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Severe hemorrhagic shock leads to excessive inflammation and immune dysfunction, which results in high mortality related to mesenteric lymph return. A recent study showed that stellate ganglion block (SGB) increased the survival rate in rats suffering hemorrhagic shock. However, whether SGB ameliorates immune dysfunction induced by hemorrhagic shock remains unknown. The aim of the present study was to verify the favorable effects of SGB on the proliferation and function of splenic CD4 + T cells isolated from rats that underwent hemorrhagic shock and to investigate the mechanism related to the SGB interaction with autophagy and posthemorrhagic shock mesenteric lymph (PHSML). Male rats underwent SGB or sham SGB and conscious acute hemorrhage followed by resuscitation and multiple treatments. After 3 h of resuscitation, splenic CD4 + T cells were isolated to measure proliferation and cytokine production following stimulation with ConA in vitro. CD4 + T cells isolated from normal rats were treated with PHSML drained from SBG-treated rats, and proliferation, cytokine production, and autophagy biomarkers were detected. Hemorrhagic shock reduced CD4 + T cell proliferation and production of interleukin (IL)-2, IL-4, and tumor necrosis factor-α-induced protein 8-like 2 (TIPE2). SGB or administration of the autophagy inhibitor 3-methyladenine (3-MA) normalized these indicators. In contrast, administration of rapamycin (RAPA) autophagy agonist or intravenous injection of PHSML inhibited the beneficial effects of SGB on CD4 + T cells from hemorrhagic shocked rats. Furthermore, PHSML incubation decreased proliferation and cytokine production, increased LC3 II/I and Beclin-1 expression, and reduced p-PI3K and p-Akt expression in normal CD4 + T cells. These adverse effects of PHSML were also abolished by 3-MA administration, as well as incubation with PHSML obtained from SGB-treated rats. SGB improves splenic CD4 + T cell function following hemorrhagic shock, which is related to the inhibition of PHSML-mediated autophagy., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is performed in patients with hemorrhagic shock who develop massive subdiaphragmatic bleeding. This procedure enables rapid and less invasive aortic blockade compared to resuscitative thoracotomy and aortic cross-clamp procedures. However, the REBOA procedure is often blindly performed in the emergency department without fluoroscopy, and the appropriateness of the procedure may be evaluated on computed tomography (CT) after REBOA. Therefore, radiologists should be familiar with the imaging features of REBOA. We present a pictorial review of the radiological findings of REBOA along with a description of the procedure, its complications, and pitfalls., (© 2021. The Author(s).)

Background: Aggressive fluid or blood component transfusion for severe hemorrhagic shock may restore macrocirculatory parameters, but not always improve microcirculatory perfusion and tissue oxygen delivery. We established an ovine model of hemorrhagic shock to systematically assess tissue oxygen delivery and repayment of oxygen debt; appropriate outcomes to guide Patient Blood Management., Methods: Female Dorset-cross sheep were anesthetized, intubated, and subjected to comprehensive macrohemodynamic, regional tissue oxygen saturation (StO2), sublingual capillary imaging, and arterial lactate monitoring confirmed by invasive organ-specific microvascular perfusion, oxygen pressure, and lactate/pyruvate levels in brain, kidney, liver, and skeletal muscle. Shock was induced by stepwise withdrawal of venous blood until MAP was 30 mm Hg, mixed venous oxygen saturation (SvO2) < 60%, and arterial lactate >4 mM. Resuscitation with PlasmaLyte® was dosed to achieve MAP > 65 mm Hg., Results: Hemorrhage impacted primary outcomes between baseline and development of shock: MAP 89 ± 5 to 31 ± 5 mm Hg (P < 0.01), SvO2 70 ± 7 to 23 ± 8% (P < 0.05), cerebral regional tissue StO2 77 ± 11 to 65 ± 9% (P < 0.01), peripheral muscle StO2 66 ± 8 to 16 ± 9% (P < 0.01), arterial lactate 1.5 ± 1.0 to 5.1 ± 0.8 mM (P < 0.01), and base excess 1.1 ± 2.2 to -3.6 ± 1.7 mM (P < 0.05). Invasive organ-specific monitoring confirmed reduced tissue oxygen delivery; oxygen tension decreased and lactate increased in all tissues, but moderately in brain. Blood volume replacement with PlasmaLyte® improved primary outcome measures toward baseline, confirmed by organ-specific measures, despite hemoglobin reduced from baseline 10.8 ± 1.2 to 5.9 ± 1.1 g/dL post-resuscitation (P < 0.01)., Conclusion: Non-invasive measures of tissue oxygen delivery and oxygen debt repayment are suitable outcomes to inform Patient Blood Management of hemorrhagic shock, translatable for pre-clinical assessment of novel resuscitation strategies., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

As care of the injured patient continues to evolve, new surgical technologies and new resuscitative therapies can change the algorithms that drive trauma care. In particular, the advent of resuscitative endovascular balloon occlusion of the aorta has changed the way trauma surgeons treat patients in extremis. The science of resuscitation continues to evolve, leading to controversy about the optimal administration of fluid and blood products. Laparoscopy has given additional tools to the trauma surgeon to potentially avoid exploratory laparotomy, and rib fracture fixation can be beneficial in the proper patient., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA), a minimally invasive alternative to resuscitative thoracotomy, has been associated with significant ischemia reperfusion injury (IRI). Resuscitation strategies using adenosine, lidocaine, and magnesium (ALM) have been shown to mitigate similar inflammatory responses in hemorrhagic and septic shock models. This study examined the effects of ALM on REBOA-associated IRI using a porcine model., Methods: Animals underwent a 20% controlled hemorrhage followed by 30 minutes of supraceliac balloon occlusion. They were assigned to one of four groups: control (n = 5), 4-hour ALM infusion starting at occlusion, 2-hour (n = 5) and 4-hour (n = 5) interventional ALM infusions starting at reperfusion. Adenosine, lidocaine, and magnesium cohorts received a posthemorrhage ALM bolus followed by their respective ALM infusion. Primary outcomes for the study assessed physiologic and hemodynamic parameters., Results: Adenosine, lidocaine, and magnesium infusion after reperfusion cohorts demonstrated a significant improvement in lactate, base deficit, and pH in the first hour following systemic reperfusion. At study endpoint, continuous ALM infusion initiated after reperfusion over 4 hours resulted in an overall improved lactate clearance when compared with the 2-hour and control cohorts. No differences in hemodynamic parameters were noted between ALM cohorts and controls., Conclusion: Adenosine, lidocaine, and magnesium may prove beneficial in mitigating the inflammatory response seen from REBOA-associated IRI as evidenced by physiologic improvements early during resuscitation. Despite this, further refinement should be sought to optimize treatment strategies., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Numerous advancements in hemorrhage control and volume replacement that comprise damage control resuscitation (DCR) have been implemented in the last decade to reduce deaths from bleeding. We sought to determine the impact of DCR interventions on mortality over 12 years in a massive transfusion protocol (MTP) population. We hypothesized that mortality would be decreased in later years, which would have used more DCR interventions., Study Design: This was a retrospective review of all MTP patients treated at a large regional Level I trauma center from 2008 to 2019. Interventions by year of implementation examined included MTP 1:1 ratio (2009), liquid plasma (2010), tranexamic acid (2012), prehospital tourniquets (2013), REBOA/TEG (2017), satellite blood station (2018), and whole blood transfusion (2019). Relative risk and odds of mortality for DCR interventions were examined., Results: There were 824 MTP patients included. The cohort was primarily male (80.6%) injured by penetrating mechanism (68.1%) with median (interquartile range) age 31 years (23-44) and New Injury Severity Score 25 (16-34). Overall mortality was unchanged [(38.3%-56.6%); P = 0.26]. Tourniquets (P = 0.02) and whole blood (WB) (P = 0.03) were associated with lower unadjusted mortality; only tourniquets remained significant after adjustment (OR: 0.39; 95% CI: 0.17-0.89; P = 0.03)., Conclusions: Despite lower mortality with use of tourniquets and WB, mortality rates due to hemorrhage have not improved at our high MTP volume institution, suggesting implementation of new in-hospital strategies is insufficient to reduce mortality. Future efforts should be directed toward moving hemorrhage control and effective resuscitation interventions to the injury scene., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Background: Unlike recent advances in blood product resuscitation, intravenous crystalloid (IVF) use after intensive care unit (ICU) admission in hemorrhagic shock has received less attention and current recommendations are based on limited evidence. To address this knowledge gap, we aimed to determine associations between IVF administration during acute ICU resuscitation and outcomes. We hypothesized that larger IVF volumes are associated with worse outcomes., Methods: We linked our trauma registry with electronic health record data (2012-2015) to identify adults with an initial lactate level of ≥4 mmol/L and documented lactate normalization (≤2 mmol/L), excluding those with isolated head Abbreviated Injury Scale score ≥3. We focused on the period from ICU admission to lactate normalization, analyzing duration, volume of IVF, and proportion of volume as 1-L boluses. We used linear regression to determine associations with ICU length of stay and duration of mechanical ventilation in survivors, and logistic regression to identify associations with acute kidney injury and home discharge while adjusting for important covariates., Results: We included 337 subjects. Median time to lactate normalization was 15 hours (interquartile range, 7-25 hours), and median IVF volume was 3.7 L (interquartile range, 1.5-6.4 L). The fourfold difference between the upper and lower quartiles of both duration and volume remained after stratifying by injury severity. Hourly volumes tapered over time but persistently aggregated at 0.5 and 1 L, with 167 subjects receiving at least one 0.5-L bolus for 6 hours after ICU admission. Administration of larger volumes was associated with longer ICU length of stay and duration of mechanical ventilation, as well as acute kidney injury., Conclusion: There is substantial variation in volume administered during acute ICU resuscitation, both absolutely and temporally, despite accounting for injury severity. Administration of larger volumes during acute ICU resuscitation is associated with worse outcomes. There is an opportunity to improve outcomes by further investigating and standardizing this important phase of care., Level of Evidence: Therapeutic/care management, level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Hemorrhagic shock in combat trauma remains the greatest life threat to casualties with potentially survivable injuries. Advances in external hemorrhage control and the increasing use of damage control resuscitation have demonstrated significant success in decreasing mortality in combat casualties. Presently, an expanding body of literature suggests that fluid resuscitation strategies for casualties in hemorrhagic shock that include the prehospital use of cold-stored or fresh whole blood when available, or blood components when whole blood is not available, are superior to crystalloid and colloid fluids. On the basis of this recent evidence, the Committee on Tactical Combat Casualty Care (TCCC) has conducted a review of fluid resuscitation for the combat casualty who is in hemorrhagic shock and made the following new recommendations: (1) cold stored low-titer group O whole blood (CS-LTOWB) has been designated as the preferred resuscitation fluid, with fresh LTOWB identified as the first alternate if CS-LTOWB is not available; (2) crystalloids and Hextend are no longer recommended as fluid resuscitation options in hemorrhagic shock; (3) target systolic blood pressure (SBP) resuscitation goals have been redefined for casualties with and without traumatic brain injury (TBI) coexisting with their hemorrhagic shock; and (4) empiric prehospital calcium administration is now recommended whenever blood product resuscitation is required., (2021.)

Background: Despite much evidence supporting the monitoring of the divergence of transcutaneous partial pressure of carbon dioxide (tcPCO 2 ) from arterial partial pressure carbon dioxide (artPCO 2 ) as an indicator of the shock status, data are limited on the relationships of the gradient between tcPCO 2 and artPCO 2 (tc-artPCO 2 ) with the systemic oxygen metabolism and hemodynamic parameters. Our study aimed to test the hypothesis that tc-artPCO 2 can detect inadequate tissue perfusion during hemorrhagic shock and resuscitation., Methods: This prospective animal study was performed using female pigs at a university-based experimental laboratory. Progressive massive hemorrhagic shock was induced in mechanically ventilated pigs by stepwise blood withdrawal. All animals were then resuscitated by transfusing the stored blood in stages. A transcutaneous monitor was attached to their ears to measure tcPCO 2 . A pulmonary artery catheter (PAC) and pulse index continuous cardiac output (PiCCO) were used to monitor cardiac output (CO) and several hemodynamic parameters. The relationships of tc-artPCO 2 with the study parameters and systemic oxygen delivery (DO 2 ) were analyzed., Results: Hemorrhage and blood transfusion precisely impacted hemodynamic and laboratory data as expected. The tc-artPCO 2 level markedly increased as CO decreased. There were significant correlations of tc-artPCO 2 with DO 2 and COs (DO 2 : r = - 0.83, CO by PAC: r = - 0.79; CO by PiCCO: r = - 0.74; all P < 0.0001). The critical level of oxygen delivery (DO 2crit ) was 11.72 mL/kg/min according to transcutaneous partial pressure of oxygen (threshold of 30 mmHg). Receiver operating characteristic curve analyses revealed that the value of tc-artPCO 2 for discrimination of DO 2crit was highest with an area under the curve (AUC) of 0.94, followed by shock index (AUC = 0.78; P < 0.04 vs tc-artPCO 2 ), and lactate (AUC = 0.65; P < 0.001 vs tc-artPCO 2 )., Conclusions: Our observations suggest the less-invasive tc-artPCO 2 monitoring can sensitively detect inadequate systemic oxygen supply during hemorrhagic shock. Further evaluations are required in different forms of shock in other large animal models and in humans to assess its usefulness, safety, and ability to predict outcomes in critical illnesses., (© 2021. The Author(s).)

Background: Inadequate intestinal perfusion resulting from hemorrhagic shock negatively affects wound healing. In this experimental study, we aimed to evaluate the effects of resuscitation with hypertonic saline on colonic anastomosis in rats with controlled hemorrhagic shock., Methods: A total of 24 male Wistar albino rats weighing between 200 and 250 g were used in this study. The rats were divided into four groups as: Control, hypotonic, isotonic, and hypertonic. Median laparotomy, colon resection, and colocolonic anastomosis were performed to the rats in the control group. After creating controlled hemorrhagic shock to rats in other three groups, resuscitation was achieved with hypotonic, isotonic, and hypertonic saline. After resuscitation, median laparotomy, colon resection, and colocolonic anastomosis were performed on rats in these three groups. On the 5th post-operative day, a median laparotomy was applied to the rats in all groups and anastomosis lines were evaluated. Anastomotic bursting pressure, tissue hydroxyproline level, and tissue fibrosis degree were compared between the groups., Results: There was no statistically significant difference between the groups in terms of anastomotic bursting pressure, tissue hydroxyproline level, and tissue fibrosis degree (respectively; p=0.320, p=0.537, p>0.05)., Conclusion: In rats with controlled hemorrhagic shock, resuscitation with hypertonic saline does not differ significantly from isotonic or hypotonic saline in terms of healing of colonic anastomosis.

Background: Improper or delayed activation of a massive transfusion protocol may have consequences to individuals and institutions. We designed a complex predictive algorithm that was packaged within a smartphone application. We hypothesized it would accurately assess the need for massive transfusion protocol activation and assist clinicians in that decision., Methods: We prospectively enrolled patients at an urban, level I trauma center. The application recorded the surgeon's initial opinion for activation and then prompted inputs for the model. The application provided a prediction and recorded the surgeon's final decision on activation., Results: Three hundred and twenty-one patients were enrolled (83% male; 59% penetrating; median Injury Severity Score 9; mean base deficit -4.11). Of 36 massive transfusion protocol activations, 26 had an app prediction of "high" or "moderate" probability. Of these, 4 (15%) patients received <10 u blood as a result of early hemorrhage control. Two hundred and eighty-five patients did not have massive transfusion protocol activated by the surgeon with 27 (9%) patients having "moderate" or "high" likelihood predicted by the application. Twenty-four of these did not require massive transfusion, and all patients had acidosis that unrelated to hemorrhagic shock. For 13 (50%) of the patients with "high" probability, the surgeon correctly altered their initial decision based on this information. The algorithm demonstrated an adjusted accuracy of 0.96 (95% confidence interval [0.93-0.98); P ≤ .001]), sensitivity = 0.99, specificity 0.72, positive predictive value 0.96, negative predictive value 0.99, and area under the receiver operating curve = 0.86., Conclusion: A smartphone-based clinical decision tools can aid surgeons in the decision to active massive transfusion protocol in real time, although it does not completely replace clinician judgment., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Hemorrhagic shock has recently been shown to cause shedding of a carbohydrate surface layer of endothelial cells known as the glycocalyx. This shedding of the glycocalyx is thought to be a mediator of the coagulopathy seen in trauma patients. Clinical studies have demonstrated increases in shed glycocalyx in the blood after trauma, and animal studies have measured glycocalyx disruption in blood vessels in the lung, skeletal muscle, and mesentery. However, no study has measured glycocalyx disruption across a wide range of vascular beds to quantify the primary locations of this shedding., Methods: In the present study, we used a rat model of hemorrhagic shock and resuscitation to more comprehensively assess glycocalyx disruption across a range of organs. Glycocalyx disruption was assessed by fluorescent-labeled wheat germ agglutinin or syndecan-1 antibody staining in flash frozen tissue., Results: We found that our model did elicit glycocalyx shedding, as assessed by an increase in plasma syndecan-1 levels. In tissue sections, we found that the greatest glycocalyx disruption occurred in vessels in the lung and intestine. Shedding to a lesser extent was observed in vessels of the brain, heart, and skeletal muscle. Liver vessel glycocalyx was unaffected, and kidney vessels, including the glomerular capillaries, displayed an increase in glycocalyx. We also measured reactive oxygen species (ROS) in the endothelial cells from these organs, and found that the greatest increase in ROS occurred in the two beds with the greatest glycocalyx shedding, the lungs, and intestine. We also detected fibrin deposition in lung vessels following hemorrhage-resuscitation., Conclusions: We conclude that the endothelium in the lungs and intestine are particularly susceptible to the oxidative stress of hemorrhage-resuscitation, as well as the resulting glycocalyx disruption. Thus, these two vessel beds may be important drivers of coagulopathy in trauma patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Background: Blood transfusion via single site intraosseous access is a critical modality when caring for a trauma victim that lacks intravascular access. Flow rates and potential clinical complications when utilizing two sites of intraosseous access are not well known., Materials and Methods: Anesthetized adult female Yorkshire swine (Sus scrofa; n = 48; 76.7 ± 1.75kg; range 66-90kg) were cannulated and then bled approximately 30% total blood volume. Swine were randomly assigned to treatment groups: single sited humerus, single sited sternum, dual sited humerus or dual sited humerus and sternum. Flow rates, hemolysis, physiologic measurements, biochemical variables, and pulmonary histologic inflammation and occlusion were contrasted between groups., Results: Dual sited intraosseous transfusion flow rates (128ml/min, 95% CI 123-132) were double the flow rates of single sites (65ml/min, 95% CI 60-70), P < .0001.Single sited humeral flow rates were greater than sternal flow rates, with respective averages of 74ml/min and 55ml/min, though not reaching statistical significance (P < 0.17). There was no significant elevation of plasma free hemoglobin in any group after transfusion as compared to baseline (P = 0.7). Groups did not significantly differ in vitals or biochemical variables. Most pulmonary specimens had some intraparenchymal fat embolism, however no animals had evidence of occlusive intra-arterial fat embolism., Conclusions: Dual anatomic site, pressure bag driven, intraosseous blood transfusion approximately doubles flow rates without evidence of clinical complications or hemolysis. Further research using a survivability model is needed to characterize long-term complications from pressurized IO transfusions., (Published by Elsevier Inc.)

Whole blood transfusion (WBT) began in 1667 as a treatment for mental illness, with predictably poor results. Its therapeutic utility and widespread use were initially limited by deficiencies in transfusion science and antisepsis. James Blundell, a British obstetrician, was recognized for the first allotransfusion in 1825. However, WBT did not become safe and therapeutic until the early 20 th century, with the advent of reliable equipment, sterilization, and blood typing. The discovery of citrate preservation in World War I allowed a separation of donor from recipient and introduced the practice of blood banking. During World War II, Elliott and Strumia were the first to separate whole blood into blood component therapy (BCT), producing dried plasma as a resuscitative product for "traumatic shock." During the 1970s, infectious disease, blood fractionation, and financial opportunities further drove the change from WBT to BCT, with few supporting data. Following a period of high-volume crystalloid and BCT resuscitation well into the early 2000s, measures to avoid the resulting iatrogenic resuscitation injury were developed under the concept of damage control resuscitation. Modern transfusion strategies for hemorrhagic shock target balanced BCT to reapproximate whole blood. Contemporary research has expanded the role of WBT to therapy for the acute coagulopathy of trauma and the damaged endothelium. Many US trauma centers are now using WBT as a front-line treatment in tandem with BCT for patients suffering hemorrhagic shock. Looking ahead, it is likely that WBT will once again be the resuscitative fluid of choice for patients in hemorrhagic shock., (Copyright © 2021 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Introduction: Electrical vagal nerve stimulation is known to decrease gut permeability and alleviate gut injury caused by traumatic hemorrhagic shock. However, the specific mechanism of action remains unclear. Glycocalyx, located on the surface of the intestinal epithelium, is associated with the buildup of the intestinal barrier. Therefore, the goal of our study was to explore whether vagal nerve stimulation affects enterocyte glycocalyx, gut permeability, gut injury, and remote lung injury., Materials and Methods: Male Sprague Dawley rats were anesthetized and their cervical nerves were exposed. The rats underwent traumatic hemorrhagic shock (with maintenance of mean arterial pressure of 30-35 mmHg for 60 min) with fluid resuscitation. Vagal nerve stimulation was added to two cohorts of animals before fluid resuscitation, and one of them was injected with methyllycaconitine to block the cholinergic anti-inflammatory pathway. Intestinal epithelial glycocalyx was detected using immunofluorescence. Intestinal permeability, the degree of gut and lung injury, and inflammation factors were also assessed., Results: Vagal nerve stimulation alleviated the damage to the intestinal epithelial glycocalyx and decreased intestinal permeability by 43% compared with the shock/resuscitation phase (P < 0.05). Methyllycaconitine partly eliminated the effects of vagal nerve stimulation on the intestinal epithelial glycocalyx (P < 0.05). Vagal nerve stimulation protected against traumatic hemorrhagic shock/fluid resuscitation-induced gut and lung injury, and some inflammatory factor levels in the gut and lung tissue were downregulated after vagal nerve stimulation (P < 0.05)., Conclusions: Vagal nerve stimulation could relieve traumatic hemorrhagic shock/fluid resuscitation-induced intestinal epithelial glycocalyx damage via the cholinergic anti-inflammatory pathway., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.)

Background: The pediatric age-adjusted shock index (SIPA) accurately identifies severely injured children following trauma without accounting for neurological status. Understanding how the presence of traumatic brain injury (TBI) affects the generalizability of SIPA as a bedside triage tool is important given high rates of TBI in the pediatric trauma population. We hypothesized that SIPA combined with TBI (SIPAB+) would more accurately identify severely injured children., Methods: Patients (1-18 years old) in the American College of Surgeons Pediatric Trauma Quality Improvement Program database (2014-2017) with an elevated SIPA upon arrival to a pediatric trauma center were included. Pediatric age-adjusted shock index combined with TBI was defined as elevated SIPA with Glasgow Coma Scale score of ≤8. Pediatric age-adjusted shock index without TBI (SIPAB-) was defined as elevated SIPA with Glasgow Coma Scale score of >9. Patients were stratified into SIPAB+ and SIPAB-. A subanalysis of patients with isolated brain injury and those with brain injury and multisystem injuries was also performed. Data were compared through univariate models and three separate logistic regression models., Results: Overall, 25,068 had an elevated SIPA, with 12.3% classified as SIPAB+ and the remainder SIPAB-. Patients classified as SIPAB+ received more blood transfusions within 4 hours of injury and had higher mortality rates. On logistic regression, SIPAB+ patients had significantly higher odds of early blood transfusion and a combination of both. Mortality and early blood transfusion were also higher in SIPAB+ patients on subanalysis for patients with isolated TBI and those with multisystem injuries., Conclusion: The use of SIPAB+ as a bedside triage tool accurately identifies traumatically injured children at high risk for early blood transfusion and/or death while incorporating the presence of neurological injury. This is true for patients with isolated TBI and those with multisystem injury, indicating its utility in predicting outcomes for TBI patients with elevated SIPA regardless of presence of concomitant injuries. Incorporation of this as a triage tool should be considered to better predict resources in this population., Level of Evidence: Prognostic, level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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 (LR 70 ), LR 60 , WB 70 , WB 60 , 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 LR 60 ( p  < 0.002) and WB 70 ( p  < 0.007) but not LR 70 or WB 60 . 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.

Trauma is a major source of morbidity and mortality for children worldwide; life-threatening hemorrhage is a primary cause of preventable death. Essential interventions in children with life-threatening hemorrhage include hemostatic resuscitation and mechanical control of bleeding. Herein we review pediatric hemostatic resuscitation, a strategy that addresses both hemorrhagic shock and the coagulopathic complications described in patients with major hemorrhage. Some components of hemostatic resuscitation may include: early and aggressive resuscitation with blood products, minimizing crystalloid and hemodilution, antifibrinolytic adjuncts such as tranexamic acid, and the novel use of low-titer group O whole-blood (LTOWB) transfusion in injured children. The following selection of important publications address the current state of hemostatic resuscitation strategies in pediatric trauma patients as well as the remaining knowledge gaps and areas for further research., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest to disclose., (Copyright © 2021. Published by Elsevier Inc.)

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., Competing Interests: Disclosure: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Low-titer group O whole blood (LTO-WB) has recently gained popularity in trauma centers for the acute resuscitation of hemorrhagic shock. However, limited supplies of Rh- product prevent implementation and strain sustainability at many trauma centers. We set out to identify whether Rh+ LTO-WB could be safely substituted for RH- product, regardless of patient's Rh status., Methods: Following Institutional Review Board approval, information on all trauma patients receiving prehospital or emergency department transfusion of uncrossed, emergency release LTO-WB (11/17-10/19) were evaluated. Patients were first divided into those who received Rh- versus Rh+ product, the assessed by Rh of the recipient. Serial hemolysis panels, transfusion reactions, and outcomes were compared., Results: Six hundred thirty-seven consecutive trauma patients received emergency release LTO-WB. Of these, 448 received Rh+ product, while 189 received Rh- LTO-WB. Patients receiving Rh+ product were more likely to be men (81 vs. 70%) and have lower field blood pressure (median 99 vs. 109) and GCS (median 7 vs. 12); all p < 0.05. There were no differences in blood product volume, hemolysis laboratories, transfusion reactions, complications, or survival. We then separated patients by Rh status (577 were Rh+, 70 were Rh-). Rh- patients were older (median age 54 vs. 39), more likely to be women (57 vs. 26%), and more likely to have sustained blunt trauma than their Rh+ counterparts (92 vs. 70%); all p < 0.05. There were no differences in hemolysis laboratories, transfusion reactions, complications, or survival between Rh+ and Rh- patients, regardless of Rh product received., Conclusion: When Rh- whole blood is unavailable or in short supply, Rh+ LTO-WB appears to be a safe alternative for the resuscitation of hemorrhagic shock in both Rh+ and Rh- patients. Use of Rh+ product may help trauma centers incorporate LTO-WB into their hospital and improve sustainability of such programs., Level of Evidence: Therapeutic, Level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Pelvic ring injuries presenting in hemorrhagic shock have historically had a mortality rate greater than 30%. To address this high mortality rate our institution has had a multi-disciplinary protocol for hemodynamically unstable pelvic ring injuries since 1993. In 2004, this protocol was revised to prioritize pre-peritoneal pelvic packing over angiography to rapidly control hemorrhage, reduce high-volume blood transfusions, and decrease the number of deaths from acute blood loss. This protocol has been successful in reducing deaths from hemorrhage by 30%. Despite the benefits of such a protocol, many trauma centers are not routinely stabilizing pelvic ring injuries or controlling pelvic hemorrhage. Subsequently, mortality rates remain high with a significant proportion of patients dying from acute blood loss. Trauma centers adhering to multi-disciplinary protocols that allow for rapid stabilization of the pelvis and simultaneous control of multiple sites of hemorrhage in hybrid operative suites are promising future directions for the management of patients with these lethal injuries., Competing Interests: Declaration of Competing Interest None of the authors have anything to declare., (Copyright © 2020. Published by Elsevier Ltd.)

Background: While massive transfusion protocols (MTPs) are associated with decreased mortality in adult trauma patients, there is limited research on the impact of MTP on pediatric trauma patients. The purpose of this study was to compare pediatric trauma patients requiring massive transfusion with all other pediatric trauma patients to identify triggers for MTP activation in injured children., Methods: Using our level I trauma center's registry, we retrospectively identified all pediatric trauma patients from January 2015 to January 2018. Massive transfusion (MT) was defined as infusion of 40 mL/kg of blood products in the first 24 hours of admission. Patients missing prehospital vital sign data were excluded from the study. We retrospectively collected data including demographics, blood utilization, variable outcome data, prehospital vital signs, prehospital transport times, and Injury Severity Scores. Statistical significance was determined using Mann-Whitney U test and χ2 test. p Values of less than 0.05 were considered significant., Results: Thirty-nine (1.9%) of the 2,035 pediatric patients met the criteria for MT. All-cause mortality in MT patients was 49% (19 of 39 patients) versus 0.01% (20 of 1996 patients) in non-MT patients. The two groups significantly differed in Injury Severity Score, prehospital vital signs, and outcome data.Both systolic blood pressure (SBP) of <100 mm Hg and shock index (SI) of >1.4 were found to be highly specific for MT with specificities of 86% and 92%, respectively. The combination of SBP of <100 mm Hg and SI of >1.4 had a specificity of 94%. The positive and negative predictive values of SBP of <100 mm Hg and SI of >1.4 in predicting MT were 18% and 98%, respectively. Based on positive likelihood ratios, patients with both SBP of <100 mm Hg and SI of >1.4 were 7.2 times more likely to require MT than patients who did not meet both of these vital sign criteria., Conclusion: Pediatric trauma patients requiring early blood transfusion present with lower blood pressures and higher heart rates, as well as higher SIs and lower pulse pressures. We found that SI and SBP are highly specific tools with promising likelihood ratios that could be used to identify patients requiring early transfusion., Level of Evidence: Therapeutic/care management, level V., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: It is difficult to estimate the ischemic consequences when using partial resuscitative endovascular balloon occlusion of the aorta (REBOA). The aim was to investigate if end-tidal carbon dioxide (ETCO2) is correlated to degree of aortic occlusion, measured as distal aortic blood flow, and distal organ metabolism, estimated as systemic oxygen consumption (VO2), in a porcine model of normovolemia and hemorrhagic shock., Materials and Methods: Nine anesthetized pigs (25-32 kg) were subjected to incremental steps of zone 1 aortic occlusion (reducing distal aortic blood flow by 33%, 66%, and 100%) during normovolemia and hemorrhagic grade IV shock. Hemodynamic and respiratory variables, and blood samples, were measured. Systemic VO2 was correlated to ETCO2 and measures of partial occlusion previously described., Results: Aortic occlusion gradually lowered distal blood flow and pressure, whereas ETCO2, VO2 and carbon dioxide production decreased at 66% and 100% aortic occlusion. Aortic blood flow correlated significantly to ETCO2 during both normovolemia and hemorrhage (R = 0.84 and 0.83, respectively) and to femoral mean pressure (R = 0.92 and 0.83, respectively). Systemic VO2 correlated strongly to ETCO2 during both normovolemia and hemorrhage (R = 0.91 and 0.79, respectively), blood flow of the superior mesenteric artery (R = 0.77 and 0.85, respectively) and abdominal aorta (R = 0.78 and 0.78, respectively), but less to femoral blood pressure (R = 0.71 and 0.54, respectively)., Conclusion: ETCO2 was correlated to distal aortic blood flow and VO2 during incremental degrees of aortic occlusion thereby potentially reflecting the degree of aortic occlusion and the ischemic consequences of partial REBOA. Further studies of ETCO2, and potential confounders, in partial REBOA are needed before clinical use., Competing Interests: The authors wish to report no conflicts of interest related to the subject matter., (Copyright © 2021 by the Shock Society.)

Background: Massive transfusion (MT) is required to resuscitate traumatically injured patients with complex derangements. Scoring systems for MT typically require laboratory values and radiological imaging that may delay the prediction of MT., Study Design: The Trauma ALgorithm Examining the Risk of massive Transfusion (Trauma ALERT) study was an observational cohort study. Prehospital and admission ALERT scores were constructed with logistic regression of prehospital and admission vitals, and FAST examination results. Internal validation was performed with bootstrap analysis and cross-validation., Results: The development cohort included 2,592 patients. Seven variables were included in the prehospital ALERT score: systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), respiratory rate (RR), SpO2, motor Glasgow Coma Scale (GCS) score, and penetrating mechanism. Eight variables from 2,307 patients were included in the admission ALERT score: admission SBP, HR, RR, GCS score, temperature, FAST examination result, and prehospital SBP and DBP.The area under the receiving operator characteristic curve for the prehospital and admission models were 0.754 (95% bootstrapped CI 0.735-0.794, P < 0.001) and 0.905 (95% bootstrapped CI 0.867-0.923, P < 0.001), respectively. The prehospital ALERT score had equivalent diagnostic accuracy to the ABC score (P = 0.97), and the admission ALERT score outperformed both the ABC and the prehospital ALERT scores (P < 0.0001)., Conclusion: The prehospital and admission ALERT scores can accurately predict massive transfusion in trauma patients without the use of time-consuming laboratory studies, although prospective studies need to be performed to validate these findings. Early identification of patients who will require MT may allow for timely mobilization of scarce resources and could benefit patients by making blood products available for treating hemorrhagic shock., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Patients presenting with hemodynamic instability associated with pelvic fractures continue to have very high mortality and surgeons continue to seek damage control strategies that may improve survival. Strategies usually require massive transfusion, immediate pelvic stabilization and another adjunctive maneuver's such as angioembolization or preperitoneal pelvic packing to prevent hemorrhagic death. One current intervention that has regained some popularity in lieu of resuscitative thoracotomy is the Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA). This requires some manner of femoral arterial access to insert a balloon into the aorta and increase central blood pressure (cardiac and cerebral perfusion) and control active pelvic bleeding. Based on several animal models and an increasing number of publications, many US level I trauma centers have now opted to use REBOA in carefully selected patients showing signs of near cardiac arrest from non-compressible torso hemorrhage. Description of the current advances in aortic occlusion using catheter-based technology in the setting of severe shock for non-compressible torso hemorrhage from pelvic ring fracture is the purpose of this report., Competing Interests: Declaration of Competing Interest The first and third author have no conflicts of interest to disclose. The corresponding author is on the clinical advisory board of Prytime Medical, Inc., (Copyright © 2020. Published by Elsevier Ltd.)

Patients with a pelvic ring injury and hemodynamic instability can be challenging to manage with high rates of morbidity and mortality rates. Protocol-based resuscitation strategies are critical to successfully manage these potentially severely injured patients in a well-coordinated manner. While some aspects of treatment may vary slightly from institution to institution, it is critical to identify pelvic injuries and their associated injuries expediently. The first step at the scene of injury or in the trauma resuscitation bay should be the immediate application of a circumferential pelvic sheet or binder, initiation of physiologically optimal fluid resuscitation in the form 1:1:1 (pRBC:FFP:platelets) or whole blood, and to consider TXA as a safe adjunct to treat coagulopathy. Providers should have a very low threshold for emergent operative intervention in the form of pelvic external fixation and/or pelvic packing. This occurs in addition to simultaneous interventions addressing the other possible sources of bleeding in patients demonstrating signs of hemorrhagic shock and failure to respond to early resuscitation and external pelvic tamponade. Finally, while arterial injury is only present in a small percentage of patients with a pelvic ring injury, percutaneous vascular intervention with selective angiography and REBOA have been shown to be efficacious for patients with clinical indicators of arterial injury or who remain hemodynamically unstable despite external pelvic tamponade and packing to address venous bleeding. They should be performed when as early as possible for patients in true extremis limit further hemorrhage and allow resuscitation efforts to continue., Competing Interests: Declaration of Competing Interest None, (Published by Elsevier Ltd.)

Abstract: Resuscitative endovascular balloon occlusion of the aorta (REBOA) allows for effective temporization of exsanguination from non-compressible hemorrhage (NCTH) below the diaphragm. However, the therapeutic window for aortic occlusion is time-limited given the ischemia-reperfusion injury generated. Significant effort has been put into translational research to develop new strategies to alleviate the ischemia-reperfusion injury and extend the application of endoaortic occlusion. Targeted regional optimization (TRO) is a partial REBOA strategy to augment proximal aortic and cerebral blood flow while targeting minimal threshold of distal perfusion beyond the zone of partial aortic occlusion. The objective of TRO is to reduce the degree of ischemia caused by complete aortic occlusion while providing control of distal hemorrhage. This review provides a synopsis of the concept of TRO, pre-clinical, translational experiences with TRO and early clinical outcomes. Early results from TRO strategies are promising; however, further studies are needed prior to large-scale implementation into clinical practice., Competing Interests: DGB is employed by Prytime Medical Inc. and help to write and edit portions of this manuscript as part of his employment responsibilities. AER, MJM, JDB, JEP, DMB, TER, and JMW have no significant financial conflicts of interest related to this paper. DGB is employed by Prytime Medical and help to write and edit portions of this manuscript as part of his employment responsibilities. Prytime Medical produces some of the devices discussed in this manuscript. AER, MJM, JDB, JEP, DMB, TER, and JMW have no significant financial conflicts of interest related to this paper., (Copyright © 2021 by the Shock Society.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Valade, Libert, Martinaud, Vicaut, Banzet and Peltzer.)

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a technique that uses internal clamping of the aorta to control abdominal, pelvic, or junctional bleeding. We created a course to train military physicians in both civilian prehospital use and battlefield use. To determine the effectiveness of this training, we conducted REBOA training for French military emergency physicians., Methods: We trained 15 military physicians, organizing the training as follows: a half-day of theoretical training, a half-day of training on mannequins, a half-day on human corpses, and a half-day on a living pig. The primary endpoint was the success rate after training. We defined success as the balloon being inflated in zone 1 of a PryTime mannequin. The secondary endpoints were the progression of each trainee during the training, the difference between the median completion duration before and after training, the median post-training duration, and the median duration for the placement of the sheath introducer before and after training., Results: Fourteen of the physicians (93%) correctly placed the balloon in the mannequin at the end of the training period. During the training, the success rate increased from 73% to 93% (p = .33). The median time for REBOA after training was only 222 seconds (interquartile range [IQR] 194-278), significantly faster than before training (330 seconds, IQR 260-360.5; p = .0033). We also found significantly faster sheath introducer placement (148 seconds, IQR 126-203 versus 145 seconds, IQR 115.5 - 192.5; p = .426)., Conclusion: The training can be performed successfully and paves the way for the use of REBOA by emergency physicians in austere conditions., (2021.)

Background: In addition to reflecting gas exchange within the lungs, end-tidal carbon dioxide (ETCO2) also reflects cardiac output based on CO2 delivery to the pulmonary parenchyma. We hypothesized that low prehospital ETCO2 values would be predictive of hemorrhagic shock in intubated trauma patients., Methods: A retrospective observational study of adult trauma patients intubated in the prehospital setting and transported to a single Level I trauma center from 2016 to 2019. Continuous prehospital ETCO2 data were linked with patient care registries. We developed a novel analytic approach that allows for reflection of prehospital ETCO2 over the entire prehospital course of care. The primary outcome was hemorrhagic shock on emergency department (ED) presentation, defined as either initial ED systolic blood pressure of 90 mm Hg or less or initial Shock Index (SI) > 0.9, and transfusion of at least one unit of blood product during their ED stay. Prehospital ETCO2 less than 25 mm Hg was evaluated for predictive value of hemorrhagic shock., Results: Three hundred and seven patients (82% men, 34% penetrating injury, 42% in hemorrhagic shock on ED arrival, 27% mortality) were included in the study. Patients in hemorrhagic shock had lower median ETCO2 values (26.5 mm Hg vs. 32.5 mm Hg; p < 0.001) than those not in hemorrhagic shock. Patients with prehospital ETCO2 less than 25 mm Hg were 3.0 times (adjusted odds ratio = 3.0; 95% confidence interval, 1.1-7.9) more likely to be in hemorrhagic shock upon ED arrival than patients with ETCO2 ≥ 25 mm Hg., Conclusion: Intubated patients with hemorrhagic shock upon ED arrival had significantly lower prehospital ETCO2 values. Incorporating ETCO2 assessment into prehospital care for trauma patients could support decisions regarding prehospital blood transfusion, and triage to higher-level trauma centers, and trauma team activation., Level of Evidence: Prognostic, level III., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The benefits of plasma as an adjunct to the treatment of haemorrhagic shock are well established; however, the mechanism by which plasma modulates the endotheliopathy of trauma remains unclear. Our recent data demonstrated a novel role of microRNA-19b in post-haemorrhagic shock endothelial dysfunction via targeting of syndecan-1. Additionally, fibrinogen, as a key component of plasma or an isolated haemostatic protein, protects the endothelium by stabilizing syndecan-1. We therefore hypothesized that fibrinogen would inhibit microRNA-19b to mitigate the endotheliopathy of trauma in a murine model of haemorrhagic shock., Materials and Methods: C57BL/6J mice were subjected to haemorrhagic shock (mean arterial pressure 35±5 mmHg for 90 minutes) followed by resuscitation with lactated Ringer's, fresh frozen plasma, fibrinogen or no resuscitation. MicroRNA-19b and syndecan-1 mRNA were measured in lung tissue by qRT-PCR. Lungs were stained for histopathologic injury, and broncheoalveolar lavage was collected for protein as a permeability indicator., Results: Pulmonary microRNA-19b was increased after haemorrhagic shock and lactated Ringers, but reduced to sham levels by plasma and fibrinogen. Conversely, pulmonary syndecan-1 mRNA was downregulated by haemorrhagic shock and lactated Ringers, but returned to sham levels by plasma and fibrinogen. Plasma and fibrinogen-based resuscitation reduced lung injury compared to haemorrhagic shock and lactated Ringers while fibrinogen also reduced broncheoalveolar lavage protein., Discussion: We have demonstrated a novel mechanism by which fibrinogen, a key component of plasma and haemostatic agent, inhibits miR-19b, possibly by mitigating the endotheliopathy of trauma. Complete demonstration of the mechanism of fibrinogen inhibition of endotheliopathy via microRNA, however, remains to be elucidated. These findings support the early and empiric use of fibrinogen in post-haemorrhagic shock resuscitation.

Trauma is a leading cause of death. Optimal outcomes depend on a coordinated effort. Providers must be prepared to act in an organized and methodical manner. Recognizing and immediately treating causes of shock after trauma offer the best chance of survival to the patient. Incorporating evidence-based knowledge and resuscitation techniques learned from the military, the trauma victim experiencing acute hypovolemia has better outcomes because of advances in the clinical management of blood loss than ever before. Treatment focuses primarily on stopping the bleeding, providing damage control resuscitation, and monitoring and treating the patient for signs of shock. If the patient can be stabilized and avoid the lethal trauma triad, definitive surgical care can be achieved., Competing Interests: Disclosure This author has no financial or conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Early assessment of the clinical status of trauma patients is crucial for guiding the treatment strategy, and it requires a rapid and systematic approach. The aim of this report is to critically review the assessment parameters currently used in the prehospital setting to quantify blood loss in trauma., Data Sources: Studies regarding hemorrhagic shock in trauma were pooled from PubMed, EMBASE, and Cochrane databases using key words such as "hemorrhagic shock," "vital signs evaluation," "trauma," "blood loss," and "emergency medical service," alone or combined., Study Selection: Articles published since 2009 in English and Italian were considered eligible if containing data on assessment parameters in blood loss in adults., Data Extraction: Sixteen articles matching the inclusion criteria were considered in our study., Data Synthesis: Current prehospital assessment measures lack precise correlation with blood loss., Conclusions: Traditional assessment parameters such as heart rate, systolic blood pressure, shock index, and Glasgow Coma Scale score often lag in providing accurate blood loss assessment. The current literature supports the need for a noninvasive, continuously monitored assessment parameter to identify early shock in the prehospital setting., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Society of Trauma Nurses.)

Extracellular vesicles (EVs) present a great potential for the development of new treatments in the biomedical field. To be used as therapeutics, many different sources have been used for EVs obtention, while only a few studies have addressed the use of platelet-derived EVs (pEVs). In fact, pEVs have been shown to intervene in different healing responses, thus some studies have evaluated their regenerative capability in wound healing or hemorrhagic shock. Even more, pEVs have proven to induce cellular differentiation, enhancing musculoskeletal or neural regeneration. However, the obtention and characterization of pEVs is widely heterogeneous and differs from the recommendations of the International Society for Extracellular Vesicles. Therefore, in this review, we aim to present the main advances in the therapeutical use of pEVs in the regenerative medicine field while highlighting the isolation and characterization steps followed. The main goal of this review is to portray the studies performed in order to enhance the translation of the pEVs research into feasible therapeutical applications.

Objective: The shortage of viable lungs is still a major obstacle for transplantation. Trauma victims who represent potential lung donors commonly present hypovolemic shock leading to pulmonary inflammation and deterioration and rejection after transplantation. Seeking to improve lung graft, new approaches to donor treatment have been tested. This study focuses on treatment with mesenchymal stem cells (MSCs) or soluble factors produced by MSCs (FS-MSC) using a rat model for lung donors after hemorrhagic shock., Methods: Forty-eight rats were divided into four groups: Sham (n=12), animals without induction of hypovolemic shock; Shock (n=12), animals submitted to hypovolemic shock (mean arterial pressure 40 mmHg); MSC (n=12), animals submitted to hypovolemic shock and treated with MSCs, and FS (n=12), animals submitted to hypovolemic shock and treated with FS-MSC. The animals were subjected to a 50-minute hypovolemic shock (40 mmHg) procedure. The treated animals were monitored for 115 minutes. We performed histopathology of lung tissue and quantification of inflammatory markers (TNF-α, IL-1β, IL-6, IL-10, iCAM and vCAM) in lung tissue and peripheral blood leukocytes (PBLs)., Results: Hemorrhagic shock resulted in higher PBLs and neutrophil infiltrate in the lungs. FS animals had lower neutrophil density comparing with Shock and MSC animals (p<0.001). No differences in the cytokine levels in lung tissue were observed between the groups., Conclusions: The lungs of rats submitted to hemorrhagic shock and treated with FS-MSC showed reduced inflammation indicated in a decrease in lung neutrophil infiltrate.

Background: Organ damages following hemorrhagic shock (HS) have been partly attributed to an immunological dysfunction. The current challenge in the management of HS patients is to prevent organ injury-induced morbidity and mortality which currently has not etiological treatment available. Mesenchymal stromal cells (MSC) are used in clinical cell therapy for immunomodulation and tissue repair. In vitro priming is often used to improve the immunomodulation efficiency of MSC before administration., Objective: Assess the effect of naive MSC (MSCn) or interleukin (IL)-1β primed (MSCp) treatment in a context of HS-induced organ injury., Methods: Rats underwent fixed pressure HS and were treated with allogenic MSCn or MSCp. Liver and kidney injuries were evaluated 6h later by histological and biochemical analysis. Whole blood was collected to measure leukocytes phenotypes. Then, in vitro characterization of MSCn or MSCp was carried out., Results: Plasma creatinine, blood urea nitrogen, and cystatin C were decrease by MSCp infusion as well as kidney injury molecule (KIM)-1 on histological kidney sections. Transaminases, GGT, and liver histology were normalized by MSCp. Systemic cytokines (IL-1α, IL-6, and IL-10) as well as CD80, 86, and PD-1/PDL-1 axis were decreased by MSCp on monocytes and granulocytes. In vitro, MSCp showed higher level of secreted immunomodulatory molecules than MSCn., Conclusion: An early administration of MSCp moderates HS-induced kidney and liver injury. IL-1β priming improves MSC efficiency by promoting their immunomodulatory activity. These data provide proof of concept that MSCp could be a therapeutic tool to prevent the appearance of organs injury following HS., (© 2021. The Author(s).)

Background: Epigenetic changes have been described in trauma patients in the form of histone acetylation events, but whether DNA-methylation occurs remains unknown. We hypothesized that the combination of hemorrhage and saline resuscitation would alter DNA-methylation and associated proteomic profiles in the rat lung., Methods: Ten rats were subjected to a pressure-controlled hemorrhage and resuscitation model consisting of hemorrhage to a mean arterial pressure (MAP) of 35mmHg for 90 minutes, followed by saline resuscitation to a MAP >70mmHg for 90 minutes (n=5) or sham (only anesthesia and cannulation). Lungs were harvested and subjected to reduced genome wide DNA-methylation analysis through bisulphite sequencing as well as proteomics analysis. Data was analyzed for differentially methylated regions and associated alterations in proteomic networks through a weighted correlation network analysis (WCNA). Pathway analysis was used to establish biological relevance of findings., Results: Hemorrhage and saline resuscitation were associated with differential methylation of 353 sites across the genome compared to the sham group. Of these, 30 were localized to gene promoter regions, 31 to exon regions and 87 to intron regions. Network analysis identified an association between hemorrhage/resuscitation and DNA-methylation events located to genes involved in areas of endothelial and immune response signaling. The associated proteomic response was characterized by activations of mRNA processing as well as endothelial Nitric Oxide Synthase (eNOS) metabolism., Conclusion: We demonstrated an association between DNA-methylation and hemorrhage/saline resuscitation. These results suggest a potential role of DNA-methylation in the host response to injury., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Noncompressible hemorrhage is a leading cause of potentially survivable combat death, with the vast majority of such deaths occurring in the out-of-hospital environment. While large animal models of this process are important for device and therapeutic development, clinical practice has changed over time and past models must follow suit. Developed in conjunction with regulatory feedback, this study presents a modernized, out-of-hospital, noncompressible hemorrhage model, in conjunction with a randomized study of past, present, and future fluid options following a hypotensive resuscitation protocol consistent with current clinical practice., Methods: We performed a randomized controlled experiment comparing three fluid resuscitation options in Yorkshire swine. Baseline data from animals of same size from previous experiments were analyzed (n = 70), and mean systolic blood pressure was determined, with a permissive hypotension resuscitation target defined as a 25% decrease from normal (67 mm Hg). After animal preparation, a grade IV to V liver laceration was induced. Animals bled freely for a 10-minute "time-to-responder" period, after which resuscitation occurred with randomized fluid in boluses to the goal target: 6% hetastarch in lactated electrolyte injection (HEX), normal saline (NS), or fresh whole blood (FWB). Animals were monitored for a total simulated "delay to definitive care" period of 2 hours postinjury., Results: At the end of the 2-hour study period, 8.3% (1 of 12 swine) of the HEX group, 50% (6 of 12 swine) of the NS group, and 75% (9 of 12 swine) of the FWB had survived (p = 0.006), with Holm-Sidak pairwise comparisons showing a significant difference between HEX and FWB and (p = 0.005). Fresh whole blood had significantly higher systemic vascular resistance and hemoglobin levels compared with other groups (p = 0.003 and p = 0.001, respectively)., Conclusion: Survival data support the movement away from HEX toward NS and, preferably, FWB in clinical practice and translational animal modeling. The presented model allows for future research including basic science, as well as translational studies of novel diagnostics, therapeutics, and devices., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We evaluated the performance of a new device to control the administration of fluid alone or co-administration of fluid and norepinephrine in a pig model of haemorrhagic shock in two sets of experiments. In the first one, resuscitation was guided using continuous arterial pressure measurements (three groups: resuscitation with fluid by a physician, CL resuscitation with fluid, and CL resuscitation with fluid and norepinephrine). In the second one, resuscitation was guided using discontinuous arterial pressure measurements (three groups: CL resuscitation with fluid alone, CL resuscitation with fluid and moderate dose norepinephrine, and CL resuscitation with fluid and a high dose of norepinephrine). Pigs were resuscitated for 1 h. In the first set of experiments, proportion of time spent in the target area of 78-88 mmHg of systolic arterial pressure was not statistically different between the three groups: manual, 71.2% (39.1-80.1); CL with fluid, 87.8% (68.3-97.4); and CL with fluid and norepinephrine, 78.1% (59.2-83.6), p = 0.151. In the second set of experiments, performance of CL resuscitation with fluid or with combination of fluid and high or moderate dose of norepinephrine was not significantly different (p = 0.543 for time in target). Pigs resuscitated with norepinephrine required less fluid and had less haemodilution than pigs resuscitated with fluid alone. Performance of CL resuscitation using continuous arterial pressure measurement was not significantly different than optimised manual treatment by a dedicated physician. Performance of CL resuscitation was reduced with discontinuous arterial pressure measurements in comparison with continuous arterial pressure measurements., (© 2020. Springer Nature B.V.)

Background: We sought to determine the extent of loss of endothelial basement membrane (BM), leukocyte recruitment, and changes in coagulation after hemorrhagic shock, followed by limited-volume resuscitation (LVR) with 5% albumin (ALB)., Methods: Anesthetized rats were bled 40% of blood volume and assigned to treatment groups: untreated (n = 6), LVR with normal saline (NS; n = 8), or LVR with ALB (n = 8). Sham rats (n = 6) underwent all procedures except hemorrhage or resuscitation. Blood samples were assayed for active proteases, such as metalloproteinase 9 (MMP-9) and a disintegrin and metalloproteinase 10 (ADAM-10), BM-type heparan sulfate proteoglycan (perlecan), cell count, and coagulation function. Leukocyte transmigration was used to estimate the net efficiency of leukocyte recruitment in cremaster venules., Results: Hemorrhage significantly lowered red cell count, but white cell and platelet counts did not change (vs. sham). Ionized calcium in plasma was significantly reduced in untreated and remained so after NS. In contrast, ionized calcium was normalized after ALB. Plasma expansion after NS and ALB further reduced leukocyte and platelet counts. Metalloproteinase 9, ADAM-10, and perlecan were significantly higher in untreated rats (vs. sham). Albumin normalized MMP-9, ADAM-10, and perlecan levels, while NS further increased MMP-9, ADAM-10, and perlecan (vs. sham). Transmigrated leukocytes doubled in the untreated group and remained elevated after NS (vs. sham) but normalized after ALB. Albumin reduced every stage of the leukocyte recruitment process to sham levels., Conclusion: Despite similar plasma expansion, NS weakened platelet function contrary to ALB. Plasma expansion with ALB resulted in restoration of BM integrity and attenuation of leukocyte recruitment to tissues, in contrast to NS. Albumin plays a critical role in restoring BM integrity, attenuating leukocyte recruitment to tissues, and optimizing hemostasis by increasing ionized calcium in plasma., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Extracellular vesicles (EVs) isolated from cardiosphere-derived cells (CDC-EVs) are coming to light as a unique cell-free therapeutic. Because of their novelty, however, there still exist prominent gaps in knowledge regarding their therapeutic potential. Herein the therapeutic potential of CDC-EVs in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock is outlined., Methods: Extracellular vesicle surface expression of procoagulant molecules (tissue factor and phosphatidylserine) was evaluated by flow cytometry. Extracellular vesicle thrombogenicity was tested using calibrated thrombogram, and clotting parameters were assessed using a flow-based adhesion model simulating blood flow over a collagen-expressing surface. The therapeutic efficacy of EVs was then determined in a rat model of acute traumatic coagulopathy induced by multiple injuries and hemorrhagic shock., Results: Extracellular vesicles isolated from cardiosphere-derived cells are not functionally procoagulant and do not interfere with platelet function. In a rat model of multiple injuries and hemorrhagic shock, early administration of EVs significantly reduced the elevation of lactate and creatinine and did not significantly enhance coagulopathy in rats with acute traumatic coagulopathy., Conclusion: The results of this study are of great relevance to the development of EV products for use in combat casualty care, as our studies show that CDC-EVs have the potential to be an antishock therapeutic if administered early. These results demonstrate that research using CDC-EVs in trauma care needs to be considered and expanded beyond their reported cardioprotective benefits., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The Prehospital Air Medical Plasma (PAMPer) trial demonstrated a survival benefit to trauma patients who received thawed plasma as part of early resuscitation. The objective of our study was to examine the association between blood transfusion and nosocomial infections among trauma patients who participated in the PAMPer trial. We hypothesized that transfusion of blood products will be associated with the development of nosocomial infections in a dose-dependent fashion., Methods: We performed a secondary analysis of prospectively collected data of patients in the PAMPer trial with hospital length of stay of at least 3 days. Demographics, injury characteristics, and number of blood products transfused were obtained to evaluate outcomes. Bivariate analysis was performed to identify differences between patients with and without nosocomial infections. Two logistic regression models were created to evaluate the association between nosocomial infections and (1) any transfusion of blood products, and (2) quantity of blood products. Both models were adjusted for age, sex, and Injury Severity Score., Results: A total of 399 patients were included: age, 46 years (interquartile range, 29-59 years); Injury Severity Score, 22 (interquartile range, 12-29); 73% male; 80% blunt mechanism; and 40 (10%) deaths. Ninety-three (27%) developed nosocomial infections, including pneumonia (n = 67), bloodstream infections (n = 14), catheter-associated urinary tract infection (n = 10), skin and soft tissue infection (n = 8), Clostridium difficile colitis (n = 7), empyema (n = 6), and complicated intra-abdominal infections (n = 3). Nearly 80% (n = 307) of patients received packed red blood cells (PRBCs); 12% received cryoprecipitate, 69% received plasma, and 27% received platelets. Patients who received any PRBCs had more than a twofold increase in nosocomial infections (odds ratio, 2.15; 95% confidence interval, 1.01-4.58; p = 0.047). The number of PRBCs given was also associated with the development of nosocomial infection (odds ratio, 1.10; 95% confidence interval, 1.05-1.16; p < 0.001)., Conclusion: Trauma patients in the PAMPer trial who received a transfusion of at least 1 U of PRBCs incurred a twofold increased risk of nosocomial infection, and the risk of infection was dose dependent., Level of Evidence: Therapeutic/care management, level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Resuscitative endovascular balloon occlusion of the aorta (REBOA) increases proximal arterial pressure, but may also induce life-threatening distal ischemia. Partial REBOA (P-REBOA) is thought to mitigate distal ischemia during aortic occlusion. However, feasible indicators of the degree of P-REBOA remain inconsistent. We hypothesised percent balloon volume could be a substitute for pressure measurements of gradients during P- REBOA. This study aimed to compare balloon volume and arterial pressure gradient, and analysed with intra-balloon pressure and balloon shape., Methods: Proximal (carotid) and distal (femoral) arterial pressures were recorded and a 7-Fr REBOA catheter was placed in four swine. Total REBOA was defined as a cessation of distal pulse pressure and maximum balloon volume was documented. The balloon volume was titrated by 20% increments of maximum capacity to adjust the degree of P-REBOA. The distal/proximal arterial pressure gradient and the intra-balloon pressures were also recorded. The changes in shape and the cross-sectional area of the balloon were evaluated with computed tomography (CT) images., Results: The proximal mean arterial pressure (MAP) plateaued after 60% balloon volume; meanwhile, distal pulse pressure was still left. The balloon pressure was traced with proximal MAP before contact with aortic wall. The balloon shape changed unevenly from "cone" to "spindle" shape, although the balloon cross-sectional area of the mid-segment linearly increased., Conclusion: Monitoring distal pressure and titrating percent balloon volume is feasible to manage P-REBOA. In this experiment, 60% balloon volume was enough inflation to elevate central pressure allowing distal perfusion. The intra-balloon pressure was not reliable due to the strong influence of proximal MAP and uneven change of the balloon shape., (© 2019. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Military experience has shown low-titer O whole blood (LTOWB) to be safe and beneficial in the resuscitation of hemorrhaging trauma patients. However, few civilian centers use LTOWB for trauma resuscitation. We evaluated the early experience and safety of a LTOWB program at a level 1 civilian trauma center., Methods: We retrospectively reviewed our trauma registry from January 2018 to June 2020 for patients admitted in shock (defined as ≥1 of the following: heart rate, >120 beats per minute; systolic blood pressure, <90 mm Hg; or shock index, >0.9) who received blood products within 24 hours. Patients were grouped by resuscitation provided: LTOWB (group 1), component therapy (CT; group 2), and LTOWB-CT (group 3). Safety, outcomes, and variables associated with LTOWB transfusion and mortality were analyzed., Results: 216 patients were included: 34 in Group 1, 95 in Group 2, and 87 in Group 3. Patientsreceiving LTOWB were more commonly male (p<0.001) and had a penetrating injury (p=0.005). Groups 1 and 3 had higher median ISS scores compared to Group 2 (19 and 20 vs 17; p=0.01). Group 3 received more median units of blood product in the first 4h (p<0.001) and in the first 24h (p<0.001). There was no difference between groups in 24h mortality or transfusion-related complications (all p>0.05). Arrival ED SBP was associated with LTOWB transfusion (odds ratio [OR] 0.98, 95% confidence interval [CI] 0.95-1.00, p=0.03). ED lactate was independently associated with 24h mortality. (OR 1.27, CI 1.02-1.58, p=0.03). LTOWB transfusion was not associated with mortality (p=0.49). Abstract., Conclusion: Severely injured patients received LTOWB-CT and more overall product units but had similar 24 h mortality when compared with the LTOWB or CT groups. No increase in transfusion-related complications was seen after LTOWB transfusion. Low-titer O whole blood should be strongly considered in the resuscitation of trauma patients at civilian centers., Level of Evidence: Retrospective, therapeutic, level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The current study explores the trends in the application of combat casualty care following the publication of clinical practice guidelines (CPGs) in five domains for 13 years., Methods: The Israel Defense Forces Trauma Registry was used to assess practice and adherence to guidelines in five domains: (a) crystalloid transfusions, (b) tranexamic acid use, (c) freeze-dried plasma use, (d) chest decompression, and (e) airway management. All patients injured between January 2006 and December 2018 were included in the analysis. Trends were analyzed and presented monthly using linear regression and were compared using the Chow test., Results: The mean ± SD crystalloid volume transfused decreased from 1,179 ± 653 mL in 2006 to 466 ± 202 mL in 2018 (B = 0.016, 0.006-0.044). The proportion of patients with an indication treated with tranexamic acid dropped from 8% (238 of 2,979 patients) to 2.5% (60 of 2,356 patients) following the stricter guideline's publication. Freeze-dried plasma administration in indicated casualties rose from 12.5% in 2013 to 48% in 2018 (B = 1.63, 1.3-2.05). The overall proportion of casualties undergoing chest decompression rose from 1% (61 of 6,036 casualties) to 1.5% (155 of 10,493 casualties) following the release of a new CPG in 2012 (p = 0.013). There were no significant trends in intubation ratios before (B = 0.987, 0.953-1.02) or after 2012 (B = 10.2, 0.996-1.05)., Conclusion: Some aspects demonstrate the desired trends in response to new CPGs; in others, initial improvement is achieved but followed by stagnation. In some medical care aspects, completely unexpected and undesirable trends are observed. Every change and update in CPGs should be based on reliable data. The effect of every change must be monitored carefully to ensure adequate adherence to lifesaving guidelines., Level of Evidence: Epidemiological study, level IV., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)