究了在体外循环大鼠模型中，使用伊马替尼预防血管渗漏是否可以维持微血管灌注并减少器官损伤标志物。
雄性 Wistar 大鼠在接受伊马替尼或载体治疗后（每组 8 只）进行体外循环。使用活体显微镜和反射光谱法测量提睾肌微循环灌注和股四头肌微血管氧饱和度。在单独的实验中测定伊文思蓝外渗。在血浆、肠、肾和肺中测定器官损伤标志物。
体外循环的开始使对照组显微镜视野中灌注的微血管数量减少了 40%[9.4（8.6-10.6）至 5.7（4.8-6.2）/视野；P<0.001 与基线相比]，而伊马替尼组则没有这种减少。在对照组中，灌注的毛细血管数量在整个实验过程中一直较低，而在用伊马替尼给药后灌注仍然正常。与对照组相比，伊马替尼治疗后微血管氧饱和度受损程度较小。与对照组相比，伊马替尼减少了血管渗漏并减少了液体复苏[3（3-6）与 12ml（7-16）；P=0.024]。伊马替尼降低了血浆中性粒细胞明胶酶相关脂质运载蛋白浓度。
使用伊马替尼预防内皮屏障功能障碍可在体外循环期间和之后维持微循环灌注和氧合。此外，伊马替尼诱导的内皮屏障完整性保护减少了液体复苏的需求，并减轻了肾脏和肺损伤标志物。
