N J Koning1, F de Lange2, M van Meurs3, R M Jongman4, Y Ahmed5, L A Schwarte6, G P van Nieuw Amerongen7, A B A Vonk8, H W Niessen9, C Baufreton10, C Boer6. 1. 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. Electronic address: n.koning@vumc.nl. 2. Departments of Cardiothoracic Anesthesiology and Intensive Care Medicine, Medical Center Leeuwarden, Leeuwarden, The Netherlands. 3. Department of Critical Care, University Medical Center Groningen, Groningen, The Netherlands. 4. Department of Critical Care, University Medical Center Groningen, Groningen, The Netherlands; Department of Anesthesiology, University Medical Center Groningen, Groningen, The Netherlands; Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands. 5. Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Department of Cardiothoracic Surgery, VU University Medical Center, Amsterdam, The Netherlands. 6. Department of Anesthesiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. 7. Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands. 8. Department of Cardiothoracic Surgery, VU University Medical Center, Amsterdam, The Netherlands. 9. Department of Cardiothoracic Surgery, VU University Medical Center, Amsterdam, The Netherlands; Department of Pathology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands. 10. Department of Cardiovascular Surgery, INSERM U1083, CNRS UMR 6214, LUNAM University, Université d'Angers, Angers, France.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
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