Endotheliopathy Of Trauma Research Articles

Characterising practice patterns of human derived, lyophilized coagulation concentrates within the trauma quality improvement program registry.

We seek to describe the current practice pattern use of prothrombin complex concentrate (PCC) and fibrinogen concentrate (FC) in trauma patients. Trauma-induced coagulopathy (TIC) and endotheliopathy of trauma (EOT) contribute significantly to mortality from traumatic haemorrhage. FC, and 4-factor PCC are potential treatments for EOT and TIC, respectively. We obtained data from the Trauma Quality Improvement Program (TQIP) registry and identified patients who received either PCC or FC using procedural codes. We used descriptive statistics to characterise practice patterns of these products. There were 6 714 002 total encounters within the TQIP from 2017 to 2022, of which 10 589 received PCC and 3009 received FC. Of the recipients, there were 35 that received both products. There were 44 that received both. The median age of PCC recipients was 77 (69-84) with 19 patients <15 years of age with the youngest being 2 years of age. There was a general upward trend in the number of facilities with documented use of PCC: 155/744, 168/766, 189/764, 206/780, 234/795, and 235/816, respectively. The median age of FC recipients was 57 (32-75) with 48 patients <15 years of age with the youngest being 1 year of age. There was a minor downward trend in the number of facilities that had documented use of FC: 55, 44, 39, 32, 38 and 40. The administration of PCC and FC remains uncommon, although there appears to be an upward trend of PCC use. Most PCC use appeared to be for anticoagulation reversal in the setting of head trauma. Data guiding the use of these products are necessary as these products become more recognised as adjuncts to traumatic haemorrhage control.

Regulation of vascular endothelial integrity by mesenchymal stem cell extracellular vesicles after hemorrhagic shock and trauma

BackgroundPatients with hemorrhagic shock and trauma (HS/T) are vulnerable to the endotheliopathy of trauma (EOT), characterized by vascular barrier dysfunction, inflammation, and coagulopathy. Cellular therapies such as mesenchymal stem cells (MSCs) and MSC extracellular vesicles (EVs) have been proposed as potential therapies targeting the EOT. In this study we investigated the effects of MSCs and MSC EVs on endothelial and epithelial barrier integrity in vitro and in vivo in a mouse model of HS/T. This study addresses the systemic effects of HS/T on multiorgan EOT.MethodsIn vitro, pulmonary endothelial cell (PEC) and Caco-2 intestinal epithelial cell monolayers were treated with control media, MSC conditioned media (CM), or MSC EVs in varying doses and subjected to a thrombin or hydrogen peroxide (H2O2) challenge, respectively. Monolayer permeability was evaluated with a cell impedance assay, and intercellular junction integrity was evaluated with immunofluorescent staining. In vivo, a mouse model of HS/T was used to evaluate the effects of lactated Ringer’s (LR), MSCs, and MSC EVs on endothelial and epithelial intercellular junctions in the lung and small intestine as well as on plasma inflammatory biomarkers.ResultsMSC EVs and MSC CM attenuated permeability and preserved intercellular junctions of the PEC monolayer in vitro, whereas only MSC CM was protective of the Caco-2 epithelial monolayer. In vivo, both MSC EVs and MSCs mitigated the loss of endothelial adherens junctions in the lung and small intestine, though only MSCs had a protective effect on epithelial tight junctions in the lung. Several plasma biomarkers including MMP8 and VEGF were elevated in LR- and EV-treated but not MSC-treated mice.ConclusionsIn conclusion, MSC EVs could be a potential cell-free therapy targeting endotheliopathy after HS/T via preservation of the vascular endothelial barrier in multiple organs early after injury. Further research is needed to better understand the immunomodulatory effects of these products following HS/T and to move toward translating these therapies into clinical studies.

Cytoprotective 3K3A-activated protein C and plasma: A comparison of therapeutics for the endotheliopathy of trauma.

Both healthy plasma and cytoprotective aPC (3K3A-aPC) have been shown to mitigate the endotheliopathy of trauma (EoT), but optimal therapeutics remain unknown. Our aim was therefore to determine optimal therapies to mitigate EoT by investigating the effectiveness of 3K3A-aPC with and without plasma-based resuscitation strategies. Electric cell-substrate impedance sensing (ECIS) was used to measure real-time permeability changes in endothelial cells. Cells were treated with a 2 μg/mL solution of aPC 30 minutes prior to stimulation with plasma taken from severely injured trauma patients (ISS > 15 and BD < -6) (TP). Healthy plasma, or plasma frozen within 24 hours (FP24), was added concomitantly with TP. Cells treated with thrombin and untreated cells were included in this study as control groups. A dose-dependent difference was found between the 5% and 10% plasma-treated groups when HUVECs were simultaneously stimulated with TP (μd 7.346 95%CI 4.574 to 10.12). There was no difference when compared to TP alone in the 5% (μd 5.713 95%CI -1.751 to 13.18) or 10% group (μd -1.633 95%CI -9.097 to 5.832). When 3K3A-aPC was added to plasma and TP, the 5% group showed improvement in permeability compared to TP alone (μd 10.11 95%CI 2.642 to 17.57), but there was no difference in the 10% group (μd -1.394 95%CI -8.859 to 6.070). The combination of 3K3A-aPC, plasma, and TP at both the 5% plasma (μd -28.52 95%CI-34.72 to -22.32) and 10% plasma concentrations (μd -40.02 95%CI -46.22 to -33.82) had higher inter-cellular permeability than the 3K3A-aPC pre-incubation group. Our data shows that FP24, in a post-trauma environment, pre-treatment with 3K3A-aPC can potentially mitigate the EoT to a greater degree than FP24 with or without 3K3A-aPC. Although further exploration is needed, this represents a potentially ideal and perhaps superior therapeutic treatment for the dysregulated thromboinflammation of injured patients. Prognostic/Epidemiological, Therapeutic/Care Management, Level III.

Blood failure: traumatic hemorrhage and the interconnections between oxygen debt, endotheliopathy, and coagulopathy.

This review explores the concept of "blood failure" in traumatic injury, which arises from the interplay of oxygen debt, the endotheliopathy of trauma (EoT), and acute traumatic coagulopathy (ATC). Traumatic hemorrhage leads to the accumulation of oxygen debt, which can further exacerbate hemorrhage by triggering a cascade of events when severe. Such events include EoT, characterized by endothelial glycocalyx damage, and ATC, involving platelet dysfunction, fibrinogen depletion, and dysregulated fibrinolysis. To manage blood failure effectively, a multifaceted approach is crucial. Damage control resuscitation strategies such as use of permissive hypotension, early hemorrhage control, and aggressive transfusion of blood products including whole blood aim to minimize oxygen debt and promote its repayment while addressing endothelial damage and coagulation. Transfusions of red blood cells, plasma, and platelets, as well as the use of tranexamic acid, play key roles in hemostasis and countering ATC. Whole blood, whether fresh or cold-stored, is emerging as a promising option to address multiple needs in traumatic hemorrhage. This review underscores the intricate relationships between oxygen debt, EoT, and ATC and highlights the importance of comprehensive, integrated strategies in the management of traumatic hemorrhage to prevent blood failure. A multidisciplinary approach is essential to address these interconnected factors effectively and to improve patient outcomes.

Endotheliopathy of trauma in children: The association of syndecan-1 with injury and poor outcomes.

The contribution of the endothelium to trauma-induced coagulopathy has not been thoroughly investigated in injured children. This is a prospective cohort study of children (younger than 18 years) who presented with a potentially severe injury to an academic pediatric trauma center. Syndecan-1 level was collected on arrival and 24 hours following hospital arrival. Children were categorized as injured versus uninjured based on results of trauma evaluation. Demographics, injury characteristics, vital signs, and clinical laboratories were recorded. A composite clinical outcome was defined as death or blood product transfusion within 24 hours of hospital arrival. Statistical tests determined the impact of injury characteristics and therapeutics on syndecan-1 levels and assessed for associations between syndecan-1 level and outcomes. A total of 121 subjects were included in the analysis: 96 injured (79%) and 25 uninjured (21%). There were no differences between groups in age (median [interquartile range (IQR)], 11 [4-14] years), sex, or race. The injured cohort had a median (IQR) Injury Severity Score of 16 (9-21), 75% had blunt mechanism, 26% were transfused within 6 hours, 3% had 24-hour mortality, and 6% had in-hospital mortality. Median (IQR) syndecan-1 level on admission was significantly higher in injured versus uninjured cohort (44 [21-75] vs. 25 [17-42]; p = 0.04). Admission base deficit was significantly correlated with syndecan-1 level ( r = 0.8, p < 0.001); no association with traumatic brain injury or injury mechanism was seen. Children with elevated syndecan-1 on admission had significantly increased odds of poor outcome; every 10 ng/mL increase in syndecan-1 was associated with 10% increased odds of death or transfusion ( p < 0.001). Transfusion with any blood product was associated with a significant decrease in syndecan-1 from arrival to 24 hours (Δ syndecan-1, -17 [-64 to -5] vs. -8 [-19 to +2]; p < 0001). Elevated admission syndecan-1 level, suggestive of endotheliopathy, was associated with shock and poor outcomes in pediatric trauma. Larger cohort studies are required to fully describe the complexities of trauma-induced coagulopathy and investigate the benefit of therapies targeting endotheliopathy in children. Prognostic and Epidemiological; Level III.

Experimental Models of Traumatic Injuries: Do They Capture the Coagulopathy and Underlying Endotheliopathy Induced by Human Trauma?

Trauma-induced coagulopathy (TIC) is a major cause of morbidity and mortality in patients with traumatic injury. It describes the spectrum of coagulation abnormalities that occur because of the trauma itself and the body's response to the trauma. These coagulation abnormalities range from hypocoagulability and hyperfibrinolysis, resulting in potentially fatal bleeding, in the early stages of trauma to hypercoagulability, leading to widespread clot formation, in the later stages. Pathological changes in the vascular endothelium and its regulation of haemostasis, a phenomenon known as the endotheliopathy of trauma (EoT), are thought to underlie TIC. Our understanding of EoT and its contribution to TIC remains in its infancy largely due to the scarcity of experimental research. This review discusses the mechanisms employed by the vascular endothelium to regulate haemostasis and their dysregulation following traumatic injury before providing an overview of the available experimental in vitro and in vivo models of trauma and their applicability for the study of the EoT and its contribution to TIC.

Early lyophilized cryoprecipitate enhances the ADAMTS13/VWF ratio to reduce systemic endotheliopathy and lessen lung injury in a mouse multiple-trauma hemorrhage model.

Recent studies in severely injured patients suggest an important role of von Willebrand Factor (VWF) and ADAMTS13 in the endotheliopathy of trauma (EoT). We hypothesized that the early use of cryoprecipitate would be effective as an endothelial protector by supplementing physiologic VWF and ADAMTS13 to reverse the EoT. We tested a pathogen-reduced lyophilized cryoprecipitate (LPRC) that could expedite the early administration of cryoprecipitate in the battlefield. A mouse multiple-trauma model with uncontrolled hemorrhage (UCH) from liver injury was utilized followed by hypotensive resuscitation (mean arterial pressure, 55-60) × 3 hours with lactated Ringer's (LR), fresh frozen plasma (FFP), conventional pathogen-reduced cryoprecipitate (CC), and LPRC. Blood was collected for measurement of syndecan-1, VWF, and ADAMTS13 by ELISA. Lungs were stained for histopathologic injury and syndecan-1 and bronchial alveolar lavage (BAL) fluid harvested for protein as an indicator of permeability. Statistical analysis was by ANOVA followed by Bonferroni correction. Following multiple trauma and UCH, blood loss was similar across groups. Mean volume of resuscitation was higher in the LR group compared with the other resuscitation groups. Lung histopathologic injury, syndecan-1 immunostaining and BAL protein were higher with LR compared with resuscitation with FFP and CC, while LPRC further reduced BAL compared with FFP and CC. The ADAMTS13/VWF ratio was significantly lower in LR but improved with FFP and CC, comparable to shams while LPRC further increased this ratio. The protective effects of CC and LPRC were comparable to FFP in ameliorating the EoT in our murine multiple trauma and UCH model. Lyophilized cryoprecipitate may also provide additional benefit by enhancing the ADAMTS13/VWF ratio. These data provide evidence of the safety and efficacy of LPRC and warrants further investigation for its potential application in military settings once approved for human administration.

SHOCK INDUCES ENDOTHELIAL PERMEABILITY AFTER TRAUMA THROUGH INCREASED ACTIVATION OF RHOA GTPASE.

Introduction: Severely injured patients develop a dysregulated inflammatory state characterized by vascular endothelial permeability, which contributes to multiple organ failure. To date, however, the mediators of and mechanisms for this permeability are not well established. Endothelial permeability in other inflammatory states such as sepsis is driven primarily by overactivation of the RhoA GTPase. We hypothesized that tissue injury and shock drive endothelial permeability after trauma by increased RhoA activation leading to break down of endothelial tight and adherens junctions. Methods: Human umbilical vein endothelial cells (HUVECs) were grown to confluence, whereas continuous resistance was measured using electrical cell-substrate impedance sensing (ECIS) Z-Theta technology, 10% ex vivo plasma from severely injured trauma patients was added, and resistance measurements continued for 2 hours. Areas under the curve (AUCs) were calculated from resistance curves. For GTPase activity analysis, HUVECs were grown to confluence and incubated with 10% trauma plasma for 5 minutes before harvesting of cell lysates. Rho and Rac activity were determined using a G-LISA assay. Significance was determined using Mann-Whitney tests or Kruskal-Wallis test, and Spearman ρ was calculated for correlations. Results: Plasma from severely injured patients induces endothelial permeability with plasma from patients with both severe injury and shock contributing most to this increased permeability. Surprisingly, Injury Severity Score (ISS) does not correlate with in vitro trauma-induced permeability (-0.05, P > 0.05), whereas base excess (BE) does correlate with permeability (-0.47, P = 0.0001). The combined impact of shock and injury resulted in a significantly smaller AUC in the injury + shock group (ISS > 15, BE < -9) compared with the injury only (ISS > 15, BE > -9; P = 0.04) or minimally injured (ISS < 15, BE > -9; P = 0.005) groups. In addition, incubation with injury + shock plasma resulted in higher RhoA activation ( P = 0.002) and a trend toward decreased Rac1 activation ( P = 0.07) compared with minimally injured control. Conclusions: Over the past decade, improved early survival in patients with severe trauma and hemorrhagic shock has led to a renewed focus on the endotheliopathy of trauma. This study presents the largest study to date measuring endothelial permeability in vitro using plasma collected from patients after traumatic injury. Here, we demonstrate that plasma from patients who develop shock after severe traumatic injury induces endothelial permeability and increased RhoA activation in vitro . Our ECIS model of trauma-induced permeability using ex vivo plasma has potential as a high throughput screening tool to phenotype endothelial dysfunction, study mediators of trauma-induced permeability, and screen potential interventions.

Metabolic systems analysis identifies a novel mechanism contributing to shock in patients with endotheliopathy of trauma (EoT) involving thromboxane A2 and LTC4

PurposeEndotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality. Increased shedding of the glycocalyx points toward the endothelial cell membrane composition as important for the clinical outcome being the rationale for this study. ResultsThe plasma metabolome of 95 severely injured trauma patients was investigated by mass spectrometry, and patients with EoT vs. non-EoT were compared by partial least square-discriminant analysis, identifying succinic acid as the top metabolite to differentiate EoT and non-EoT patients (VIP score = 3). EoT and non-EoT patients’ metabolic flux profile was inferred by integrating the corresponding plasma metabolome data into a genome-scale metabolic network reconstruction analysis and performing a functional study of the metabolic capabilities of each group. Model predictions showed a decrease in cholesterol metabolism secondary to impaired mevalonate synthesis in EoT compared to non-EoT patients. Intracellular task analysis indicated decreased synthesis of thromboxanA2 and leukotrienes, as well as a lower carnitine palmitoyltransferase I activity in EoT compared to non-EoT patients. Sensitivity analysis also showed a significantly high dependence of eicosanoid-associated metabolic tasks on alpha-linolenic acid as unique to EoT patients. ConclusionsModel-driven analysis of the endothelial cells’ metabolism identified potential novel targets as impaired thromboxane A2 and leukotriene synthesis in EoT patients when compared to non-EoT patients. Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings.

Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma.

Background: The endotheliopathy of trauma (EoT) is associated with increased mortality following injury. Herein, we describe the plasma proteome related to EoT in order to provide insight into the role of the endothelium within the systemic response to trauma. Methods: 99 subjects requiring the highest level of trauma activation were included in the study. Enzyme-linked immunosorbent assays of endothelial and catecholamine biomarkers were performed on admission plasma samples, as well as untargeted proteome quantification utilizing high-performance liquid chromatography and tandem mass spectrometry. Results: Plasma endothelial and catecholamine biomarker abundance was elevated in EoT. Patients with EoT (n = 62) had an increased incidence of death within 24 h at 21% compared to 3% for non-EoT (n = 37). Proteomic analysis revealed that 52 out of 290 proteins were differentially expressed between the EoT and non-EoT groups. These proteins are involved in endothelial activation, coagulation, inflammation, and oxidative stress, and include known damage-associated molecular patterns (DAMPs) and intracellular proteins specific to several organs. Conclusions: We report a proteomic profile of EoT suggestive of a surge of DAMPs and inflammation driving nonspecific activation of the endothelial, coagulation, and complement systems with subsequent end-organ damage and poor clinical outcome. These findings support the utility of EoT as an index of cellular injury and delineate protein candidates for therapeutic intervention.

Defining Endotheliopathy in Murine Polytrauma Models.

"Endotheliopathy of trauma" is recognized as endothelial dysfunction following traumatic injury leading to poor patient outcomes. Acute post-traumatic disruptions in endothelial cell function have been associated with profound physiologic, hemodynamic, and coagulation derangements. The goal of this study was to define the generation and extent of endotheliopathy in murine polytrauma models by evaluating the post-traumatic release of serum biomarkers of ongoing cellular injury. Mice were randomized to undergo moderately severe concussive TBI by weight drop, 60-min hemorrhagic shock to MAP 25 mmHg with subsequent resuscitation with Lactated Ringer's, submandibular bleed (SMB), and/or midline laparotomy with rectus muscle crush. Mice were sacrificed at 1, 4, or 24 h for serum biomarker evaluation. Serum biomarkers revealed differential timing of elevation and injury-dependent release.At 24 h, soluble thrombomodulin was significantly elevated in combined TBI + shock + lap crush compared to untouched, and shock alone. Syndecan-1 levels were significantly elevated after shock 1 to 24 h compared to untouched cohorts with a significant elevation in TBI + shock + lap crush 24 h after injury compared to shock alone. UCHL-1 was significantly elevated in shock mice at 1 to 24 h post-injury compared to untouched mice. UCHL-1 was also significantly elevated in the TBI + shock cohort 24 h after injury compared to shock alone. Hyaluronic acid release at 4 h was significantly elevated in shock alone compared to the untouched cohort with further elevations in TBI + shock + lap crush and TBI + shock compared to shock alone at 24 h. Hyaluronic acid was also increased in lap crush and laparotomy only cohort compared to untouched mice 24 h after injury. A murine model of polytrauma including TBI, hemorrhagic shock, and laparotomy abdominal crush is a reliable method for evaluation of endotheliopathy secondary to trauma as indicated by differential changes in serum biomarkers.

The effects of human prothrombin complex concentrate on hemorrhagic shock-induced lung injury in rats: Implications for testing human blood products in rodents.

Hemorrhagic shock (HS) and trauma can result in an endotheliopathy of trauma, characterized by endothelial compromise, inflammation, and aberrant coagulation. Kcentra, a prothrombin concentrate, has been demonstrated to mitigate pulmonary vascular leak in a murine model of HS. We investigated the effects of Kcentra in a rat model of HS, to achieve physiologic endpoints of relevance. Rats subjected to a grade intravenous splenic injury and controlled hemorrhage for 60 minutes were resuscitated with shed volumes of (1) Lactated Ringer's (LR) solution, (2) LR + 20 IU/kg Kcentra, (3) LR + 50 IU/kg Kcentra, (4) rat fresh frozen plasma (RFFP), or (5) human fresh frozen plasma (HFFP). Blood was harvested for monitoring metabolic and coagulation function. Rat lungs were evaluated for lung injury and permeability. Animals resuscitated with LR displayed a significant increase in pulmonary vascular permeability (sham, 407.9 ± 122.4; shock + LR, 2040 ± 1462). Resuscitation with RFFP (606.5 ± 169.3) reduced leak; however, treatment with Kcentra (HS + Kcentra [20 IU/kg]: 1792 ± 903.4, HS + Kcentra [50 IU/kg]: 1876 ± 1103), and HFFP (1450 ± 533.2) had no significant effect on permeability. Kcentra modestly altered clotting parameters. Metabolic measures, such as lactate, pH, and base deficit, were restored to baseline levels by both RFFP and HFFP, but not Kcentra or LR. Kcentra did not alter pulmonary vascular permeability, but modestly increased clotting potential in injured rats. This suggests that there may be a xenogenic reaction of human products in rats and that the effects of Kcentra on vascular stability may be distinct from its ability to modulate clotting. Our data indicate that the species chosen and utilized for in vivo preclinical testing of human derived blood products is of critical importance in determining their efficacy in animal models and is the primary impetus to communicate these results.

Prehospital plasma is associated with distinct biomarker expression following injury.

BACKGROUNDPrehospital plasma improves survival in severely injured patients transported by air ambulance. We hypothesized that prehospital plasma would be associated with a reduction in immune imbalance and endothelial damage.METHODSWe sampled blood from 405 trauma patients enrolled in the Prehospital Air Medical Plasma (PAMPer) trial upon hospital admission (0 hours) and 24 hours post admission across 6 U.S. sites. We assayed samples for 21 inflammatory mediators and 7 markers associated with endothelial function and damage. We performed hierarchical clustering analysis (HCA) of these biomarkers of the immune response and endothelial injury. Regression analysis was used to control for differences across study and to assess any association with prehospital plasma resuscitation.RESULTSHCA distinguished two patient clusters with different injury patterns and outcomes. Patients in cluster A had greater injury severity and incidence of blunt trauma, traumatic brain injury, and mortality. Cluster A patients that received prehospital plasma showed improved 30-day survival. Prehospital plasma did not improve survival in cluster B patients. In an adjusted analysis of the most seriously injured patients, prehospital plasma was associated with an increase in adiponectin, IL-1β, IL-17A, IL-23, and IL-17E upon admission, and a reduction in syndecan-1, TM, VEGF, IL-6, IP-10, MCP-1, and TNF-α, and an increase in IL-33, IL-21, IL-23, and IL-17E 24 hours later.CONCLUSIONPrehospital plasma may ameliorate immune dysfunction and the endotheliopathy of trauma. These effects of plasma may contribute to improved survival in injured patients.TRIAL REGISTRATIONNCT01818427.FUNDINGDepartment of Defense; National Institutes of Health, U.S. Army.

Endothelial glycocalyx shedding in patients with burns

Shedding of syndecan-1 from the endothelial glycocalyx layer (EGL), referred to as endotheliopathy of trauma (EoT), is associated with poorer outcomes. This study aims to determine if EoT is also present in the burn population. We enrolled 458 burn and non-burn trauma patients at a Level 1 trauma center and defined EoT by a syndecan-1 level of ≥40 ng/mL. Sixty-eight of the enrolled patients had burns with a median TBSA of 19%, with 27.9% also suffering inhalational injury (II). Mortality was similar between the burn and non-burn group, also for patients with EoT. The incidence of II was significantly greater in the EoT+ burn group compared to the EoT− group (p = 0.038). Patients with II received significantly larger amounts of i.v. fluids (p = 0.001). The incidence of EoT was significantly different between the II-groups, as was mortality (pEoT = 0.038, pmortality < 0.001).EoT is attributed to the shock rather than the mechanism of trauma and may in burns be associated to II rather than TBSA. Patients with burns and II had worse outcomes and higher mortality compared to patients with burns alone. Burn injury induces EGL shedding similar to that in non-burn patients with EoT, and results in similar higher rate of mortality.

Effect of Coagulation Factor Concentrates on Markers of Endothelial Cell Damage in Experimental Hemorrhagic Shock.

Plasma-based resuscitation showed protective effects on the endothelial glycocalyx compared with crystalloid resuscitation. There is paucity of data regarding the effect of coagulation factor concentrates (CFC) on the glycocalyx in hemorrhagic shock (HS). We hypothesized that colloid-based resuscitation supplemented with CFCs offers a therapeutic value to treat endothelial damage following HS. Eighty-four rats were subjected to pressure-controlled (mean arterial pressure (MAP) 30-35 mm Hg) and lab-guided (targeted cutoff: lactate >2.2. mmol/L and base deficit > 5.5 mmol/L) HS. Animals were resuscitated with fresh frozen plasma (FFP), human albumin (HA) or Ringer's lactate (RL) and RL or HA supplemented with fibrinogen concentrate (FC) or prothrombin complex concentrate (PCC). Serum epinephrine and the following markers of endothelial damage were assessed at baseline and at the end-of-observation (120 min after shock was terminated): syndecan-1, heparan sulfate, and soluble vascular endothelial growth factor receptor 1 (sVEGFR 1). Resuscitation with FFP had no effect on sVEGFR1 compared with crystalloid-based resuscitation (FFP: 19.3 ng/mL vs. RL: 15.9 ng/mL; RL+FC: 19.7 ng/mL; RL+PCC: 18.9 ng/mL; n.s.). At the end-of-observation, syndecan-1 was similar among all groups. Interestingly, HA+FC treated animals displayed the highest syndecan-1 concentration (12.07 ng/mL). Resuscitation with FFP restored heparan sulfate back to baseline (baseline: 36 ng/mL vs. end-of-observation: 36 ng/mL). The current study revealed that plasma-based resuscitation normalized circulating heparan sulfate but not syndecan-1. Co-administration of CFC had no further effect on glycocalyx shedding suggesting a lack of its therapeutic potential. VExperimental in vivo study.

Plasma for burn shock resuscitation: is it time to go back to the future?

Patients with burn shock can be challenging to resuscitate. Burn shock produces a variety of physiologic derangements: Patients are hypovolemic from volume loss, have a increased systemic vascular resistance, and may have a depressed cardiac output depending on the extent of the thermal injury. Additionally, the burn wound produces a significant inflammatory cascade of events that contributes to the shock state. Fluid resuscitation is foundational for the initial treatment of burn shock. Typical resuscitation is with intravenous lactated Ringer's in accordance with well-established formulas based on burn wound size. In the past century, as therapies to treat thermal injuries were being developed, plasma was the fluid used for burn resuscitation; in fact, plasma was used in World War II and throughout the 1950s and 1960s. Plasma was abandoned because of infectious risks and complications. Despite huge strides in transfusion medicine and the increased safety of blood products, plasma has never been readopted for burn resuscitation. Over the past 15 years, there has been a paradigm shift in trauma resuscitation: Less crystalloid and more blood products are used; this strategy has demonstrated improved outcomes. Plasma is a physiologic fluid that stabilizes the endothelium. The endotheliopathy of trauma has been described and is mitigated by transfusion strategies with a 1:1 ratio of RBCs to plasma. Thermal injury also results in endothelial dysfunction: the endotheliopathy of burns. Plasma is likely a better resuscitation fluid for patients with significant burn wounds because of its capability to restore intravascular volume status and treat the endotheliopathy of burns.

Elevated Syndecan-1 after Trauma and Risk of Sepsis: A Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial

Endotheliopathy of trauma is characterized by breakdown of the endothelial glycocalyx. Elevated biomarkers of endotheliopathy, such as serum syndecan-1 (Synd-1) ≥ 40 ng/mL, have been associated with increased need for transfusions, complications, and mortality. We hypothesized that severely injured trauma patients who exhibit elevated Synd-1 levels shortly after admission have an increased likelihood of developing sepsis. We analyzed a subset of patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial who survived at least 72 hours after hospital admission, and we determined elevated Synd-1 levels (≥ 40 ng/mL) 4 hours after hospital arrival. Sepsis was defined a priori as meeting systemic inflammatory response criteria and having a known or suspected infection. Univariate analysis was performed to identify variables associated with elevated Synd-1 levels and sepsis. Significant variables at a value of p < 0.2 in the univariate analysis were chosen by purposeful selection and analyzed in a mixed effects multivariate logistic regression model to account for the 12 different study sites. We included 512 patients. Of these, 402 (79%) had elevated Synd-1 levels, and 180 (35%) developed sepsis. Median Synd-1 levels at 4 hours after admission were 70 ng/dL (interquartile range [IQR] 36 to 157 ng/dL) in patients who did not develop sepsis, and 165ng/dL [IQR 67 to 336 ng/dL] in those who did (p < 0.001). Adjusting for treatment arm and site, multivariable analyses revealed that elevated Synd-1 status, Injury Severity Score (ISS), and total blood transfused were significantly associated with an increased likelihood of developing sepsis. Elevated Synd-1 levels 4 hours after admission in severely injured adult trauma patients who survived the initial 72 hours after hospital admission are associated with subsequent sepsis.

Early Identification of the Patient with Endotheliopathy of Trauma by Arrival Serum Albumin.

Traumatic endotheliopathy (EoT) is associated with glycocalyx breakdown and capillary leak resulting in the extravasation of proteins. We hypothesized that lower serum albumin levels are associated with EoT, poor outcomes, and can be used for early EoT screening in trauma patients. We enrolled severely injured trauma patients with serum albumin levels available on admission. Syndecan-1 and soluble thrombomodulin were quantified from plasma by ELISA. Demographic and clinical data were obtained. We evaluated the association of serum albumin and EoT+ (syndecan-1 level ≥40 ng/mL), followed by dichotomization by serum albumin level, and subgroup comparisons. Of the 258 patients enrolled 92 (36.0%) were EoT+ (syndecan-1 ≥ 40 ng/mL). Median albumin levels in the EoT+ group were 3.4 g/dL, and 3.8 g/dL in EoT- patients, P < 0.05. In a multifactorial analysis, lower albumin levels were inversely associated with the likelihood of EoT+. With receiver characteristic curve analysis, we determined a cutoff albumin level < 3.6 g/dL for EoT+ prediction (area under the curve 0.70; 95% CI: 0.63, 0.77). After dichotomizing by albumin <3.6 or ≥3.6 g/dL, 51.5% of patients had low albumin. Low albumin patients were more likely to have EoT+, as well as higher soluble thrombomodulin (both P < 0.05). Furthermore, they required more frequently blood transfusions, had fewer hospital-free days and higher mortality rate than those with normal albumin. EoT is a syndrome associated with leakage of albumin from the intravascular compartment, which re-emphasizes that arrival albumin may be a novel and timely approach to the identification of patients needing endothelial rescue therapy.

Fluid therapy in trauma resuscitation : A review of changing practices.

Background: Haemorrhage is the leading preventable cause of post trauma death. Acute trauma resuscitation has evolved over the last decade. The ATLS guidance used since 2012 is being updated in 2018.Objectives : To search relevant representative literature over 6 years between 2012 and 2018 to gain an insight into changing concepts, practices and recent advances in acute trauma fluid resuscitation and provide a structured review of the topic.Search methods: A relevant MEDLINE search was undertaken to obtain a list of 1512 articles from which 107 were utilised to prepare this review.Selection criteria:1. Inclusion: Articles from human medicine relevant to fluid resuscitation in trauma published in English between January 2012 and January 2018. 2.Exclusion: Articles restricted to Brain, spinal trauma or cardiovascular trauma, post traumatic arrest patients, animal or human laboratory model studies and articles on septic, postoperative, obstetric patients and single case studies were excluded.Results: This review categorises the topic into various parts to explain the evolving understanding of fluid resuscitation, trauma induced coagulopathy and endotheliopathy of trauma. The strategies for acute fluid management like damage-controlled resuscitation, balanced and haemostatic resuscitation and massive transfusion protocol are explained. A detailed discussion is carried out regarding crystalloid, colloid and blood transfusion. Special consideration is given to specific age groups, combat casualties and prehospital trauma care.Conclusions: Fluid resuscitation in trauma is a complex and rapidly evolving subject. Massive transfusion protocols and principles of damage control are significant for patient outcome. Standard guidance like ATLS is relevant and important for training professionals to deliver systematic, high quality of trauma care. There is scope for local improvisation based on resources and need for more high-quality trials and frequent systematic reviews.Bangladesh Crit Care J March 2018; 6(1): 31-39

Endotheliopathy of Trauma is an on-Scene Phenomenon, and is Associated with Multiple Organ Dysfunction Syndrome: A Prospective Observational Study.

Trauma patients are vulnerable to coagulopathy and inflammatory dysfunction associated with endotheliopathy of trauma (EoT). In vitro evidence has suggested that tranexamic acid (TXA) may ameliorate endotheliopathy. We aimed to investigate how soon after injury EoT occurs, its association with multiple organ dysfunction syndrome (MODS), and whether TXA ameliorates it. A prospective observational study included 91 trauma patients enrolled within 60 min of injury and 19 healthy controls. Blood was sampled on enrolment and again 4 to 12 h later. ELISAs measured serum concentrations of syndecan-1 and thrombomodulin as biomarkers of EoT. MODS was compared between groups according to biomarker dynamics: persistently abnormal; abnormal to normal; and persistently normal. Timing of EoT was estimated by plotting biomarker data against time, and then fitting generalized additive models. Biomarker dynamics were compared between those who did or did not receive prehospital TXA. Median age was 38 (interquartile range [IQR] 24-55) years; 78 of 91 were male. Median injury severity score (ISS) was 22 (IQR 12-36). EoT was estimated to occur at 5 to 8 min after injury. There were no significant differences in ISS between those with or without prehospital EoT. Forty-two patients developed MODS; 31 of 42 with persistently abnormal; 8 of 42 with abnormal to normal; and 3 of 42 with persistently normal biomarkers; P < 0.05. There were no significant differences between TXA and non-TXA groups. EoT was present at the scene of injury. MODS was more likely when biomarkers of EoT were persistently raised. There were no significant differences between TXA and non-TXA groups. Prehospital interventions aimed at endothelial restoration may represent a clinically meaningful target for prehospital resuscitation.