Traumatic Hemorrhagic Shock Research Articles

The effect of tranexamic acid dosing regimen on trauma/hemorrhagic shock-related glycocalyx degradation and endothelial barrier permeability: An in vitro model.

Improved outcomes with early tranexamic acid (TXA) following trauma hemorrhagic shock (T/HS) may be related to its antifibrinolytic, as well as anti-inflammatory properties. Previous in vitro studies have shown that early TXA administration protects against T/HS endothelial barrier dysfunction and associated glycocalyx degradation. An intact endothelial glycocalyx may protect against subsequent neutrophil mediated tissue injury. We postulated that early TXA administration would mitigate against glycocalyx damage and resultant neutrophil adherence and transmigration through the endothelial barrier. This was studied in vitro using a microfluidic flow platform. Human umbilical vein endothelial cell monolayers were subjected to control or shock conditions (hypoxia + epinephrine) followed by administration of TXA 90 minutes or 180 minutes later. "Early" TXA administration protected against glycocalyx degradation, biomarkers of increased permeability and the development of a fibrinolytic phenotype. This was associated with decreased neutrophil endothelial adherence and transmigration. There were no differences in low versus high TXA concentrations. The protective effects were only significant with "early" TXA administration. There was a concentration and temporal effect of TXA administration on endothelial glycocalyx degradation. This was associated with "vascular leakiness" as indexed by the relative ratio of Ang-2/1 and polymorphonuclear neutrophil transmigration. Tranexamic acid if administered in patients with T/HS should be administered "early"; this includes in the prehospital setting.

Mesenchymal Stem Cells Derived Extracellular Vesicles Alleviate Traumatic Hemorrhagic Shock Induced Hepatic Injury via IL-10/PTPN22-Mediated M2 Kupffer Cell Polarization.

Traumatic hemorrhagic shock (THS) is a major cause of mortality and morbidity worldwide in severely injured patients. Mesenchymal stem cells (MSCs) possess immunomodulatory properties and tissue repair potential mainly through a paracrine pathway mediated by MSC-derived extracellular vesicles (MSC-EVs). Interleukin 10 (IL-10) is a potent anti-inflammatory cytokine that plays a crucial role during the inflammatory response, with a broad range of effects on innate and adaptive immunity, preventing damage to the host and maintaining normal tissue homeostasis. However, the function and mechanism of IL-10 in MSC-mediated protective effect in THS remain obscure. Here, we show that MSCs significantly attenuate hepatic injury and inflammation from THS in mice. Notably, these beneficial effects of MSCs disappeared when IL-10 was knocked out in EVs or when recombinant IL-10 was administered to mice. Mechanistically, MSC-EVs function to carry and deliver IL-10 as cargo. WT MSC-EVs restored the function of IL-10 KO MSCs during THS injury. We further demonstrated that EVs containing IL-10 mainly accumulated in the liver during THS, where they were captured by Kupffer cells and induced the expression of PTPN22. These effects subsequently shifted Kupffer cells to an anti-inflammatory phenotype and mitigated liver inflammation and injury. Therefore, our study indicates that MSC-EVs containing IL-10 alleviate THS-induced hepatic injury and may serve as a cell-free therapeutic approach for THS.

The effects of hydroxyethyl starch and gelatine on lung tissue and coagulation during the resuscitation of rats with traumatic haemorrhagic shock.

This study was constructed to compare the effects of resuscitation with gelatine and hydroxyethyl starch (HES) on coagulopathy, haemodynamics, and tissue damage during an uncontrolled haemorrhagic shock model in rats. Twenty 6-month-old Sprague-Dawley rats were included in the study and divided into 4 groups. There was no haemorrhage in the sham group. The others were randomised into haemorrhage without volume replacement (control group), haemorrhage and gelatine (group G), and haemorrhage and HES (group V). Blood samples for thromboelastogram and annexin 5 values were obtained before bleeding and after resuscitation. In the control group, R (16.18 ± 2.74) and K (5.8 ± 1.1) were significantly higher than in all other groups ( P = 0.001), and the TEG alpha angle was 39.54 ± 5.94°, which was found to be significantly lower than in the sham group ( P = 0.001). In group V, the TEG MA value was found to be significantly lower at 30.54 ± 8.89 ( P = 0.001). The annexin A5 value was significantly higher in the control group, group V, and group G than in the sham group and was highest in the control group ( P = 0.001). Lung damage score measurement was 0.60 ± 0.19 in the control group, higher than in the gelatine and HES groups ( P = 0.001). Lung tissue damage and coagulation were positively affected by HES or gelatine resuscitation. A reduction in clot formation in the HES group might be observed due to the possible negative effect on platelets. Therefore, we concluded that the use of gelatine might be advantageous until blood transfusion is initiated in traumatic haemorrhagic shock.

Antioxidant and Neuroprotective Effects of L-arginine Administration After Traumatic Brain Injury and Hemorrhagic Shock in Rats.

To investigate the effect of fluid resuscitation and L-arginine administration on oxidant status markers, blood gases, lactate and apoptosis in the brain tissue of a rat model of TBI with hemorrhagic shock. A total of 60 rats were divided into six groups: control, isotonic saline-treated, 7.5% NaCl-treated (hypertonic saline), L-arginine-treated (100 mg/kg), saline + L-arginine-treated and 7.5% NaCl + L-arginine-treated groups. Closed head contusive weight-drop injuries were performed with hemorrhagic shock in all of the groups. Mean arterial pressure (MAP), pulse rate, lactate, malondialdehyde (MDA), total antioxidant capacity (TAC) and apoptosis were investigated. In a total of 48 rats, MAP levels remained higher than 60 mmHg for 3 hours in all of the treatment groups. The highest MAP values in each group were recorded. Higher MDA and lower TAC levels were observed in the control group than in all of the treatment groups (all p < 0.05). The number of apoptotic cells was highest in the control group and lowest in the L-arginine group. L-arginine administration may be an alternative treatment option for individualized fluid resuscitation in patients with TBI and hemorrhagic shock.

ETS-Related Gene Activation Preserves Adherens Junctions and Permeability in Microvascular Endothelial Cells.

ERG (ETS-related gene) is a member of the ETS (Erythroblast-transformation specific) family of transcription factors abundantly present in vascular endothelial cells. Recent studies demonstrate that ERG has important roles in blood vessel stability and angiogenesis. However, it is unclear how ERG is potentially involved in microvascular barrier functions and permeability. A wide variety of diseases and clinical conditions including trauma-hemorrhagic shock and burn injury are associated with microvascular dysfunctions, which causes excessive microvascular permeability, tissue edema and eventually, multiple organ dysfunction and death. The main purpose of this study was to determine the specific role of ERG in regulating microvascular permeability in human lung microvascular endothelial cells (HLMEC) and to evaluate if exogenous ERG will protect the barrier. The HLMECs were grown on Transwell inserts as monolayers and were transfected with ERG CRISPR/cas9 knockdown plasmid, ERG CRISPR activation plasmid, recombinant ERG protein or their respective controls. Recombinant vascular endothelial growth factor (VEGF) was used as an inducer of permeability for evaluating the effect of ERG activation on permeability. Changes in barrier integrity and permeability were studied using monolayer permeability assay and immunofluorescence of adherens junction proteins (VE-cadherin and β-catenin) respectively. CRISPR/cas9-based ERG knockdown as well as VEGF treatment induced monolayer hyperpermeability, VE-cadherin, and β-catenin junctional relocation and cytoskeletal F-actin stress fiber formation. CRISPR based ERG activation and recombinant ERG transfection attenuated VEGF-induced monolayer hyperpermeability. ERG activation preserved the adherens junctions and cytoskeleton. These results demonstrate that ERG is a potent regulator of barrier integrity and permeability in human lung microvascular endothelial cells and endogenously or exogenously enhancing ERG provides protection against barrier dysfunction and hyperpermeability.

New Applications of HBOC-201: A 25-Year Review of the Literature.

If not cured promptly, tissue ischemia and hypoxia can cause serious consequences or even threaten the life of the patient. Hemoglobin-based oxygen carrier-201 (HBOC-201), bovine hemoglobin polymerized by glutaraldehyde and stored in a modified Ringer's lactic acid solution, has been investigated as a blood substitute for clinical use. HBOC-201 was approved in South Africa in 2001 to treat patients with low hemoglobin (Hb) levels when red blood cells (RBCs) are contraindicated, rejected, or unavailable. By promoting oxygen diffusion and convective oxygen delivery, HBOC-201 may act as a direct oxygen donor and increase oxygen transfer between RBCs and between RBCs and tissues. Therefore, HBOC-201 is gradually finding applications in treating various ischemic and hypoxic diseases including traumatic hemorrhagic shock, hemolysis, myocardial infarction, cardiopulmonary bypass, perioperative period, organ transplantation, etc. However, side effects such as vasoconstriction and elevated methemoglobin caused by HBOC-201 are major concerns in clinical applications because Hbs are not encapsulated by cell membranes. This study summarizes preclinical and clinical studies of HBOC-201 applied in various clinical scenarios, outlines the relevant mechanisms, highlights potential side effects and solutions, and discusses the application prospects. Randomized trials with large samples need to be further studied to better validate the efficacy, safety, and tolerability of HBOC-201 to the extent where patient-specific treatment strategies would be developed for various clinical scenarios to improve clinical outcomes.

17\u03b1-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial

BackgroundTraumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS.MethodsAll methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation).ResultsA comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood–brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration.ConclusionsEE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

Advances in prehospital hemorrhagic shock management since Paris' terrorist attacks in 2015: A before-and-after retrospective study.

In France, in 2015, prehospital emergency doctors were faced with civilian casualties in hemorrhagic shock resulting from terrorist attacks with automatic rifle fire and explosive weapons. The present study aimed to evaluate the impact of these attacks on the advanced life support (ALS) team's practices and equipment and on physician training in the prehospital management of traumatic hemorrhagic shock. This before-and-after multicenter study evaluated professional practices based on a questionnaire sent to emergency department heads and medical practitioners in 370 ALS teams in metropolitan France. We analyzed 672 responses from 209 (56.5 percent) ALS teams in 91 of 95 emergency medical services (EMS) headquarters. Of these 91, 73 (80.2 percent) had a protocol in use for managing traumatic hemorrhagic shock after the attacks, compared with 45 (49.5 percent) who had protocols in use before the attacks (p < 0.001). Ultrasound equipment was available in 49 (53.8 percent) of the EMS headquarters after the attacks, compared to 39 (42.9 percent) before (p < 0.001). Limb tourniquets were available in 90 (98.9 percent) EMS headquarters after the attacks, versus 27 (29.7 percent) before (p < 0.001). Tranexamic acid was available in 88 (96.7 percent) EMS headquarters after the attacks, versus 71 (78 percent) before (p < 0.001). During the post-attack period, training in war medicine did not affect individual practices, neither for using the shock index or the Focused Assessment with Sonography for Trauma (FAST) nor the tourniquet. However, this training was associated with more frequent use of hemostatic dressings (p = 0.002). Following the attacks in Paris and Nice, ALS teams received additional equipment and training to prepare for future mass causality events.

Role of TLR5 in the Translocation and Dissemination of Commensal Bacteria in the Intestine after Traumatic Hemorrhagic Shock.

Enterogenous infection is a major cause of death during traumatic hemorrhagic shock (THS). It has been reported that Toll-like receptor 5 (TLR5) plays an integral role in regulating mucosal immunity and intestinal homeostasis of the microbiota. However, the roles played by TLR5 on intestinal barrier maintenance and commensal bacterial translocation post-THS are poorly understood. In this research, we established THS models in wild-type (WT) and Tlr5−/− (genetically deficient in TLR5 expression) mice. We found that THS promoted bacterial translocation, while TLR5 deficiency played a protective role in preventing commensal bacteria dissemination after THS. Furthermore, intestinal microbiota analysis uncovered that TLR5 deficiency enhanced the mucosal biological barrier by decreasing RegIIIγ-mediated bactericidal activity against G+ anaerobic bacteria. We then sorted small intestinal TLR5+ lamina propria dendritic cells (LPDCs) and analyzed TH1 differentiation in the intestinal lamina propria and a coculture system consisting of LPDCs and naïve T cells. Although TLR5 deficiency attenuated the regulation of TH1 polarization by LPDCs, it conferred stability to the cells during THS. Moreover, retinoic acid (RA) released from TLR5+ LPDCs could play a key role in modulating TH1 polarization. We also found that gavage administration of RA alleviated bacterial translocation in THS-treated WT mice. In summary, we documented that TLR5 signaling plays a pivotal role in regulating RegIIIγ-induced killing of G+ anaerobic bacteria, and LPDCs mediated TH1 differentiation via RA. These processes prevent intestinal bacterial translocation and enterogenous infection after THS, suggesting that therapeutically targeting LPDCs or gut microbiota can interfere with bacterial translocation after THS.

Early Treatment With a Single Dose of Mesenchymal Stem Cell Derived Extracellular Vesicles Modulates the Brain Transcriptome to Create Neuroprotective Changes in a Porcine Model of Traumatic Brain Injury and Hemorrhagic Shock.

Cell-based therapies using mesenchymal stem cell derived extracellular vesicles (EVs) improve neurologic outcomes in animal models of traumatic brain injury (TBI), stroke, and hemorrhage. Using a porcine 7-day survival model of TBI and hemorrhagic shock (HS), we previously demonstrated that EV-treatment was associated with reduced brain lesion size, neurologic severity score, and cerebral inflammation. However, the underlying cellular and genomic mechanisms remain poorly defined. We hypothesize that EV treatment modulates the brain transcriptome to enhance neuroprotection and neurorestoration following TBI + HS. Swine were subjected to severe TBI (8-mm cortical impact) and HS (40% blood volume). After 1 h of shock, animals were randomized (n = 4/group) to treatment with either lactated Ringer's (LR) or LR + EV. Both groups received fluid resuscitation after 2 h of shock, and autologous packed red blood cells 5 h later.After 7-days, brains were harvested and RNA-sequencing was performed. The transcriptomic data were imported into the iPathway pipeline for bioinformatics analyses. 5,273 genes were differentially expressed in the LR + EV group versus LR alone (total 9,588 measured genes). Genes with the greatest upregulation were involved in synaptic transmission and neuronal development and differentiation, while downregulated genes were involved in inflammation. GO-terms experiencing the greatest modulation were involved in inflammation, brain development, and cell adhesion. Pathway analysis revealed significant modulation in the glutamatergic and GABAergic systems. Network analysis revealed downregulation of inflammation, and upregulation of neurogenesis, and neuron survival and differentiation. In a porcine model of TBI + HS, EV treatment was associated with an attenuation of cerebral inflammatory networks and a promotion of neurogenesis and neuroplasticity. These transcriptomic changes could explain the observed neuroprotective and neurorestorative properties associated with EV treatment.

Blood product resuscitation mitigates the effects of aeromedical evacuation after polytrauma.

The combined injury of traumatic brain injury and hemorrhagic shock has been shown to worsen coagulopathy and systemic inflammation, thereby increasing posttraumatic morbidity and mortality. Aeromedical evacuation to definitive care may exacerbate postinjury morbidity because of the inherent hypobaric hypoxic environment. We hypothesized that blood product resuscitation may mitigate the adverse physiologic effects of postinjury flight. An established porcine model of controlled cortical injury was used to induce traumatic brain injury. Intracerebral monitors were placed to record intracranial pressure, brain tissue oxygenation, and cerebral perfusion. Each of the 42 pigs was hemorrhaged to a goal mean arterial pressure of 40 ± 5 mm Hg for 1 hour. Pigs were grouped according to resuscitation strategy used-Lactated Ringer's (LR) or shed whole blood (WB)-then placed in an altitude chamber for 2 hours at ground, 8,000 ft, or 22,000 ft, and then observed for 4 hours. Hourly blood samples were analyzed for proinflammatory cytokines and lactate. Internal jugular vein blood flow was monitored continuously for microbubble formation with altitude changes. Cerebral perfusion, tissue oxygenation, and intracranial pressure were unchanged among the six study groups. Venous microbubbles were not observed even with differing altitude or resuscitation strategy. Serum lactate levels from hour 2 of flight to the end of observation were significantly elevated in 22,000 + LR compared with 8,000 + LR and 22,000 + WB. Serum IL-6 levels were significantly elevated in 22,000 + LR compared with 22,000 + WB, 8,000 + LR and ground+LR at hour 1 of observation. Serum tumor necrosis factor-α was significantly elevated at hour 2 of flight in 8,000 + LR versus ground+LR, and in 22,000 + LR vs. 22,000 + WB at hour 1 of observation. Serum IL-1β was significantly elevated hour 1 of flight between 8,000 + LR and ground+LR. Crystalloid resuscitation during aeromedical transport may cause a prolonged lactic acidosis and proinflammatory response that can predispose multiple-injury patients to secondary cellular injury. This physiologic insult may be prevented by using blood product resuscitation strategies.

Protective effect of Lactobacillus-containing probiotics on intestinal mucosa of rats experiencing traumatic hemorrhagic shock.

This study was conducted to assess whether Lactobacillus-containing probiotics could protect intestinal mucosa in rats during traumatic hemorrhagic shock and to determine its underlying mechanisms. Healthy male Sprague–Dawley rats (300 ± 20 g) were randomly divided into four groups. During the study, reverse transcription polymerase chain reaction, western blotting, and hematoxylin and eosin methods were used. There was a significant increase in the expression of toll-like receptor 4 (TLR4) in the rats that experienced traumatic hemorrhagic shock, along with increased mRNA of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. Pretreatment with Lactobacillus-containing probiotics reduced TLR4 expression, decreased phosphorylation (Ser536) and acetylation (Lys310) of p65, and decreased TNF-α and IL-6 mRNA. The probiotics combined acetate Ringer’s group showed a less severe pathological manifestation compared to the other experimental groups. Lactobacillus-containing probiotics inhibited nuclear factor-kappa B signaling via the downregulation of TLR4, resulting in inflammatory homeostasis, which might be the mechanism whereby Lactobacillus protects the intestinal mucosa from damage caused by the traumatic hemorrhagic shock.

Whole Blood for Resuscitation of Traumatic Hemorrhagic Shock in Adults.

Injured patients with traumatic hemorrhagic shock often require resuscitation with transfusion of red blood cells, plasma, and platelets. Resuscitation with whole blood (WB) has been used in military settings, and its use is increasingly common in civilian practice. We provide an overview of the benefits and challenges, guidelines, and unanswered questions related to the use of WB in the treatment of civilian trauma-related hemorrhage. Implications for advanced practice nurses and nursing staff are also discussed.

Therapeutic Potential of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in the Prevention of Organ Injuries Induced by Traumatic Hemorrhagic Shock.

Severe trauma is the principal cause of death among young people worldwide. Hemorrhagic shock is the leading cause of death after severe trauma. Traumatic hemorrhagic shock (THS) is a complex phenomenon associating an absolute hypovolemia secondary to a sudden and significant extravascular blood loss, tissue injury, and, eventually, hypoxemia. These phenomena are responsible of secondary injuries such as coagulopathy, endotheliopathy, microcirculation failure, inflammation, and immune activation. Collectively, these dysfunctions lead to secondary organ failures and multi-organ failure (MOF). The development of MOF after severe trauma is one of the leading causes of morbidity and mortality, where immunological dysfunction plays a central role. Damage-associated molecular patterns induce an early and exaggerated activation of innate immunity and a suppression of adaptive immunity. Severe complications are associated with a prolonged and dysregulated immune–inflammatory state. The current challenge in the management of THS patients is preventing organ injury, which currently has no etiological treatment available. Modulating the immune response is a potential therapeutic strategy for preventing the complications of THS. Mesenchymal stromal cells (MSCs) are multipotent cells found in a large number of adult tissues and used in clinical practice as therapeutic agents for immunomodulation and tissue repair. There is growing evidence that their efficiency is mainly attributed to the secretion of a wide range of bioactive molecules and extracellular vesicles (EVs). Indeed, different experimental studies revealed that MSC-derived EVs (MSC-EVs) could modulate local and systemic deleterious immune response. Therefore, these new cell-free therapeutic products, easily stored and available immediately, represent a tremendous opportunity in the emergency context of shock. In this review, the pathophysiological environment of THS and, in particular, the crosstalk between the immune system and organ function are described. The potential therapeutic benefits of MSCs or their EVs in treating THS are discussed based on the current knowledge. Understanding the key mechanisms of immune deregulation leading to organ damage is a crucial element in order to optimize the preparation of EVs and potentiate their therapeutic effect.

Experience of Emergency Nursing and Complication Management in Patients with Severe Traumatic Hemorrhagic Shock

Experience of Emergency Nursing and Complication Management in Patients with Severe Traumatic Hemorrhagic Shock

Over my dead body: Self-determination, proxy consent, and proportionate reason in the treatment of a Jehovah's Witness patient with severe traumatic hemorrhagic shock

When a Jehovah’s Witness patient is traumatically injured, the lack of uniform professional consensus guidelines and the cultural knowledge deficit of many clinicians adds an additional layer of legal and ethical complexity to the inherent difficulty of managing a critically ill patient. We present here the case of an incapacitated Jehovah's Witness patient with severe traumatic hemorrhagic shock. We go on to discuss the historical and contemporary case law on proxy refusal of blood transfusion for the incapacitated adult, as well as the ethics of self-determination and the application of the principle of proportionate reason in the management of the critically injured Jehovah's Witness patient.

Choice of Whole Blood versus Lactated Ringer's Resuscitation Modifies the Relationship between Blood Pressure Target and Functional Outcome after Traumatic Brain Injury plus Hemorrhagic Shock in Mice.

Civilian traumatic brain injury (TBI) guidelines recommend resuscitation of patients with hypotensive TBI with crystalloids. Increasing evidence, however, suggests that whole blood (WB) resuscitation may improve physiological and survival outcomes at lower resuscitation volumes, and potentially at a lower mean arterial blood pressure (MAP), than crystalloid after TBI and hemorrhagic shock (HS). The objective of this study was to assess whether WB resuscitation with two different MAP targets improved behavioral and histological outcomes compared with lactated Ringer's (LR) in a mouse model of TBI+HS. Anesthetized mice (n = 40) underwent controlled cortical impact (CCI) followed by HS (MAP = 25-27 mm Hg; 25 min) and were randomized to five groups for a 90 min resuscitation: LR with MAP target of 70 mm Hg (LR70), LR60, WB70, WB60, and monitored sham. Mice received a 20 mL/kg bolus of LR or autologous WB followed by LR boluses (10 mL/kg) every 5 min for MAP below target. Shed blood was reinfused after 90 min. Morris Water Maze testing was performed on days 14-20 post-injury. Mice were euthanized (21 d) to assess contusion and total brain volumes. Latency to find the hidden platform was greater versus sham for LR60 (p < 0.002) and WB70 (p < 0.007) but not LR70 or WB60. The WB resuscitation did not reduce contusion volume or brain tissue loss. The WB targeting a MAP of 60 mm Hg did not compromise function versus a 70 mm Hg target after CCI+HS, but further reduced fluid requirements (p < 0.03). Using LR, higher achieved MAP was associated with better behavioral performance (rho = -0.67, p = 0.028). Use of WB may allow lower MAP targets without compromising functional outcome, which could facilitate pre-hospital TBI resuscitation.

Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis

AbstractTrauma-induced organ failure is characterized by endothelial dysfunction. The aim of this study was to investigate the role of von Willebrand factor (VWF) and its cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13) in the occurrence of endothelial permeability and organ failure in trauma. In an observational study in a level-1 trauma center, 169 adult trauma patients with clinical signs of shock and/or severe injuries were included. Trauma was associated with low ADAMTS13 and high VWF antigen levels, thus generating an imbalance of ADAMTS13 to VWF. Patients who developed organ failure (23%) had greater ADAMTS13-to-VWF imbalances, persistently lower platelet counts, and elevated levels of high-molecular-weight VWF multimers compared with those without organ failure, suggesting microthrombi formation. To investigate the effect of replenishing low ADAMTS13 levels on endothelial permeability and organ failure using either recombinant human ADAMTS13 (rhADAMTS13) or plasma transfusion, a rat model of trauma-induced shock and transfusion was used. Rats in traumatic hemorrhagic shock were randomized to receive crystalloids, crystalloids supplemented with rhADAMTS13, or plasma transfusion. A 70-kDa fluorescein isothiocyanate–labeled dextran was injected to determine endothelial leakage. Additionally, organs were histologically assessed. Both plasma transfusion and rhADAMTS13 were associated with a reduction in pulmonary endothelial permeability and organ injury when compared with resuscitation with crystalloids, but only rhADAMTS13 resulted in significant improvement of a trauma-induced decline in ADAMTS13 levels. We conclude that rhADAMTS13 and plasma transfusion can reduce organ failure following trauma. These findings implicate the ADAMTS13-VWF axis in the pathogenesis of organ failure.

A New Time-Window Prediction Model For Traumatic Hemorrhagic Shock Based on Interpretable Machine Learning.

ABSTRACTEarly warning prediction of traumatic hemorrhagic shock (THS) can greatly reduce patient mortality and morbidity. We aimed to develop and validate models with different stepped feature sets to predict THS in advance. From the PLA General Hospital Emergency Rescue Database and Medical Information Mart for Intensive Care III, we identified 604 and 1,614 patients, respectively. Two popular machine learning algorithms (i.e., extreme gradient boosting [XGBoost] and logistic regression) were applied. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the performance of the models. By analyzing the feature importance based on XGBoost, we found that features in vital signs (VS), routine blood (RB), and blood gas analysis (BG) were the most relevant to THS (0.292, 0.249, and 0.225, respectively). Thus, the stepped relationships existing in them were revealed. Furthermore, the three stepped feature sets (i.e., VS, VS + RB, and VS + RB + sBG) were passed to the two machine learning algorithms to predict THS in the subsequent T hours (where T = 3, 2, 1, or 0.5), respectively. Results showed that the XGBoost model performance was significantly better than the logistic regression. The model using vital signs alone achieved good performance at the half-hour time window (AUROC = 0.935), and the performance was increased when laboratory results were added, especially when the time window was 1 h (AUROC = 0.950 and 0.968, respectively). These good-performing interpretable models demonstrated acceptable generalization ability in external validation, which could flexibly and rollingly predict THS T hours (where T = 0.5, 1) prior to clinical recognition. A prospective study is necessary to determine the clinical utility of the proposed THS prediction models.

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.

Besides being powerhouses of the cell, mitochondria released into extracellular space act as intercellular signaling. Mitochondria and their components mediate cell-to-cell communication in free form or embedded in a carrier. The pathogenesis of cardiovascular disease is complex, which shows close relationship with inflammation and metabolic abnormalities. Since mitochondria sustain optimal function of the heart, extracellular mitochondria are emerging as a key regulator in the development of cardiovascular disease. In this review, we provide recent findings in the presence and forms of mitochondria transfer between cells, as well as the effects of these mitochondria on vascular inflammation and ischemic myocardium. Mitochondrial transplantation is a novel treatment paradigm for patients suffering from acute cardiovascular accident and challenges the traditional methods of mitochondria isolation.