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      Bosutinib reduces endothelial permeability and organ failure in a rat polytrauma transfusion model 1

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          Abstract

          Background

          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.

          Methods

          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.

          Results

          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 −1) compared with vehicle (6.1 [5.1–7.2] ml kg −1, 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).

          Conclusions

          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.

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          Most cited references 36

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          Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial.

          Severely injured patients experiencing hemorrhagic shock often require massive transfusion. Earlier transfusion with higher blood product ratios (plasma, platelets, and red blood cells), defined as damage control resuscitation, has been associated with improved outcomes; however, there have been no large multicenter clinical trials. To determine the effectiveness and safety of transfusing patients with severe trauma and major bleeding using plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio. Pragmatic, phase 3, multisite, randomized clinical trial of 680 severely injured patients who arrived at 1 of 12 level I trauma centers in North America directly from the scene and were predicted to require massive transfusion between August 2012 and December 2013. Blood product ratios of 1:1:1 (338 patients) vs 1:1:2 (342 patients) during active resuscitation in addition to all local standard-of-care interventions (uncontrolled). Primary outcomes were 24-hour and 30-day all-cause mortality. Prespecified ancillary outcomes included time to hemostasis, blood product volumes transfused, complications, incidence of surgical procedures, and functional status. No significant differences were detected in mortality at 24 hours (12.7% in 1:1:1 group vs 17.0% in 1:1:2 group; difference, -4.2% [95% CI, -9.6% to 1.1%]; P = .12) or at 30 days (22.4% vs 26.1%, respectively; difference, -3.7% [95% CI, -10.2% to 2.7%]; P = .26). Exsanguination, which was the predominant cause of death within the first 24 hours, was significantly decreased in the 1:1:1 group (9.2% vs 14.6% in 1:1:2 group; difference, -5.4% [95% CI, -10.4% to -0.5%]; P = .03). More patients in the 1:1:1 group achieved hemostasis than in the 1:1:2 group (86% vs 78%, respectively; P = .006). Despite the 1:1:1 group receiving more plasma (median of 7 U vs 5 U, P < .001) and platelets (12 U vs 6 U, P < .001) and similar amounts of red blood cells (9 U) over the first 24 hours, no differences between the 2 groups were found for the 23 prespecified complications, including acute respiratory distress syndrome, multiple organ failure, venous thromboembolism, sepsis, and transfusion-related complications. Among patients with severe trauma and major bleeding, early administration of plasma, platelets, and red blood cells in a 1:1:1 ratio compared with a 1:1:2 ratio did not result in significant differences in mortality at 24 hours or at 30 days. However, more patients in the 1:1:1 group achieved hemostasis and fewer experienced death due to exsanguination by 24 hours. Even though there was an increased use of plasma and platelets transfused in the 1:1:1 group, no other safety differences were identified between the 2 groups. clinicaltrials.gov Identifier: NCT01545232.
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            Effective treatment of edema and endothelial barrier dysfunction with imatinib.

            Tissue edema and endothelial barrier dysfunction as observed in sepsis and acute lung injury carry high morbidity and mortality, but currently lack specific therapy. In a recent case report, we described fast resolution of pulmonary edema on treatment with the tyrosine kinase inhibitor imatinib through an unknown mechanism. Here, we explored the effect of imatinib on endothelial barrier dysfunction and edema formation. We evaluated the effect of imatinib on endothelial barrier function in vitro and in vivo. In human macro- and microvascular endothelial monolayers, imatinib attenuated endothelial barrier dysfunction induced by thrombin and histamine. Small interfering RNA knock-downs of the imatinib-sensitive kinases revealed that imatinib attenuates endothelial barrier dysfunction via inhibition of Abl-related gene kinase (Arg/Abl2), a previously unknown mediator of endothelial barrier dysfunction. Indeed, Arg was activated by endothelial stimulation with thrombin, histamine, and vascular endothelial growth factor. Imatinib limited Arg-mediated endothelial barrier dysfunction by enhancing Rac1 activity and enforcing adhesion of endothelial cells to the extracellular matrix. Using mouse models of vascular leakage as proof-of-concept, we found that pretreatment with imatinib protected against vascular endothelial growth factor-induced vascular leakage in the skin, and effectively prevented edema formation in the lungs. In a murine model of sepsis, imatinib treatment (6 hours and 18 hours after induction of sepsis) attenuated vascular leakage in the kidneys and the lungs (24 hours after induction of sepsis). Thus, imatinib prevents endothelial barrier dysfunction and edema formation via inhibition of Arg. These findings identify imatinib as a promising approach to permeability edema and indicate Arg as novel target for edema treatment.
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              Prehospital Plasma during Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock

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                Author and article information

                Contributors
                Journal
                Br J Anaesth
                Br J Anaesth
                BJA: British Journal of Anaesthesia
                Elsevier
                0007-0912
                1471-6771
                06 March 2021
                May 2021
                06 March 2021
                : 126
                : 5
                : 958-966
                Affiliations
                [1 ]Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
                [2 ]Laboratory of Experimental Intensive Care and Anesthesiology, Department of Trauma Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
                [3 ]Department of Trauma Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
                [4 ]Department of Pulmonary Diseases, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
                [5 ]Department of Physiology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
                [6 ]Department of Pathology, Amsterdam Infection & Immunity Institute, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
                [7 ]Department of Pathology, Leiden University Medical Center, University of Leiden, Leiden, The Netherlands
                [8 ]Van't Hoff Institute for Molecular Sciences (HIMS), University of Amsterdam, Amsterdam, The Netherlands
                [9 ]Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
                [10 ]Department of Anesthesiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
                [11 ]Department of Intensive Care Medicine, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands
                Author notes
                []Corresponding author. d.j.kleinveld@ 123456amsterdamumc.nl
                Article
                S0007-0912(21)00090-8
                10.1016/j.bja.2021.01.032
                8258973
                33685634
                © 2021 The Author(s)

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                Categories
                Critical Care

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