Plasma Restoration of Endothelial Glycocalyx in a Rodent Model of Hemorrhagic Shock

Department of Surgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Anesthesia and analgesia (Impact Factor: 3.47). 02/2011; 112(6):1289-95. DOI: 10.1213/ANE.0b013e318210385c
Source: PubMed


The use of plasma-based resuscitation for trauma patients in hemorrhagic shock has been associated with a decrease in mortality. Although some have proposed a beneficial effect through replacement of coagulation proteins, the putative mechanisms of protection afforded by plasma are unknown. We have previously shown in a cell culture model that plasma decreases endothelial cell permeability in comparison with crystalloid. The endothelial glycocalyx consists of proteoglycans and glycoproteins attached to a syndecan backbone, which together protect the underlying endothelium. We hypothesize that endothelial cell protection by plasma is due, in part, to its restoration of the endothelial glycocalyx and preservation of syndecan-1 after hemorrhagic shock.
Rats were subjected to hemorrhagic shock to a mean arterial blood pressure of 30 mm Hg for 90 minutes followed by resuscitation with either lactated Ringer's (LR) solution or fresh plasma to a mean arterial blood pressure of 80 mm Hg and compared with shams or shock alone. After 2 hours, lungs were harvested for syndecan mRNA, immunostained with antisyndecan-1, or stained with hematoxylin and eosin. To specifically examine the effect of plasma on the endothelium, we infused small bowel mesentery with a lanthanum-based solution, identified venules, and visualized the glycocalyx by electron microscopy. All data are presented as mean ± SEM. Results were analyzed by 1-way analysis of variance with Tukey post hoc tests.
Electron microscopy revealed degradation of the glycocalyx after hemorrhagic shock, which was partially restored by plasma but not LR. Pulmonary syndecan-1 mRNA expression was higher in animals resuscitated with plasma (2.76 ± 0.03) in comparison with shock alone (1.39 ± 0.22) or LR (0.82 ± 0.03) and correlated with cell surface syndecan-1 immunostaining. Shock also resulted in significant lung injury by histopathology scoring (1.63 ± 0.26), which was mitigated by resuscitation with plasma (0.67 ± 0.17) but not LR (2.0 ± 0.25).
The protective effects of plasma may be due in part to its ability to restore the endothelial glycocalyx and preserve syndecan-1 after hemorrhagic shock.

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    • "Shock-mediated injury of the vascular endothelium has been examined as a mechanism of TAC. This injury also includes disruption of the covering glycocalyx throughout the vascular space [60] [61] [62] [63] [64]. Negatively charged proteoglycans, glycoproteins, and glycolipids, including significant amounts of heparin-like molecules [65,66] of the glycocalyx have a dynamic role in a number of endothelial cell functions [67]. "
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    ABSTRACT: The early recognition and management of hemorrhage shock are among the most difficult tasks challenging the clinician during primary assessment of the acutely bleeding patient. Often with little time, within a chaotic setting, and without sufficient clinical data, a decision must be reached to begin transfusion of blood components in massive amounts. The practice of massive transfusion has advanced considerably and is now a more complete and, arguably, more effective process. This new therapeutic paradigm, referred to as damage control resuscitation (DCR), differs considerably in many important respects from previous management strategies for catastrophic blood loss. We review several important elements of DCR including immediate correction of specific coagulopathies induced by hemorrhage and management of several extreme homeostatic imbalances that may appear in the aftermath of resuscitation. We also emphasize that the foremost objective in managing exsanguinating hemorrhage is always expedient and definitive control of the source of bleeding. Copyright © 2015. Published by Elsevier Ltd.
    Blood Reviews 01/2015; 46(4). DOI:10.1016/j.blre.2014.12.006 · 5.57 Impact Factor
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    • "Rapid reconstitution of the vascular volume may thus induce increased atrial stretching and ANP release, directly inducing glycococalyx shedding and increased fluid extravasation. Of note, recent evidence suggests that FFP may protect or even reconstitute the endothelial glycocalyx [29],[30], which may account for the less pronounced fluid extravasation observed in the FFP groups in this study. "
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    ABSTRACT: Background Optimal fluid resuscitation strategy following combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remain controversial and the effect of resuscitation infusion speed on outcome is not well known. We have previously reported that bolus infusion of fresh frozen plasma (FFP) protects the brain compared with bolus infusion of 0.9% normal saline (NS). We now hypothesize reducing resuscitation infusion speed through a stepwise infusion speed increment protocol using either FFP or NS would provide neuroprotection compared with a high speed resuscitation protocol.Methods23 Yorkshire swine underwent a protocol of computer controlled TBI and 40% hemorrhage. Animals were left in shock (mean arterial pressure of 35 mmHg) for two hours prior to resuscitation with bolus FFP (n¿=¿5, 50 ml/min) or stepwise infusion speed increment FFP (n¿=¿6), bolus NS (n¿=¿5, 165 ml/min) or stepwise infusion speed increment NS (n¿=¿7). Hemodynamic variables over a 6-hour observation phase were recorded. Following euthanasia, brains were harvested and lesion size as well as brain swelling was measured.ResultsBolus FFP resuscitation resulted in greater brain swelling (22.36¿±¿1.03% vs. 15.58¿±¿2.52%, p¿=¿0.04), but similar lesion size compared with stepwise resuscitation. This was associated with a lower cardiac output (CO: 4.81¿±¿1.50 l/min vs. 5.45¿±¿1.14 l/min, p¿=¿0.03). In the NS groups, bolus infusion resulted in both increased brain swelling (37.24¿±¿1.63% vs. 26.74¿±¿1.33%, p¿=¿0.05) as well as lesion size (3285.44¿±¿130.81 mm3 vs. 2509.41¿±¿297.44 mm3, p¿=¿0.04). This was also associated with decreased cardiac output (NS: 4.37¿±¿0.12 l/min vs. 6.35¿±¿0.10 l/min, p¿<¿0.01).Conclusions In this clinically relevant model of combined TBI and HS, stepwise resuscitation protected the brain compared with bolus resuscitation.
    Scandinavian Journal of Trauma Resuscitation and Emergency Medicine 08/2014; 22(1):46. DOI:10.1186/s13049-014-0046-2 · 2.03 Impact Factor
    • "Also, given that ACT is associated with endothelial damage[31] and glycocalyx degradation,[32] it is notable that freshly thawed FFP exerts a protective effect on the endothelium and glycocalyx and reduces its permeability in animal models of hemorrhagic shock models.[3334] It could be speculated that early administration of high levels of freshly thawed FFP in patients with acute traumatic coagulopathy may contribute to improved survival by protecting the endothelium and thereby attenuating the downstream organ damage associated with capillary leakage. "
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    ABSTRACT: Continued hemorrhage remains a major contributor of mortality in massively transfused patients and controversy regarding the optimal management exists although recently, the concept of hemostatic resuscitation, i.e., providing large amount of blood products to critically injured patients in an immediate and sustained manner as part of an early massive transfusion protocol has been introduced. The aim of the present review was to investigate the potential effect on survival of proactive administration of plasma and/or platelets (PLT) in trauma patients with massive bleeding. English databases were searched for reports of trauma patients receiving massive transfusion (10 or more red blood cell (RBC) within 24 hours or less from admission) that tested the effects of administration of plasma and/or PLT in relation to RBC concentrates on survival from January 2005 to November 2010. Comparison between highest vs lowest blood product ratios and 30-day mortality was performed. Sixteen studies encompassing 3,663 patients receiving high vs low ratios were included. This meta-analysis of the pooled results revealed a substantial statistical heterogeneity (I(2) = 58%) and that the highest ratio of plasma and/or PLT or to RBC was associated with a significantly decreased mortality (OR: 0.49; 95% confidence interval: 0.43-0.57; P<0.0001) when compared with lowest ratio. Meta-analysis of 16 retrospective studies concerning massively transfused trauma patients confirms a significantly lower mortality in patients treated with the highest fresh frozen plasma (FFP) and/or PLT ratio when compared with the lowest FFP and/or PLT ratio. However, optimal ranges of FFP: RBC and PLT : RBC should be established in randomized controlled trials.
    Journal of Emergencies Trauma and Shock 04/2012; 5(2):120-5. DOI:10.4103/0974-2700.96479
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