Resolvin D1 Attenuates the Organ Injury Associated With Experimental Hemorrhagic Shock.

OBJECTIVE: To evaluate the potential changes in the plasma levels of resolvin D1 (RvD1) in patients with trauma and hemorrhage. Having found that trauma results in a profound reduction in plasma RvD1 in patients, we have then investigated the effects of RvD1 on the organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat. BACKGROUND: HS is a common cause of death in trauma due to excessive systemic inflammation and multiple organ failure. RvD1 is a member of the resolvin family of pro-resolution mediators. METHODS: Blood samples were drawn from critically injured patients (n = 27, ACITII-prospective observational cohort study) within 2 hours of injury for targeted liquid chromatography tandem mass spectrometry. HS rats (removal of blood to reduce arterial pressure to 30 ±â€Š2 mm Hg, 90 minutes, followed by resuscitation) were treated with RvD1 (0.3 or 1 µg/kg intravenous (i.v.)) or vehicle (n = 7). Parameters of organ injury and dysfunction were determined. RESULTS: Plasma levels of RvD1 (mg/dL) were reduced in patients with trauma+HS (0.17 ±â€Š0.08) when compared with healthy volunteers (0.76 ±â€Š0.25) and trauma patients (0.62 ±â€Š0.20). In rats with HS, RvD1 attenuated the kidney dysfunction, liver injury, and tissue ischemia. RvD1 also reduced activation of the nuclear factor (NF)-κB pathway and reduced the expression of pro-inflammatory proteins such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1ß, and interleukin-6. CONCLUSION: Plasma RvD1 is reduced in patients with trauma-HS. In rats with HS, administration of synthetic RvD1 on resuscitation attenuated the multiple organ failure associated with HS by a mechanism that involves inhibition of the activation of NF-κB.

Elevated cytokine, chemokine, and growth and differentiation factor-15 levels in hemorrhagic shock and encephalopathy syndrome: A retrospective observational study.

Patients with hemorrhagic shock and encephalopathy syndrome (HSES) have a high early mortality rate, which may be caused by a 'cytokine storm'. However, there is little information on how cytokines and chemokines change over time in these patients. We aimed to describe the characteristics of HSES by examining changes in serum biomarker levels over time. Six patients with HSES were included. We retrospectively evaluated their clinical course and imaging/laboratory data. We measured serum levels of multiple cytokines [interleukin 1ß (IL-1ß), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-gamma, and tumor necrosis factor alpha], chemokines (IL-8, monocyte chemoattractant protein-1, interferon-inducible protein-10), and growth and differentiation factor (GDF)-15. The highest cytokine and chemokine levels were noted in the first 24 h, and decreased thereafter. The GDF-15 level was markedly high. Cytokine, chemokine, and GDF-15 levels were significantly higher in patients with HSES than in controls in the first 24 h, except for IL-2 and IL-4. Patients with HSES have high inflammatory cytokine and chemokine levels, a high GDF-15 level in the first 24 h, and high lactate levels. Our study provides new insights on the pathophysiology of HSES, a detailed clinical picture of patients with HSES, and potential biomarkers.

Prehospital whole blood reduces early mortality in patients with hemorrhagic shock.

BACKGROUND: Low titer O+ whole blood (LTOWB) is being increasingly used for resuscitation of hemorrhagic shock in military and civilian settings. The objective of this study was to identify the impact of prehospital LTOWB on survival for patients in shock receiving prehospital LTOWB transfusion. STUDY DESIGN AND METHODS: A single institutional trauma registry was queried for patients undergoing prehospital transfusion between 2015 and 2019. Patients were stratified based on prehospital LTOWB transfusion (PHT) or no prehospital transfusion (NT). Outcomes measured included emergency department (ED), 6-h and hospital mortality, change in shock index (SI), and incidence of massive transfusion. Statistical analyses were performed. RESULTS: A total of 538 patients met inclusion criteria. Patients undergoing PHT had worse shock physiology (median SI 1.25 vs. 0.95, p < .001) with greater reversal of shock upon arrival (-0.28 vs. -0.002, p < .001). In a propensity-matched group of 214 patients with prehospital shock, 58 patients underwent PHT and 156 did not. Demographics were similar between the groups. Mean improvement in SI between scene and ED was greatest for patients in the PHT group with a lower trauma bay mortality (0% vs. 7%, p = .04). No survival benefit for patients in prehospital cardiac arrest receiving LTOWB was found (p > .05). DISCUSSION: This study demonstrated that trauma patients who received prehospital LTOWB transfusion had a greater improvement in SI and a reduction in early mortality. Patient with prehospital cardiac arrest did not have an improvement in survival. These findings support LTOWB use in the prehospital setting. Further multi-institutional prospective studies are needed.

Compensatory reserve detects subclinical shock with more expeditious prediction for need of life-saving interventions compared to systolic blood pressure and blood lactate.

INTRODUCTION: We conducted a prospective observational study on 205 trauma patients at a level I trauma facility to test the hypothesis that a compensatory reserve measurement (CRM) would identify higher risk for progression to shock and/or need a life-saving interventions (LSIs) earlier than systolic blood pressure (SBP) and blood lactate (LAC). METHODS: A composite outcome metric included blood transfusion, procedural LSI, and mortality. Discrete measures assessed as abnormal (ab) were SBP <90 mmHg, CRM <60%, and LAC >2.0. A graded categorization of shock was defined as: no shock (normal [n] SBP [n-SBP], n-CRM, n-LAC); sub-clinical shock (ab-CRM, n-SBP, n-LAC); occult shock (n-SBP, ab-CRM, ab-LAC); or overt shock (ab-SBP, ab-CRM, ab-LAC). RESULTS: Three patients displayed overt shock, 53 displayed sub-clinical shock, and 149 displayed no shock. After incorporating lactate into the analysis, 86 patients demonstrated no shock, 25 were classified as sub-clinical shock, 91 were classified as occult shock, and 3 were characterized as overt shock. Each shock subcategory revealed a graded increase requiring LSI and transfusion. Initial CRM was associated with progression to shock (odds ratio = 0.97; p < .001) at an earlier time than SBP or LAC. CONCLUSIONS: Initial CRM uncovers a clinically relevant subset of patients who are not detected by SBP and LAC. Our results suggest CRM could be used to more expeditiously identify injured patients likely to deteriorate to shock, with requirements for blood transfusion or procedural LSI.

Hemorrhagic shock and hemostatic resuscitation in canine trauma.

Hemorrhage is a significant cause of death among military working dogs and in civilian canine trauma. While research specifically aimed at canine trauma is limited, many principles from human trauma resuscitation apply. Trauma with significant hemorrhage results in shock and inadequate oxygen delivery to tissues. This leads to aberrations in cellular metabolism, including anaerobic metabolism, decreased energy production, acidosis, cell swelling, and eventual cell death. Considering blood and endothelium as a single organ system, blood failure is a syndrome of endotheliopathy, coagulopathy, and platelet dysfunction. In severe cases following injury, blood failure develops and is induced by inadequate oxygen delivery in the presence of hemorrhage, tissue injury, and acute stress from trauma. Severe hemorrhagic shock is best treated with hemostatic resuscitation, wherein blood products are used to restore effective circulating volume and increase oxygen delivery to tissues without exacerbating blood failure. The principles of hemostatic resuscitation have been demonstrated in severely injured people and the authors propose an algorithm for applying this to canine patients. The use of plasma and whole blood to resuscitate severely injured canines while minimizing the use of crystalloids and colloids could prove instrumental in improving both mortality and morbidity. More work is needed to understand the canine patient that would benefit from hemostatic resuscitation, as well as to determine the optimal resuscitation strategy for these patients.

Idarucizumab (PRAXBIND®) as a sole reversal agent in an unstable hemorrhagic shock patient on an unknown anticoagulant with elevated protime/international normalized ratio (PT/INR).

Dabigatran is a direct oral anticoagulant thrombin inhibitor approved for stroke prophylaxis in patients with non-valvular atrial fibrillation and prophylaxis or treatment of venous thromboembolism. Since approval, there has been increasing concern regarding bleeding risk, predominantly in the elderly population and those with renal disease. We present a case of an 85-year-old female with an unknown medication history, shortness of breath and severe anemia due to an upper gastrointestinal bleed. Laboratory abnormalities were significant for INR 6.43 and serum creatinine 2.21 mg/dL. While in the emergency department the patient decompensated requiring intubation, aggressive crystalloid resuscitation, blood products and initiation of vasopressors. The inability to distinguish between warfarin- and dabigatran-induced coagulopathies paired with the lack of medical information complicated selection of the appropriate anticoagulation reversal agent. In an attempt to prevent a prothrombotic state, prothrombin complex concentrates (PCC) were held and reversal was accomplished with idarucizumab alone, although warfarin-induced coagulopathy remained a possibility. 30 min after administration, repeat PT/INR was 16.1 s and 1.55, respectively. It was later confirmed that the patient was on sole dabigatran therapy. This case highlights the potential for dabigatran to cause extreme elevation in PT/INR in patients with acute renal failure, which may mimic warfarin-induced coagulopathy. Further, it demonstrates significant, rapid correction of abnormal coagulation assays following administration of idarucizumab in a patient with severe INR elevation and suspected dabigatran use.

RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock.

BACKGROUND: Type 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated. OBJECTIVE: To investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model. METHODS: Circulating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well. RESULTS: The number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS. CONCLUSIONS: These results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.

Intraosseous transfusion of hemoglobin vesicles in the treatment of hemorrhagic shock with collapsed vessels in a rabbit model.

BACKGROUNDS: Intravenous transfusion sometimes encounters difficulty under prehospital conditions when peripheral vessels are collapsed and inaccessible. We investigated whether the cellular type hemoglobin-based oxygen carriers (Hemoglobin Vesicles: HbVs) allow intraosseous administration into blood circulation for the resuscitation of rabbits with severe hemorrhagic shock. STUDY DESIGN AND METHODS: New Zealand white rabbits (2.5 kg average) were set in severe hemorrhagic shock [mean arterial pressure (MAP): 21 ± 2 mm Hg, Hb 5.1 ± 0.8 g/dL]. Immediately thereafter, 12 mL/kg of HbVs, 5% human serum albumin (HSA), autologous whole blood (WB), stored red blood cells (RBCs) or 36 mL/kg of Lactated Ringer's (LR) were intraosseously transfused, followed by an additional intraosseous transfusion with 8 mL/kg of HSA (following HbV, HSA or stored RBC transfusion), or WB or 24 mL/kg of LR (following LR transfusion), respectively. RESULTS: Intraosseous transfusion of HbVs increased MAP (48 ± 9 mm Hg) and improved hypohemoglobinemia (7.1 ± 0.6 g/dL) as well as WB or RBC transfusion. In contrast, neither HSA nor LR improved hemodynamics or Hb levels. Seven out of 10 rabbits receiving HbVs survived for 24 hours, while only one out of 10 rabbits receiving LR survived (WB and RBC; 100% survivals, HSA; 30% survival). CONCLUSIONS: Intraosseous infusion of HbVs might be an effective initial treatment to maintain hemodynamics during acute hemorrhagic shock. This approach could be used in emergency situations in which access to peripheral vessels is difficult.

A comparison between leukocyte reduced low titer whole blood vs non-leukocyte reduced low titer whole blood for massive transfusion activation.

BACKGROUND: Hemorrhagic shock is the leading cause of survivable death in trauma patients and recent literature has focused on resuscitation strategies including transfusing low-titer group O whole blood (LTOWB). Debate remains regarding whether leukocyte reduced (LR) whole blood is of clinical benefit or detriment to patients requiring massive transfusion. This study compares survival outcomes between LR-LTOWB and non-LR LTOWB. STUDY DESIGN AND METHODS: The objective of this prospective, observational study was to detect any difference in 24-hour survival between patients receiving LR-LTOWB and non-LR LTOWB during their massive transfusion activation. Secondary objectives were to report any difference in ICU LOS, ventilation days, in-hospital survival, and hospital LOS. Data collected included patient sex, age, mechanism of injury, Injury Severity Score (ISS), Trauma Injury Severity Score (TRISS), cause of death, and number of LTOWB transfused. RESULTS: A total of 167 patients received 271 LTOWB transfusions. There were 97 patients that received 168 units of LR-LTOWB while 70 patients received 103 units of non-LR LTOWB. The two study groups were comparable in terms of age, sex, ISS, TRISS, and the number of LTOWB transfused. The use of LR LTOWB during the initial massive transfusion activation in traumatically injured patients was not associated with increased 24-hour survival compared to when using non-LR LTOWB. No transfusion associated adverse events were reported. CONCLUSIONS: The administration of either LR or non-LR LTOWB was not associated with >24 hours survival in patients presenting with massive hemorrhage. The high cost and the rapid decline in platelet count of LR whole blood may be a consideration.

Protective Effect of Phosphatidylserine Blockade in Hemorrhagic Shock.

BACKGROUND: Phosphatidylserine (PS) is a key cell membrane phospholipid normally maintained on the inner cell surface but externalizes to the outer surface in response to cellular stress. We hypothesized that PS exposure mediates organ dysfunction in hemorrhagic shock. Our aims were to evaluate PS blockade on (1) pulmonary, (2) renal, and (3) gut function, as well as (4) serum lysophosphatidic acid (LPA), an inflammatory mediator generated by PS externalization, as a possible mechanism mediating organ dysfunction. MATERIALS AND METHODS: Rats were either (1) monitored for 130 min (controls, n = 3), (2) hemorrhaged then resuscitated (hemorrhage only group, n = 3), or (3) treated with Diannexin (DA), a PS blocking agent, followed by hemorrhage and resuscitation (DA + hemorrhage group, n = 4). Pulmonary dysfunction was assessed by arterial partial pressure of oxygen, renal dysfunction by serum creatinine, and gut dysfunction by mesenteric endothelial permeability (LP). LPA levels were measured in all groups. RESULTS: Pulmonary: there was no difference in arterial partial pressure of oxygen between groups. Renal: after resuscitation, creatinine levels were lower after PS blockade with DA versus hemorrhage only group (P = 0.01). Gut: LP was decreased after PS blockade with DA versus hemorrhage only group (P < 0.01). Finally, LPA levels were also lower after PS blockade with DA versus the hemorrhage only group but higher than the control group (P < 0.01). CONCLUSIONS: PS blockade with DA decreased renal and gut dysfunction associated with hemorrhagic shock and attenuated the magnitude of LPA generation. Our findings suggest potential for therapeutic targets in the future that could prevent organ dysfunction associated with hemorrhagic shock.

Safety of Pressurized Intraosseous Blood Infusion Strategies in a Swine Model of Hemorrhagic Shock.

BACKGROUND: Current guidelines support intraosseous access for trauma resuscitation when intravenous access is not readily available. However, safety of intraosseous blood transfusions with varying degrees of infusion pressure has not been previously characterized. MATERIALS AND METHODS: Adult female Yorkshire swine (Sus scrofa; n = 36; mean (M): 80 kg, 95% CI: 78-82 kg) were cannulated and then bled approximately 30% total blood volume. Swine were randomly assigned to proximal humerus intraosseous blood infusion with either Rapid Infuser, or Pressure Bag, or Push-Pull methods (n = 12 each). Flow rates, infusion pressures, vitals, biochemical variables, and pulmonary and renal tissue pathology were contrasted between groups. RESULTS: Flow rates were greater for the Push-Pull strategy than Pressure Bag (96.5 mL/min versus 72.6 mL/min, P = 0.02) or Rapid Infuser (96.5 mL/min versus 60 mL/min, P = 0.002) strategies. The pressures generated during the Push-Pull transfusion (3058 mmHg) were greater than the other strategies (≤360 mmHg). After the observation period, plasma-free hemoglobin levels were higher in the Push-Pull strategy than in the Rapid Infuser (40 mg/dL versus 12 mg/dL, P = 0.02) or Pressure Bag (40 mg/dL versus 12 mg/dL, P = 0.01). Groups did not significantly differ in vitals, biochemical variables, or tissue pathology. CONCLUSIONS: Push-Pull conferred the highest flow rates, but with higher infusion pressures and evidence of intravascular hemolysis. Rapid Infuser and Pressure Bag infusions had no increase from baseline in plasma-free hemoglobin. Pressure Bag infusion was noted to confer an advantage in flow rates over Rapid Infuser. Intraosseous blood transfusion with pressure bags can safely bridge toward central access in the early phases of trauma resuscitation.

Engagement of Posthemorrhagic Shock Mesenteric Lymph on CD4+ T Lymphocytes In Vivo and In Vitro.

BACKGROUND: Immune dysfunction is associated with posthemorrhagic shock mesenteric lymph (PHSML) return. To determine the proliferation and cytokine production capacity of CD4+ T lymphocytes, the effect of PHSML drainage on spleen CD4+ T lymphocytes in a mouse model of hemorrhagic shock was assessed. METHODS: The normal spleen CD4+ T lymphocytes were in vitro incubated with either drained normal mesenteric lymph (NML), PHSML during hypotension (PHSML-H), or PHSML from 0 h to 3 h after resuscitation (PHSML-R) to verify direct proliferation effects of PHSML. RESULTS: Hemorrhagic shock led to reduction of proliferation and mRNA expression of interleukin 2 (IL-2) and IL-2 receptor in CD4+ T lymphocytes and to decrease in IL-2 and interferon γ (IFN-γ) levels in supernatants. In contrast, the interleukin-4 levels were increased. These effects were reversed by PHSML drainage. Moreover, NML incubation promoted CD4+ T lymphocyte proliferation, whereas both PHSML-H and PHSML-R treatment had a biphasic effects on CD4+ T lymphocyte proliferation, exhibiting an enhanced effect at early stages and an inhibitory effect at later stages. Compared with NML, PHSML-H increased IL-2 expression at 12 h, but decreased expression of both IL-2 and IFN-γ at 24 h. By contrast, PHSML-R induced significant increases in IL-2 and IFN-γ levels at 24 h. Interleukin-4 expression in CD4+ T lymphocytes was reduced at 12 h, but augmented at 24 h after incubation with either PHSML-H or PHSML-R. CONCLUSIONS: The results indicate that PHSML has a direct inhibitory effect on CD4+ T lymphocyte proliferation that induces an inflammatory response, which is associated with cellular immune dysfunction.

Deoxyribonuclease Reduces Tissue Injury and Improves Survival After Hemorrhagic Shock.

BACKGROUND: Hemorrhagic shock (HS) caused by rapid loss of a large amount of blood is the leading cause of early death after severe injury. When cells are damaged during HS, many intracellular components including DNA are released into the circulation and function as endogenous damage-associated molecular patterns (DAMPs) that can trigger excessive inflammatory response and subsequently multiple organ dysfunction. We hypothesized that the administration of deoxyribonuclease I (DNase I) could reduce cell-free DNA and attenuate tissue damage in HS. METHODS: Eight-week-old male C57BL/6 mice underwent HS by controlled bleeding from the femoral artery for 90 min, followed by resuscitation with Ringer's lactate solution (vehicle) or DNase I (10 mg/kg BW). RESULTS: At 20 h after HS, serum levels of cell-free DNA were increased by 7.6-fold in the vehicle-treated HS mice compared with sham, while DNase I reduced its levels by 47% compared with the vehicle group. Serum levels of tissue injury markers (lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase) and proinflammatory cytokine interleukin 6 were significantly reduced in the DNase I-treated mice. In the lungs, messenger RNA levels of proinflammatory cytokines (interleukin 6 and interleukin 1 ß), chemoattractant macrophage inflammatory protein - 2, and myeloperoxidase activity were significantly decreased in HS mice after DNase I. Finally, DNase I significantly improved the 10-day survival rate in HS mice. CONCLUSIONS: Administration of DNase I attenuates tissue damage and systemic and lung inflammation, leading to improvement of survival in HS mice. Thus, DNase I may potentially serve as an adjunct therapy for managing patients with HS.

Heparin Attenuates Visceral Apoptosis in a Swine Model of Hemorrhagic Shock and Reperfusion Injury.

BACKGROUND: The use of unfractionated heparin in hypovolemic shock, aortic clamping, and visceral reperfusion is still not established, despite evidence of inhibition of early cell damage. This study investigated the potential protective effect of unfractionated heparin on hepatic and renal apoptosis in a porcine ischemia and reperfusion model. METHODS: Twenty-one male swine (Sus scrofa) were divided into 3 groups: sham (n = 5), heparin (n = 8), and nonheparin (n = 8). The heparin and nonheparin groups underwent hypovolemic shock for 30 min, supraceliac aortic clamping for 1 h and reperfusion for 3 h. Unfractionated heparin 200 mg/kg was administered to the heparin group during aortic clamping. Hemodynamic and laboratory parameters were monitored, including aminotransferase and serum urea. Histological lesion scores were applied to hematoxylin and eosin-stained liver and kidney sections. Apoptosis quantification was performed by caspase-3 immunohistochemistry. RESULTS: The proposed model caused a severe cardiocirculatory disturbance in the heparin and nonheparin groups, observed by the carotid-femoral pressure gradient and lactic acidosis. There was no significant difference in hemodynamic and laboratory parameters between these two groups. The mean values of liver and renal histological lesion scores did not present any significant differences. Caspase-3 immunoexpression was lower in the heparin than the nonheparin group for both liver and kidney. CONCLUSIONS: Attenuation of liver and kidney cell apoptosis in pigs undergoing systemic heparinization suggests a potential use for heparin in modulating cell death under critical hemodynamic conditions.

Current state of transfusion in traumatic brain injury and associated coagulopathy.

Traumatic brain injury (TBI)-induced coagulopathy has long been recognized as a significant risk for poor outcomes in patients with TBI, but its pathogenesis remains poorly understood. As a result, current treatment options for the condition are limited and ineffective. The lack of information is most significant for the impact of blood transfusions on patients with isolated TBI and in the absence of confounding influences from trauma to the body and limbs and the resultant hemorrhagic shock. Here we discuss recent progress in understanding the pathogenesis of TBI-induced coagulopathy and the current state of blood transfusions for patients with TBI and associated coagulopathy.

Effect of leukoreduction and pathogen reduction on the hemostatic function of whole blood.

BACKGROUND: There is renewed interest in the use of whole blood (WB) for resuscitation of patients in hemorrhagic shock. Leukoreduction with platelet-sparing filters and pathogen reduction may be used to improve the safety profile of WB, yet the effects of leukoreduction and pathogen reduction on WB hemostatic function are not well characterized. STUDY DESIGN AND METHODS: Blood from 32 healthy group O donors was divided into treatment groups (n = 8 for each group): untreated, pathogen reduced (PR+ ), leukoreduced using an in-line filter (LR+ ), or PR+ LR+ . Units were stored without agitation for 21 days between 1° and 6°C, with sampling on days 0 (pre- and post-treatments), 1, 3, 5, 10, 15, and 21 for hemostatic function as assessed by thromboelastometry, thrombin generation, platelet activation factors, and platelet impedance aggregometry. RESULTS: From day 3 (D3) to D15 of storage, platelet count was reduced in PR+ /LR+ units compared to PR- /LR- units. From D10 to D21 of storage, maximum clot firmness (MCF) was reduced in PR+ /LR+ units compared to PR- /LR- units. From D3 to D21 of storage, platelet aggregation was reduced in PR+ /LR+ units compared to PR- /LR- units. Total thrombin generation was similar in all groups from D0 to D21. CONCLUSIONS: The combination of LR with a platelet-sparing filter and PR significantly reduces hemostatic function compared to either treatment alone or untreated WB. The clinical consequences of LR and PR of WB in patients with severe bleeding should be examined in trials before both are used in combination in patients.

Characterizing red blood cell age exposure in massive transfusion therapy: the scalar age of blood index (SBI).

BACKGROUND: The mortality of trauma patients requiring massive transfusion to treat hemorrhagic shock approaches 17% at 24 hours and 26% at 30 days. The use of stored RBCs is limited to less than 42 days, so older RBCs are delivered first to rapidly bleeding trauma patients. Patients who receive a greater quantity of older RBCs may have a higher risk for mortality. METHODS AND MATERIALS: Characterizing blood age exposure requires accounting for the age of each RBC unit and the quantity of transfused units. To address this challenge, a novel Scalar Age of Blood Index (SBI) that represents the relative distribution of RBCs received is introduced and applied to a secondary analysis of the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) randomized controlled trial (NCT01545232, https://clinicaltrials.gov/ct2/show/NCT01545232). The effect of the SBI is assessed on the primary PROPPR outcome, 24-hour and 30-day mortality. RESULTS: The distributions of blood storage ages successfully maps to a parameter (SBI) that fully defines the blood age curve for each patient. SBI was a significant predictor of 24-hour and 30-day mortality in an adjusted model that had strong predictive ability (odds ratio, 1.15 [1.01-1.29], p = 0.029, C-statistic, 0.81; odds ratio, 1.14 [1.02-1.28], p = 0.019, C-statistic, 0.88, respectively). CONCLUSION: SBI is a simple scalar metric of blood age that accounts for the relative distribution of RBCs among age categories. Transfusion of older RBCs is associated with 24-hour and 30-day mortality, after adjustment for total units and clinical covariates.

UCH-L1 is a Poor Serum Biomarker of Murine Traumatic Brain Injury After Polytrauma.

BACKGROUND: Several serum biomarkers have been studied to diagnose incidence and severity of traumatic brain injury (TBI), but a reliable biomarker in TBI has yet to be identified. Ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) has been proposed as a biomarker in clinical and preclinical studies, largely in the setting of isolated TBI or concussion. The aim of this study was to evaluate the performance of UCH-L1 as a serum biomarker in the setting of polytrauma and TBI. METHODS: Multiple variations of murine TBI and polytrauma models were used to evaluate serum biomarkers. The different models included TBI with and without hemorrhagic shock and resuscitation, isolated extremity vascular ligation, extremity ischemia/reperfusion, and blunt tail injury. Blood was drawn at intervals after injury, and serum levels of neuron-specific enolase, UCH-L1, creatine kinase, and syndecan-1 were evaluated by enzyme-linked immunosorbent assay. RESULTS: UCH-L1 levels were not significantly different between TBI, tail injury, and sham TBI. By contrast, neuron-specific enolase levels were increased in TBI mice compared with tail injury and sham TBI mice. UCH-L1 levels increased regardless of TBI status at 30 min and 4 h after hemorrhagic shock and resuscitation. In mice that underwent femoral artery cannulation followed by hemorrhagic shock/resuscitation, UCH-L1 levels were significantly elevated compared with shock sham mice at 4 h (3158 ± 2168 pg/mL, 4 h shock versus 0 ± 0 pg/mL, 4 h shock sham; P < 0.01) and at 24 h (3253 ± 2954 pg/mL, 24 h shock versus 324 ± 482 pg/mL, 24 h shock sham; P = 0.03). No differences were observed in UCH-L1 levels between the sham shock and the arterial ligation, vein ligation, or extremity ischemia/reperfusion groups at any time point. Similar to UCH-L1, creatine kinase was elevated only after shock compared with sham mice at 4, 24, and 72 h after injury. CONCLUSIONS: Our study demonstrates that UCH-L1 is not a specific marker for TBI but is elevated in models that induce central and peripheral nerve ischemia. Given the increase in UCH-L1 levels observed after hemorrhagic shock, we propose that UCH-L1 may be a useful adjunct in quantifying severity of shock or global ischemia rather than as a specific marker of TBI.

Improved Long-term Survival with Remote Limb Ischemic Preconditioning in a Rat Fixed-Pressure Hemorrhagic Shock Model.

PURPOSE: We investigated whether bilateral, lower limb remote ischemic preconditioning (RIPC) improved long-term survival using a rat model of hemorrhagic shock/resuscitation. METHODS: Rats were anesthetized, intubated and ventilated, and randomly assigned to RIPC, induced by inflating bilateral pressure cuffs around the femoral arteries to 200 mmHg for 5 min, followed by 5-min release of the cuffs (repeated for 4 cycles), or control group (cuffs were inflated to 30 mmHg). Hemorrhagic shock was induced by withdrawing blood to a fixed mean blood pressure of 30 mmHg for 30 min, followed by 30 min of resuscitation with shed blood. Rats remained anesthetized for 1 h during which hemodynamics were monitored then they were allowed to survive for 6 weeks. RESULTS: The percentage of estimated total blood volume withdrawn to maintain a level of 30 mmHg was similar in both groups. RIPC significantly increased survival at 6 weeks: 5 of 27 (19%) rats in the control group and 13 of 26 (50%; p = 0.02) rats in the RIPC group survived. Blood pressure was higher in the RIPC group. The diastolic internal dimension of the left ventricle, an indicator of circulating intravascular blood volume, was significantly larger in the RIPC group at 1 h after initiation of resuscitation compared to the control group (p = 0.04). Left ventricular function assessed by fractional shortening was comparable in both groups at 1 h after initiation of resuscitation. Blood urea nitrogen (BUN) was within normal range in the RIPC group (17.3 ± 1.2 mg/dl) but elevated in the control group (22.0 ± 1.7 mg/dl) at 48 h after shock. CONCLUSIONS: RIPC significantly improved short-term survival in rats that were subjected to hemorrhagic shock, and this benefit was maintained long term. RIPC led to greater circulating intravascular blood volume in the early phase of resuscitation and improved BUN.

Comparison of Intraosseous, Arterial, and Venous Blood Sampling for Laboratory Analysis in Hemorrhagic Shock.

BACKGROUND: Intraosseous (IO) access is often indicated for administration of drugs and fluids in emergencies when venous access is challenging. There is no consensus regarding whether and which laboratory analyses may be performed on IO aspirates, and research on hemodynamically unstable subjects is limited. METHODS: Twelve anesthetized pigs were sampled from IO, venous, and arterial accesses during stable circulation and after hemorrhage corresponding to 20% and 40% of the blood volume. Samples were analyzed for blood gases and acid-base status, electrolytes, hematocrit, creatinine, glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (γ-GT), alkaline phosphatase (ALP), and creatine kinase (CK). RESULTS: Average differences of blood gases and acid-base parameters, sodium, creatinine, hematocrit, ALT, and γ-GT and between IO and venous samples were small at baseline and after hemorrhage while differences for lactate and glucose increased with hypovolemia. Both IO-arterial and venoarterial differences in acid-base parameters increased with hypovolemia. Dispersions of differences were often large. CONCLUSIONS: Average levels of blood gases, acid base parameters, hematocrit, CK, AST, γ-GT, creatinine, and ALT, but not lactate and glucose, were similar in IO and venous samples in hypovolemia. However, precision was limited, indicating that IO test results should be confirmed when other vascular access is established, and that analysis of IO samples should be limited to acute situations and not used for detailed diagnostics in this setting.