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Administration of antifibrinolytic medications, including tranexamic acid (TXA), may reduce head injury-related mortality. The effect of these medications on post-traumatic brain injury (TBI) inflammatory response is unknown. The goal of this study was to investigate the role of available antifibrinolytic medications on both systemic and cerebral inflammation after TBI.An established murine weight drop model was used to induce a moderate TBI. Mice were administered 1, 10, or 100 mg/kg of TXA, 400 mg/kg of aminocaproic acid (Amicar, Hospira, Lake Forest, IL), 100 kIU/kg of aprotonin, or equivalent volume of normal saline (NS) 10 minutes after recovery. Mice were euthanized at 1, 6, or 24 hours. Serum and cerebral tissue were analyzed for neuron-specific enolase and inflammatory cytokines. Hippocampal histology was evaluated at 30 days for phosphorylated tau accumulation.One hour after TBI, mice given TXA displayed decreased cerebral cytokine concentrations of tumor necrosis factor α (TNF-α) and, by 24 hours, displayed decreased concentrations of cerebral TNF-α, interleukin (IL)-6, and monocyte chemoattractant protein 1 compared with TBI-NS. However, serum concentrations of TNF-α and macrophage inflammatory protein 1α (MIP-1α) were significantly elevated from 1 to 24 hours in TBI-TXA groups compared with TBI-NS. The concentration of phosphorylated tau was significantly decreased in a dose-dependent manner in TBI-TXA groups compared with TBI-NS. By contrast, Amicar administration increased cerebral cytokine levels of IL-6 1 hour after TBI, with serum elevations noted in TNF-α, MIP-1α, and monocyte chemoattractant protein 1 at 24 hours compared with TBI-NS. Aprotonin administration increased serum TNF-α, IL-6, and MIP-1α from 1 to 24 hours without differences in cerebral cytokines compared with TBI-NS.Tranexamic acid administration may provide acute neuroinflammatory protection in a dose-dependent manner. Amicar administration may be detrimental after TBI with increased cerebral and systemic inflammatory effects. Aprotonin administration may increase systemic inflammation without significant contributions to neuroinflammation. While no antifibrinolytic medication improved systemic inflammation, these data suggest that TXA may provide the most beneficial inflammatory modulation after TBI.

Massive transfusion with older packed red blood cells is associated with increased morbidity and mortality. As packed red blood cells age, they undergo biochemical and structural changes known as the storage lesion. We developed a novel solution to increase viscosity in stored packed red blood cells. We hypothesized that packed red blood cell storage in this solution would blunt storage lesion formation and mitigate the inflammatory response after resuscitation.Blood was obtained from 8- to 10-week-old C57BL/6 male donor mice or human volunteers and stored as packed red blood cell units for 14 days for mice or 42 days for humans in either standard AS-3 storage solution or EAS-1587, the novel packed red blood cell storage solution. Packed red blood cells were analyzed for microvesicles, cell-free hemoglobin, phosphatidylserine, band-3 protein, glucose utilization, and osmotic fragility. Additional mice underwent hemorrhage and resuscitation with packed red blood cells stored in either AS-3 or EAS-1587. Serum was analyzed for inflammatory markers.Murine packed red blood cells stored in EAS-1587 demonstrated reductions in microvesicle and cell-free hemoglobin accumulation as well as preserved band-3 expression, increase glucose utilization, reductions in phosphatidylserine expression, and susceptibility to osmotic stress. Serum from mice resuscitated with packed red blood cells stored in EAS-1587 demonstrated reduced proinflammatory cytokines. Human packed red blood cells demonstrated a reduction in microvesicle and cell-free hemoglobin as well as an increase in glucose utilization.Storage of packed red blood cells in a novel storage solution mitigated many aspects of the red blood cell storage lesion as well as the inflammatory response to resuscitation after hemorrhage. This modified storage solution may lead to improvement of packed red blood cell storage and reduce harm after massive transfusion.

Introduction: The optimal management strategies for patients with polytraumatic injuries that include traumatic brain injury (TBI) are not well defined. Specific interventions including tranexamic acid (TXA), propranolol, and hypertonic saline (HTS) have each demonstrated benefits in patient mortality after TBI, but have not been applied to TBI patients with concomitant hemorrhage. The goals of our study were to determine the inflammatory effects of resuscitation strategy using HTS or shed whole blood (WB) and evaluate the cerebral and systemic inflammatory effects of adjunct treatment with TXA and propranolol after combined TBI + hemorrhagic shock. Methods: Mice underwent TBI via weight drop and were subsequently randomized into six experimental groups: three with HTS resuscitation and three with WB resuscitation. Mice were then subjected to controlled hemorrhagic shock for 1 h to a goal MAP of 25 mmHg. Mice were then treated with an i.p. dose of 4 mg/kg propranolol, 100 mg/kg TXA, or normal saline (NS) as a control. Mice were killed at 1, 6, or 24 h for serum and cerebral biomarker evaluation by multiplex ELISA and serum neuron-specific enolase, a biomarker of cerebral cellular injury. Results: Mice resuscitated with HTS had elevated serum proinflammatory cytokines compared with WB resuscitated groups at 6 and 24 h after injury, with no significant difference in cerebral cytokine levels. Within the TBI/shock + HTS groups, the addition of propranolol or TXA did not significantly alter serum cytokine concentration, but cerebral IL-2, IL-12, and macrophage inflammatory protein-1α (MIP-1α) decreased after propranolol administration. In the TBI/shock + WB cohorts, the addition of both propranolol and TXA increased systemic proinflammatory cytokine levels at 6 and 24 h after injury as demonstrated by serum IL-2, IL-12, MIP-1α, and IL-1β compared with NS control. By contrast, TBI/shock + WB mice demonstrated a significant reduction in cerebral IL-2, IL-12, and MIP-1α in propranolol treated mice 6 h after injury compared with NS group. While serum neuron-specific enolase was significantly increased 1 and 24 h after injury in TBI/shock + HTS + TXA cohorts compared with NS control, it was significantly reduced in the TBI/shock + WB + propranolol mice compared with NS control 24 h after injury. Conclusions: Whole blood resuscitation can reduce the acute postinjury neuroinflammatory response after combined TBI/shock compared with HTS. The addition of either propranolol or TXA may modulate the postinjury systemic and cerebral inflammatory response with more improvements noted after propranolol administration. Multimodal treatment with resuscitation and pharmacologic therapy after TBI and hemorrhagic shock may mitigate the inflammatory response to these injuries to improve recovery.

BACKGROUND: Pulmonary contusions (PCs) have historically been viewed as a serious complicating factor in thoracic injury. Recently, there has been conflicting evidence regarding the influence of PCs on outcomes; however, many studies do not stratify contusions by severity and may miss clinical associations. We sought to identify if contusion severity is associated with worse outcomes. METHODS: A previously published chest wall injury database at an urban Level I trauma center was retrospectively reviewed. All severely injured subjects (defined as Injury Severity Score [ISS] ≥ 15) with moderate to severe thoracic injury (defined as a chest wall Abbreviated Injury Scale [AIS] ≥ 3) who required mechanical ventilation for > 24 h were stratified by contusion severity. Moderate to severe contusions were defined as AIS contusion ≥ 3 and Blunt Pulmonary Contusion 18 (BPC18) score ≥ 3. RESULTS: Over 5 y, 3,836 patients presented with chest wall injuries, of which 1,176 (30.6%) had concomitant contusions. When screened for inclusion criteria, 339 subjects with contusions and 211 subjects without contusions (no-PC) were identified. Of these, 234 had moderate to severe contusions defined by AIS contusion ≥ 3 (PC-A) and 230 had moderate to severe contusions by BPC18 ≥ 3 (PC-B). Compared to no-PC, both PC-A and PC-B groups had significantly lower mortality (17.9% and 17.4%, respectively, vs 28.9%); however, PC-A and PC-B groups had longer durations of mechanical ventilation (6 and 7 d, respectively, vs 5 d), longer ICU length of stay (10 and 10 vs 8 d), and longer overall hospital length of stay (15 and 15 vs 13 d). CONCLUSIONS: In severely injured polytrauma patients, PCs are seen with more severe chest injuries. Furthermore, moderate to severe contusions are associated with longer durations of mechanical ventilation, ICU length of stay, and hospital length of stay. Despite practice pattern changes, contusions appear to contribute significantly to the clinical course of the blunt chest wall injured patients.

BackgroundThe majority of critical care air transport (CCAT) flights are regulated, meaning that a theater-validating flight surgeon has confirmed that the patient is medically cleared for flight and that evacuation is appropriate. If the conditions on the ground do not allow for this process, the flight is unregulated. Published data are limited regarding CCAT unregulated missions to include the period of troop drawdown at the end of the Afghanistan conflict. The objective of our study was to characterize the unregulated missions within Afghanistan during troop drawdown and compare them to regulated missions during the same timeframe.Study DesignWe performed a retrospective review of all CCAT medical records of patients transported via CCAT within Afghanistan between January 2017 and December 2019. We abstracted data from the records, including mission characteristics, patient demographics, injury descriptors, preflight military treatment facility procedures, CCAT procedures, in-flight CCAT treatments, in-flight events, and equipment issues. Following descriptive and comparative analysis, a Cochran–Armitage test was performed to evaluate the statistical significance of the trend in categorical data over time. Multivariable regression was used to assess the association between vasopressors and preflight massive transfusions, preflight surgical procedures, injury patterns, and age.ResultsWe reviewed 147 records of patients transported via CCAT: 68 patients were transported in a regulated fashion and 79 on an unregulated flight. The number of patients evacuated increased year-over-year (n = 22 in 2017, n = 57 in 2018, and n = 68 in 2019, P ConclusionDuring the troop drawdown in Afghanistan, the number of unregulated missions increased geometrically because the medical footprint was decreasing. During unregulated missions, CCAT providers used ketamine more frequently, consistent with Tactical Combat Casualty Care guidelines. In addition, TBI was the only predictor of vasopressor use and may reflect an attempt to adhere to unmonitored TBI clinical guidelines. Interoperability between CCAT and AE teams is critical to meet mass casualty needs in unregulated mission environments and highlights a need for joint training. It remains imperative to evaluate changes in mission requirements to inform en route combat casualty care training.

Packed red blood cell (pRBC) units administered during resuscitation from hemorrhagic shock are of varied storage ages. We have previously shown that RBC-derived microparticles' impact on thrombogenesis. However, the impact of storage age on pRBC coagulability is unknown. Therefore, we sought to investigate the effect of storage age on innate coagulability and aggregability of stored pRBCs.pRBCs prepared from male C57BL/6J mice were stored in Additive Solution-3 according to our standardized murine blood banking protocols for 14 days. Rotational thromboelastometry (ROTEM) was used to assess the innate coagulation status of fresh and 14-day old pRBCs. Viscoelastic coagulation parameters of clotting time (CT), clot formation time (CFT), alpha angle, and maximum clot firmness (MCF) were analyzed to determine coagulability. Plasma was added to the fresh pRBCs and 15-day old pRBCs to determine if the storage-associated coagulopathy was reversible with plasma. Statistical analyses were conducted with a Student's t-test.Fifteen-day old pRBCs demonstrated a significant reduction in MCF (10.3 vs. 24.4 mm, P-value0.001) and alpha angle (6.0 vs. 27.2 degrees, P-value0.001) as well as significant prolongation of CFT and CT (1126.5 vs. 571.4 s, P-value0.001) compared to fresh pRBCs. FFP addition to 15-day old and fresh pRBCs, demonstrated a significant reduction in MCF and persistent prolongation of CFT. This suggests that pRBCs lost coagulability as they aged and this deficit was not completely corrected by plasma administration.Storage duration may be an important factor in coagulation potential of pRBCs. Transfusion with older pRBCs may contribute to coagulopathy in massively transfused patients.

Introduction Combined burn injury and hemorrhagic shock are a common cause of injury in wounded warfighters. Current protocols for resuscitation for isolated burn injury and isolated hemorrhagic shock are well defined, but the optimal strategy for combined injury is not fully established. Direct peritoneal resuscitation (DPR) has been shown to improve survival in rats after hemorrhagic shock, but its role in a combined burn/hemorrhage injury is unknown. We hypothesized that DPR would improve survival in mice subjected to combined burn injury and hemorrhage. Materials and Methods Male C57/BL6J mice aged 8 weeks were subjected to a 7-second 30% total body surface area scald in a 90°C water bath. Following the scald, mice received DPR with 1.5 mL normal saline or 1.5 mL peritoneal dialysis solution (Delflex). Control mice received no peritoneal solution. Mice underwent a controlled hemorrhage shock via femoral artery cannulation to a systolic blood pressure of 25 mm Hg for 30 minutes. Mice were then resuscitated to a target blood pressure with either lactated Ringer’s (LR) or a 1:1 ratio of packed red blood cells (pRBCs) and fresh frozen plasma (FFP). Mice were observed for 24 hours following injury. Results Median survival time for mice with no DPR was 1.47 hours in combination with intravascular LR resuscitation and 2.08 hours with 1:1 pRBC:FFP. Median survival time significantly improved with the addition of intraperitoneal normal saline or Delflex. Mice that received DPR followed by 1:1 pRBC:FFP required less intravascular volume than mice that received DPR with LR, pRBC:FFP alone, and LR alone. Intraperitoneal Delflex was associated with higher levels of tumor necrosis factor alpha and macrophage inflammatory protein 1 alpha and lower levels of interleukin 10 and intestinal fatty acid binding protein. Intraperitoneal normal saline resulted in less lung injury 1 hour postresuscitation, but increased to similar severity of Delflex at 4 hours. Conclusions After a combined burn injury and hemorrhage, DPR leads to increased survival in mice. Survival was similar with the use of normal saline or Delflex. DPR with normal saline reduced the inflammatory response seen with Delflex and delayed the progression of acute lung injury. DPR may be a valuable strategy in the treatment of patients with combined burn injury and hemorrhage.

BACKGROUND: Recent military and civilian experience suggests that fresh whole blood may be the preferred for treatment of hemorrhagic shock, but its use is limited by its 21-day shelf life. The red blood cell storage lesion and coagulation status of packed red blood cells (pRBCs) salvaged from expired whole blood are unknown. We hypothesized that packed red blood cells can be salvaged from previously stored whole blood. METHODS: Cold stored, low-titer, O-positive, non-leukoreduced, whole blood units were obtained at 21 days of storage. Erythrocytes were separated by centrifugation, resuspended in AS-3, and stored for 21 additional days as salvaged pRBCs. The red blood cell storage lesion parameters of microvesicles, Band-3, free hemoglobin, annexin V, and erythrocyte osmotic fragility were measured and compared to pRBCs prepared at the time of donation and stored in AS-3 for 42 days (standard pRBCs). In additional experiments, murine pRBCs were prepared from expired whole blood units and compared to those stored under standard conditions. Mice underwent hemorrhage and resuscitation with standard and salvaged pRBC units and serum cytokines and free hemoglobin were determined. RESULTS: There were no significant differences in microvesicle formation or cell-free hemoglobin concentration between salvaged and standard pRBCs. There was decreased Band-3 and increased phosphatidylserine in the salvaged units as well as greater osmotic fragility. Salvaged pRBCs maintained consistent clot firmness. After hemorrhage and resuscitation in a murine model, salvaged pRBCs did not demonstrate increased serum cytokine levels. CONCLUSIONS: Salvaged pRBCs from previously stored whole blood accumulate the red blood cell storage lesion in a similar fashion to standard pRBCs and maintain consistent coagulability when reconstituted with plasma. Salvaged pRBCs are not associated with an increased inflammatory response when used for resuscitation in a murine model. Salvaged pRBCs may be a viable product for utilization in the treatment of traumatic hemorrhagic shock. LEVEL OF EVIDENCE: Level II (prospective laboratory study, therapeutic)

Non-compressible torso hemorrhage accounts for a significant portion of preventable trauma deaths. We report here on the development of injectable, targeted supramolecular nanotherapeutics based on peptide amphiphile (PA) molecules that are designed to target tissue factor (TF) and, therefore, selectively localize to sites of injury to slow hemorrhage. Eight TF-targeting sequences were identified, synthesized into PA molecules, co-assembled with non-targeted backbone PA at various weight percentages, and characterized via circular dichroism spectroscopy, transmission electron microscopy, and X-ray scattering. Following intravenous injection in a rat liver hemorrhage model, two of these PA nanofiber co-assemblies exhibited the most specific localization to the site of injury compared to controls (p

Acute lung injury is a major complication of hemorrhagic shock and the required resuscitation with large volumes of crystalloid fluids and blood products. We previously identified a role of macrophage-derived chemokine (CCL22/MDC) pulmonary inflammation following hemorrhage and resuscitation. However, further details regarding the induction of CCL22/MDC and its precise role in pulmonary inflammation after trauma remain unknown. In the current study we used in vitro experiments with a murine alveolar macrophage cell line, as well as an in vivo mouse model of hemorrhage and resuscitation, to identify key regulators in CCL22/MDC production. We show that trauma induces expression of IFNγ, which leads to production of CCL22/MDC through a signaling mechanism involving p38 MAPK, NF-κB, JAK, and STAT-1. IFNγ also activates TNFα production by alveolar macrophages, potentiating CCL22/MDC production via an autocrine mechanism. Neutralization of IFNγ or TNFα with specific antibodies reduced histological signs of pulmonary injury after hemorrhage and reduced inflammatory cell infiltration into the lungs.

Introduction:Acute care research (ACR) is uniquely challenged by the constraints of recruiting participants and conducting research procedures within minutes to hours of an unscheduled critical illness or injury. Existing competencies for clinical research professionals (CRPs) are gaining traction but may have gaps for the acute environment. We sought to expand existing CRP competencies to include the specialized skills needed for ACR settings.Methods:Qualitative data collected from job shadowing, clinical observations, and interviews were analyzed to assess the educational needs of the acute care clinical research workforce. We identified competencies necessary to succeed as an ACR-CRP, and then applied Bloom’s Taxonomy to develop characteristics into learning outcomes that frame both knowledge to be acquired and job performance metrics.Results:There were 28 special interest competencies for ACR-CRPs identified within the eight domains set by the Joint Task Force (JTF) of Clinical Trial Competency. While the eight domains were not prioritized by the JTF, in ACR an emphasis on Communication and Teamwork, Clinical Trials Operations, and Data Management and Informatics was observed. Within each domain, distinct proficiencies and unique personal characteristics essential for success were identified. The competencies suggest that a combination of competency-based training, behavioral-based hiring practices, and continuing professional development will be essential to ACR success.Conclusion:The competencies developed for ACR can serve as a training guide for CRPs to be prepared for the challenges of conducting research within this vulnerable population. Hiring, training, and supporting the development of this workforce are foundational to clinical research in this challenging setting.

Background The aim of this review was to describe emerging therapies that could serve as a prehospital intervention to slow or stop noncompressible torso hemorrhage in the civilian and military settings. Hemorrhage accounts for 90% of potentially survivable military deaths and 30%-40% of trauma deaths. There is a great need to develop novel therapies to slow or stop noncompressible torso hemorrhage at the scene of the injury. Methods A comprehensive literature search was performed using PubMed (1966 to present) for therapies not approved by the Food and Drug Administration for noncompressible torso hemorrhage in the prehospital setting. Therapies were divided into compressive versus intravascular injectable therapies. Ease of administration, skill required to use the therapy, safety profile, stability, shelf-life, mortality benefit, and efficacy were reviewed. Results Multiple potential therapies for noncompressible torso hemorrhage are currently under active investigation. These include (1) tamponade therapies, such as gas insufflation and polyurethane foam injection; (2) freeze-dried blood products and alternatives such as lyophilized platelets; (3) nanoscale injectable therapies such as polyethylene glycol nanospheres, polyethylenimine nanoparticles, SynthoPlate, and tissue factor–targeted nanofibers; and (4) other injectable therapies such as polySTAT and adenosine, lidocaine, and magnesium. Although each of these therapies shows great promise at slowing or stopping hemorrhage in animal models of noncompressible hemorrhage, further research is needed to ensure safety and efficacy in humans. Conclusions Multiple novel therapies are currently under active investigation to slow or stop noncompressible torso hemorrhage in the prehospital setting and show promising results.

Introduction Traumatic brain injury (TBI) has become increasingly prevalent among the injuries sustained in the military. Many wounded warriors require emergency medical evacuation via helicopter and subsequently fixed wing transport. During aeromedical evacuation, both pilots and patients experience whole body vibration due to engine, rotor, and propeller rotation. The impact of posttraumatic vibration and hypoxia exposure characteristic of the aeromedical evacuation environment on TBI is currently unknown. Methods A swine TBI model of controlled cortical impact was utilized. The pigs first underwent TBI or sham injury and were subsequently exposed to vibration or no vibration and hypoxia or normoxia for 2 hours. They were monitored for an additional 4 hours following vibration/hypoxia and blood was drawn at hourly intervals for cytokine and serum biomarker analysis. Continuous physiologic and neurologic monitoring were utilized. Prior to the conclusion of the experiment, the animals underwent brain magnetic resonance imaging. At the end of the study, the brain was extracted for histologic analysis. Results Physiologic parameters except for peripheral capillary oxygen saturation (SpO2) were similar between all groups. The hypoxia groups demonstrated the expected decrease in SpO2 and pO2 during the hypoxic period, and this was sustained throughout the study period. The pH, pCO2 and electrolytes were similar among all groups. Neuron specific enolase was increased over time in the TBI group, however it was similar to the sham TBI group at all time points. There were no differences in IL-1β, IL-6, IL-8, TNFα, GFAP, HIF1α, syndecan-1, or S100β serum levels between groups. The mean ICP during cortical impact in the TBI group was 279.8 ± 56.2 mmHg. However, the postinjury ICP was not different between groups at any subsequent time point. Brain tissue oxygenation and perfusion were similar between all groups. Conclusion In this novel study evaluating the effect of vibration on short-term outcomes following TBI, we demonstrate that the moderate vibration and hypoxia simulating aeromedical evacuation do not impact short term outcomes following TBI.

Introduction During storage, packed red blood cells undergo a series of physical, metabolic, and chemical changes collectively known as the red blood cell storage lesion. One key component of the red blood cell storage lesion is the accumulation of microparticles, which are submicron vesicles shed from erythrocytes as part of the aging process. Previous studies from our laboratory indicate that transfusion of these microparticles leads to lung injury, but the mechanism underlying this process is unknown. In the present study, we hypothesized that microparticles from aged packed red blood cell units induce pulmonary thrombosis. Materials and methods Leukoreduced, platelet-depleted, murine packed red blood cells (pRBCS) were prepared then stored for up to 14 days. Microparticles were isolated from stored units via high-speed centrifugation. Mice were transfused with microparticles. The presence of pulmonary microthrombi was determined with light microscopy, Martius Scarlet Blue, and thrombocyte stains. In additional studies microparticles were labelled with CFSE prior to injection. Murine lung endothelial cells were cultured and P-selectin concentrations determined by ELISA. In subsequent studies, P-selectin was inhibited by PSI-697 injection prior to transfusion. Results We observed an increase in microthrombi formation in lung vasculature in mice receiving microparticles from stored packed red blood cell units as compared with controls. These microthrombi contained platelets, fibrin, and microparticles. Treatment of cultured lung endothelial cells with microparticles led to increased P-selectin in the media. Treatment of mice with a P-selectin inhibitor prior to microparticle infusion decreased microthrombi formation. Conclusions These data suggest that microparticles isolated from aged packed red blood cell units promote the development of pulmonary microthrombi in a murine model of transfusion. This pro-thrombotic event appears to be mediated by P-selectin.

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.

Purpose of Review With the projected increase in the geriatric patient population, it is of the utmost importance to understand and optimize conditions in the perioperative period to ensure the best surgical outcome. Age-associated changes in respiratory physiology affect the surgical management of geriatric patients. This review focuses on perioperative pulmonary management of elderly individuals. Recent Findings The physiological changes associated with aging include both physical and biochemical alterations that are detrimental to pulmonary function. There is an increased prevalence of chronic lung disease such as COPD and interstitial lung disease which can predispose patients to postoperative pulmonary complications. Additionally, elderly patients, especially those with chronic lung disease, are at risk for frailty. Screening tools have been developed to evaluate risk and aid in the judicious selection of patients for surgical procedures. The concept of “prehabilitation” has been developed to best prepare patients for surgery and may be more influential in the reduction of postoperative pulmonary complications than postoperative rehabilitation. Understanding the age-associated changes in metabolism of drugs has led to dose adjustments in the intraoperative and postoperative periods, reducing respiratory depression and lung protective ventilation and minimally invasive procedures have yielded reductions in postoperative pulmonary complications. Summary The perioperative management of the geriatric population can be divided into three key areas: preoperative risk mitigation, intraoperative considerations, and postoperative management. Preoperative considerations include patient selection and thorough history and physical, along with smoking cessation and prehabilitation in a subset of patients. Operative aspects include careful selection of anesthetic agents, lung protective ventilation, and choice of surgical procedure. Postoperative management should focus on selective use of agents that may contribute to respiratory depression and encouragement of rehabilitation.

While patients undergoing treatment for hematologic malignancies are at risk for a variety of infections, gastrointestinal mucormycosis is a rare and feared complication. Diagnosis requires a high index of suspicion and timely evaluation. Prompt treatment improves patient outcomes.

Aims/objectives The aim of this study was to evaluate the hemostatic consequences of whole blood leukoreduction (LR). Background Whole blood is being used for trauma resuscitation in the military, and an increasing number of civilian trauma centres across the nation. The benefits of LR, such as decreased infectious and transfusion-related complications, are well established, but the effects on hemostatic parameters remain a concern. Methods Twenty-four units of whole blood were assigned to one of the four groups: non-leukoreduced (NLR), leukoreduced at 1 h and a height of 33 in. (LR-1), leukoreduced at 4 h and a height of 33 in. (LR-4(33)), or leukoreduced at 4 h and a height of 28 in. (LR-4(28)). Viscoelastic parameters, platelet aggregation, cell counts, physiological parameters and thrombin potential were evaluated immediately before and after LR, and on days 1, 7, 14 and 21 following LR. Results The viscoelastic parameters and thrombin generation potential were unchanged between the groups. Platelet aggregation was reduced in the LR-1 group compared with NLR after 7 days. The LR-4(28) group also showed a trend of reduced platelet aggregation compared with NLR. Aggregation in LR-4(33) was similar to NLR throughout the storage time. Physiological and electrolyte changes over the whole blood storage period were not affected by LR. Conclusion Our study shows that whole blood can be LR at 4 h after collection and a height of 33 in. while maintaining platelet count and without altering platelet function and hemostatic performance.

PURPOSE OF REVIEW: The first description of non-invasive ventilation use began in the 1920s. Since then, its role in patient care has evolved through increased clinical knowledge and scientific advancements. The utilization of non-invasive ventilation has broadened from initial application in acute in-hospital ICU settings to now include the outpatient settings. This review discusses the history of non-invasive ventilation and its role in acute in-hospital chronic obstructive pulmonary disease (COPD) exacerbations, cardiogenic pulmonary edema, and weaning from mechanical ventilation in the elderly. The elderly population represents a significant portion of patients hospitalized for the aforementioned conditions. These groups often have more limitations related to the use of invasive mechanical ventilation (IMV), therefore, it is essential to understand the impact of non-invasive ventilation on hospital outcomes. RECENT FINDINGS: There is strong clinical evidence supporting the use of non-invasive ventilation in patients with respiratory failure secondary to acute COPD exacerbations and cardiogenic pulmonary edema. When compared to standard medical management of these conditions, there is a consistent and significant reduction in the rate of endotracheal intubation and in-hospital mortality. SUMMARY: The basis of noninvasive ventilation applicability has been determined by significant reduction in mortality and intubation rates. Although survival benefits have been observed, there still remain limitations to the clinical applicability of non-invasive ventilation in certain patient populations and conditions that require further investigation.

BACKGROUNDRates of damage control laparotomy (DCL) vary widely and consensus on appropriate indications does not exist. The purposes of this multicenter quality improvement (QI) project were to decrease the use of DCL and to identify indications where consensus exists.METHODSIn 2016, six US Level I

BACKGROUNDIn patients for whom surgical equipoise exists for damage control laparotomy (DCL) and definitive laparotomy (DEF), the effect of DCL and its associated resource utilization are unknown. We hypothesized that DEF would be associated with fewer abdominal complications and less resource utili

BACKGROUND/AIMS:During sepsis, an unchecked pro-inflammatory response can be detrimental to the host. We investigated the potential protective effect of amitriptyline (AT). METHODS:We used two murine models of sepsis: Cecal ligation and puncture and endotoxemia following LPS challenge. Aural temperatures were taken and cytokines quantified by cytometric bead assay. Lung injury was determined histologically and by protein determination in bronchoalveolar lavage fluid. Cell accumulation in the peritoneum was analyzed by flow cytometry, as well as cytokine production and p38-phosphorylation. Neutrophil chemotaxis was evaluated using an in vitro transwell assay. RESULTS:Our findings demonstrate that AT-treated septic mice have improved survival and are protected from pulmonary edema. Treatment with AT significantly decreased serum levels of KC and monocyte chemoattractant protein-1, as well as the accumulation of neutrophils and monocytes in the peritoneum of septic mice. Peritoneal IL-10 levels in septic mice were increased upon AT treatment. Direct treatment of septic mice with IL-10 recapitulated the effects of AT. Endotoxemic mice also exhibited enhanced IL-10 production upon AT-administration and peritoneal macrophages were identified as the ATinfluenced producers of IL-10. Treatment of these cells with AT in vitro resulted in increased p38-phosphorylation and IL-10 generation, whereas ceramide and p38 inhibition had the opposite effect. CONCLUSION:Altogether, AT treatment improved survival, increased IL-10 levels, and mitigated a pro-inflammatory response during sepsis. We conclude that AT is a promising therapeutic to temper inflammation during septic shock. CA extern

IntroductionWhile damage control surgery and resuscitation techniques have revolutionized the care of injured service members who sustain severe traumatic hemorrhage, the physiologic and inflammatory consequences of hemostatic resuscitation and staged abdominal surgery in the face of early aeromedical evacuation (AE) have not been investigated. We hypothesized that post-injury AE with an open abdomen would have significant physiologic and inflammatory consequences compared to AE with a closed abdomen.Materials and MethodsEvaluation of resuscitation and staged abdominal closure was performed using a murine model of hemorrhagic shock with laparotomy. Mice underwent controlled hemorrhage to a systolic blood pressure of 25 mmHg and received either no resuscitation, blood product resuscitation, or Hextend resuscitation to a systolic blood pressure of either 50 mmHg (partial resuscitation) or 80 mmHg (complete resuscitation). Laparotomies were either closed prior to AE (closed abdomens) or left open during AE (open abdomens) and subsequently closed. AE was simulated with a 1-hour exposure to a hypobaric hypoxic environment at 8,000 feet altitude. Mice were euthanized at 0, 4, or 24 hours following AE. Serum was collected and analyzed for physiologic variables and inflammatory cytokine levels. Samples of lung and small intestine were collected for tissue cytokine and myeloperoxidase analysis as indicators of intestinal inflammation. Survival curves were also performed.ResultsUnresuscitated mice sustained an 85% mortality rate from hemorrhage and laparotomy, limiting the assessment of the effect of simulated AE in these subgroups. Overall survival was similar among all resuscitated groups regardless of the presence of hypobaric hypoxia, type of resuscitation, or abdominal closure status. Simulated AE had no observed effects on acid/base imbalance or the inflammatory response as compared to ground level controls. All mice experienced both metabolic acidosis and an acute inflammatory response after hemorrhage and injury, represented by an initial increase in serum interleukin (IL)-6 levels. Furthermore, mice with open abdomens had an elevated inflammatory response with increased levels of serum IL-10, serum tumor necrosis factor alpha, intestinal IL-6, intestinal IL-10, and pulmonary myeloperoxidase.ConclusionThese results demonstrate the complex interaction of AE and temporary or definitive abdominal closure after post-injury laparotomy. Contrary to our hypothesis, we found that AE in those animals with open abdomens is relatively safe with no difference in mortality compared to those with closed abdomens. However, given the physiologic and inflammatory changes observed in animals with open abdomens, further evaluation is necessary prior to definitive recommendations regarding the safety or downstream effects of exposure to AE prior to definitive abdominal closure.

Whole blood is a powerful resuscitation strategy for trauma patients but has a shorter shelf life than other blood products. The red blood cell storage lesion in whole blood has not previously been investigated beyond the standard storage period. In the present study, we hypothesized that erythrocytes in stored whole blood exhibit similar aspects of the red blood cell storage lesion and that transfusion of extended storage whole blood would not result in a more severe inflammatory response after hemorrhage in a murine model. To test this hypothesis, we stored low-titer, O-positive, whole blood units, and packed red blood cells (pRBCs) for up to 42 days, then determined aspects of the red blood cell storage lesion. Compared with standard storage pRBCs, whole blood demonstrated decreased microvesicle and free hemoglobin at 21 days of storage and no differences in osmotic fragility. At 42 days of storage, rotational thromboelastometry demonstrated that clotting time was decreased, alpha angle was increased, and clot formation time and maximum clot firmness similar in whole blood as compared with pRBCs with the addition of fresh frozen plasma. In a murine model, extended storage whole blood demonstrated decreased microvesicle formation, phosphatidylserine, and cell-free hemoglobin. After hemorrhage and resuscitation, TNF-a, IL-6, and IL-10 were decreased in mice resuscitated with whole blood. Red blood cell survival was similar at 24 h after transfusion. Taken together, these data suggest that red blood cells within whole blood stored for an extended period of time demonstrate similar or reduced accumulation of the red blood cell storage lesion as compared with pRBCs. Further examination of extended-storage whole blood is warranted.

Background Transfusion of blood products is the ideal resuscitative strategy after hemorrhage. Unfortunately, older packed red blood cells have been associated with increased morbidity and mortality after massive transfusion. These packed red blood cells accumulate biochemical and structural changes known as the red blood cell storage lesions. The effect of washing on the formation of red blood cell storage lesions is unknown. We hypothesized that washing packed red blood cells during storage would decrease the development of the red blood cell storage lesions. Methods Blood from 8- to 10-week-old male mice donors was stored as packed red blood cells for 14 days. A subset of packed red blood cells were washed with phosphate-buffered saline on storage day 7 and resuspended in AS-1 solution for an additional 7 days as washed packed red blood cells. Subsequently, the packed red blood cells were analyzed for microvesicle release, band-3 erythrocyte membrane integrity protein (Band-3), expression of phosphatidylserine, cell viability (calcein), accumulation of cell-free hemoglobin, and osmotic fragility. Results In the washed packed red blood cells group, there was less microvesicle accumulation, greater Band-3 expression, less phosphatidylserine expression, a decrease in cell-free hemoglobin accumulation, and a decrease in osmotic fragility, but no differences in red blood cells viability. Conclusion Washing packed red blood cells during storage decreases the accumulation of red blood cell storage lesions. This strategy may lessen the sequelae associated with transfusion of older packed red blood cells.

BACKGROUND The Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) study evaluated the effects of plasma and platelets on hemostasis and mortality after hemorrhage. The pulmonary consequences of resuscitation strategies that mimic whole blood, remain unknown. METHODS A secondary analysis of the PROPPR study was performed. Injured patients predicted to receive a massive transfusion were randomized to 1:1:1 versus 1:1:2 plasma-platelet-red blood cell ratios at 12 Level I North American trauma centers. Patients with survival >24 h, an intensive care unit (ICU) stay, and a recorded PaO2/FiO2 (P/F) ratio were included. Acute respiratory distress syndrome (ARDS) was defined as a P/F ratio

Background Prolonged storage of packed red blood cells (pRBCs) induces a series of harmful biochemical and metabolic changes known as the RBC storage lesion. RBCs are currently stored in an acidic storage solution, but the effect of pH on the RBC storage lesion is unknown. We investigated the effect of modulation of storage pH on the RBC storage lesion and on erythrocyte survival after transfusion. Methods Murine pRBCs were stored in Additive Solution-3 (AS3) under standard conditions (pH, 5.8), acidic AS3 (pH, 4.5), or alkalinized AS3 (pH, 8.5). pRBC units were analyzed at the end of the storage period. Several components of the storage lesion were measured, including cell-free hemoglobin, microparticle production, phosphatidylserine externalization, lactate accumulation, and byproducts of lipid peroxidation. Carboxyfluorescein-labeled erythrocytes were transfused into healthy mice to determine cell survival. Results Compared with pRBCs stored in standard AS3, those stored in alkaline solution exhibited decreased hemolysis, phosphatidylserine externalization, microparticle production, and lipid peroxidation. Lactate levels were greater after storage in alkaline conditions, suggesting that these pRBCs remained more metabolically viable. Storage in acidic AS3 accelerated erythrocyte deterioration. Compared with standard AS3 storage, circulating half-life of cells was increased by alkaline storage but decreased in acidic conditions. Conclusions Storage pH significantly affects the quality of stored RBCs and cell survival after transfusion. Current erythrocyte storage solutions may benefit from refinements in pH levels.

Erythrocyte-derived microparticles (MPs) are sub-micrometer, biologically active vesicles shed by red blood cells as part of the biochemical changes that occur during storage. We hypothesized that MPs from stored red blood cells would activate endothelial cells. MPs from aged murine packed red blood cells (pRBCs) were isolated and used to treat confluent layers of cultured endothelial cells. Endothelial expression of leukocyte adhesion molecules, endothelial-leukocyte adhesion molecule-1 (ELAM-1) and intercellular adhesion molecule-1(ICAM-1), and inflammatory mediator, interleukin-6 (IL-6), was evaluated at 0.5, 6, 12, and 24 h of treatment. Healthy C57BL/6 mice were transfused with a MP suspension and lung sections were analyzed for adhesion molecules and sequestered interstitial leukocytes. Increased levels of ELAM-1 and ICAM-1 were found on cultured endothelial cells 6 h after MP stimulation (6.91 vs. 4.07 relative fluorescent intensity [RFI], P < 0.01, and 5.85 vs. 3.55 RFI, P = 0.01, respectively). IL-6 in cell culture supernatants was increased after 12 h of MP stimulation compared with controls (1.24 vs. 0.73 ng/mL, P = 0.03). In vivo experiments demonstrated that MP injection increased ELAM-1 and ICAM-1 expression at 1 h (18.56 vs. 7.08 RFI, P < 0.01, and 23.66 vs. 6.87 RFI, P < 0.01, respectively) and caused increased density of pulmonary interstitial leukocytes by 4 h of treatment (69.25 vs. 29.25 cells/high powered field, P < 0.01). This series of experiments supports our hypothesis that erythrocyte-derived MPs are able to activate pulmonary endothelium, leading to the pulmonary sequestration of leukocytes following the transfusion of stored pRBCs.

Critical Care Air Transport Teams (CCATTs) are integral to the U.S. Air Force aeromedical evacuation paradigm. The current study was conducted to evaluate predictors of nontechnical skills (NOTECHS) in CCATT trainees.Sixteen CCATTs were studied over a 6-month period. Team members completed a biographical survey and teams were videotaped during a simulated CCATT mission. Teams and individuals were assigned a "red flag score" using a validated assessment tool for NOTECHS. Salivary cortisol levels were measured at baseline and pre- and postsimulation exercises.63% of participants reported regular intensive care unit (ICU) experience and 67% had flown real-world CCATT missions. Sixteen simulated missions were reviewed, with 69 crisis events identified. Task saturation was observed in 42% of crisis events. Average team red flag score correlated with task saturation during the simulated missions (odds ratio = 0.5). Daily ICU experience (p0.03) and previous deployment (p0.04) correlated with NOTECHS performance. Cortisol levels increased from baseline as the result of the simulation (p0.01) but did not correlate with red flag scores or biographical data.Task saturation occurred frequently and correlated with performance of NOTECHS. Previous real-world CCATT experience and daily ICU care correlated with improved performance of NOTECHS.

BACKGROUND During storage, packed red blood cells (pRBCs) undergo a number of biochemical, metabolic, and morphologic changes, collectively known as the "storage lesion." We aimed to determine the effect of cryopreservation on the red blood cell storage lesion compared with traditional 4°C storage. METHODS Previously cryopreserved human pRBCs were compared with age-matched never-frozen pRBCs obtained from the local blood bank. The development of the red cell storage lesion was evaluated after 7, 14, 21, 28, and 42 days of storage at 4°C in AS-3 storage medium. We measured physiological parameters including cell counts, lactic acid, and potassium concentrations as well as signs of eryptosis including loss of phosphatidylserine (PS) asymmetry, microparticle production, and osmotic fragility in hypotonic saline. RESULTS Compared with controls, previously cryopreserved pRBC at 7 days of storage in AS-3 showed lower red cell counts (3.7 vs. 5.3 × 10 cells/μL, P

INTRODUCTION Hypertonic crystalloid solutions, colloids, and fresh whole blood (FWB) have all been proposed for prehospital resuscitation after hemorrhage. However, there are no direct comparisons of the efficacy of these different fluids. We compared Hextend, 3% hypertonic saline (HS), and FWB in a porcine model of hemorrhagic shock. MATERIALS AND METHODS Female swine (n = 5/group) underwent splenectomy and pressure-controlled hemorrhage followed by resuscitation with Hextend, 3% HS, or FWB. They were maintained at a target mean arterial pressure (MAP) for 4 h, holding or infusing fluid as necessary. Sham animals for comparison underwent splenectomy alone. RESULTS The mean volume required to maintain target MAP was significantly higher for 3% HS (1,016 ± 386 mL) than for Hextend (346 ± 299 mL, P

Hemorrhagic shock is a leading cause of mortality within the trauma population, and blood transfusion is the standard of care. Leukoreduction filters remove donor leukocytes prior to transfusion of blood products. While the benefits of leukocyte depletion are well documented in scientific literature, these benefits do not translate directly to the clinical setting. This review summarizes current research regarding leukoreduction in the clinical arena, as well as studies performed exclusively in the trauma population.

BACKGROUND: Penetrating injuries to the extremity proximal to the elbow or knee are anatomic criteria for full trauma team activation (FFTA) by the American College of Surgeon’s Committee on Trauma standards. This criterion lacks objective evidence-based support. Overtriage of trauma team activation may result in excessive costs and resource burden at trauma centers. We hypothesized that FFTA for penetrating injuries to the proximal extremities by anatomic criteria alone may lead to significant overtriage. METHODS: A 3-year retrospective review (2013–2015) was completed of all patients evaluated at an urban Level I trauma center with isolated penetrating extremity injuries. Data included the number of full and limited trauma team activations as well as criterion met, Injury Severity Score (ISS), injury, limb characteristics, and disposition. Overtriage was defined as FFTA for an ISS of 15 or less, with a goal rate less than 50%. RESULTS: We identified 6,335 total trauma team activations with 795 isolated penetrating extremity injuries. Of these injuries, 413 (51.9%) were injuries proximal to the joint. Within this subgroup, 71.2% of patients were discharged from the emergency department with a median ISS of 1 and no additional intervention. Only 5.3% of patients that did not meet additional FFTA criteria underwent immediate operative intervention. By comparison, 21% of FFTAs and 5.8% of limited trauma team activations underwent immediate operative intervention during the 3-year period. Of the 413 isolated penetrating proximal-extremity injuries, only one had an ISS of 15 or greater, resulting in a 99.7% overtriage rate. CONCLUSION: Penetrating injuries to the extremities are common in urban trauma centers. Full trauma team activation based on anatomic, rather than physiologic, criteria may lead to a significant overtriage rate. Further distinction in the level of trauma team activation may be made based on hard signs of neurovascular injury. LEVEL OF EVIDENCE: Epidemiological study, level III; Care Management, level IV.

Introduction Acute hemorrhage remains the leading cause of death in potentially survivable injuries. The use of topical hemostatic agents has increased over the last two decades with the evolution of damage control surgery. By 2008, the military widely adopted Combat Gauze as the hemostatic dressing of choice for compressible hemorrhage. The goal of this study was to compare the performance of a novel fibrin sealant patch to Combat Gauze in two clinically relevant models of hemorrhage. Materials and methods Yorkshire swine underwent unilateral femoral artery puncture or a grade V liver laceration with timed free bleeding then received either the fibrin patch or Combat Gauze packing with 3 minutes of standardized pressure. Animals were then resuscitated to maintain a mean arterial pressure of 60 mmHg for 4 hours. Hemostasis, blood loss, resuscitation volume, survival, vessel patency, and hematologic parameters were evaluated. Results Hemostasis was equivalent in both groups after hepatic and vascular injury. Survival was 80% in the fibrin patch vascular injury group and 100% in all other groups. Hematologic parameters were not significantly different between treatment groups. Femoral artery patency was 80% in both groups after vascular injury. With simulated ambulation after vessel injury, 60% of the Combat Gauze group and 80% of the fibrin patch group remained hemostatic (p > 0.05). In simulated re-exploration with packing removal, all animals rebled after hemostatic product removal. Conclusion There was no significant difference in hemostasis between a novel fibrin patch and Combat Gauze after extremity arterial or hepatic injury. This novel fibrin patch may have a clinical advantage over the Combat Gauze, as it can be left in the body, thereby limiting the potential need for reoperation.

Background Leukoreduction prior to packed red blood cell (pRBC) storage is not a universally accepted practice. Our laboratory has previously shown that microvesicles (MVs) accumulate in pRBC units during storage and play an important role in lung injury after resuscitation. Currently, the effect of leukoreduction on MV formation in stored pRBC units is unknown. In the present study, we investigated the hypothesis that leukoreduction of pRBC units prior to storage would attenuate the production of MVs and decrease pulmonary inflammation after hemorrhage and resuscitation. Methods Leukoreduced and nonleukoreduced pRBC units were prepared from human donors and C57/Bl6 mice and stored for up to 42 d and 14 d, respectively. At intervals during storage, MVs were isolated from pRBC units, quantified and characterized based on size, morphology, and levels of proinflammatory cytokines. In additional experiments, mice underwent controlled hemorrhage followed by resuscitation with normal saline (NS) with or without equal numbers of MVs isolated from leukoreduced or nonleukoreduced stored mouse pRBC. Histologic lung sections were evaluated for the presence of tissue edema and inflammatory cells. Results For both human and mouse pRBCs, the number of MVs significantly increased throughout the storage period. There were significantly fewer MVs present in leukoreduced units. The average MV size significantly increased over time and was similar between groups. Levels of interleukin 1α (IL-1α), regulated on activation, normal T cell expressed and secreted (RANTES), and macrophage-derived chemokine (MDC) were lower in MVs from leukoreduced pRBC units as compared with MVs from nonleukoreduced units. Hemorrhaged mice resuscitated with NS with the addition of MV from leukoreduced pRBC demonstrated significantly less pulmonary edema and inflammatory cell recruitment as compared to those resuscitated with NS with the addition of MV from nonleukoreduced pRBC. Conclusions Prestorage leukoreduction of pRBC units reduces the formation and proinflammatory properties of MV, which in turn decreases lung injury secondary to MV from stored pRBC units after hemorrhage and resuscitation.

BACKGROUND: Closed-loop controllers (CLCs) embedded within portable mechanical ventilators may allow for autonomous weaning. The ability of CLCs to maintain adequate oxygenation in the setting of hemorrhage and lung injury is unknown. We hypothesized that a portable ventilator with a CLC for inspired fraction of oxygen (FIO2) could provide oxygenation in a porcine model of hemorrhage and lung injury. METHODS: Female pigs randomized to the study group (n = 6) underwent a pressure-controlled bleed (mean arterial pressure = 40 mm Hg for 30 minutes). Acute lung injury was induced by saline lung lavage followed by intentional infliction of barotrauma. Sham pigs (n = 6) underwent placement of monitoring devices without hemorrhage or lung injury. All pigs were then placed on a portable ventilator modified with a CLC algorithm, which uses feedback from pulse oximetry (SpO2) and FIO2 trends to adjust FIO2 and maintain a target SpO2 of 94% (2%). The initial FIO2 was set at 0.60. Tidal volume, positive end-expiratory pressure, rate, and inspiratory-to-expiratory ratio were constant unless changes were required clinically. RESULTS: Study pigs had lower mean arterial pressures than shams at all time points except baseline. PaO2/FIO2 ratios were less than 300 and significantly lower than both baseline values and corresponding sham values at all time points. The CLC weaned the FIO2 at a reduced rate in study pigs relative to shams with a final mean FIO2 of 0.54 and 0.29 in study and sham pigs, respectively (p G 0.05). There was a significant divergence in the study and sham FIO2 curves but no significant difference in oxygen saturation or hypoxemia. CONCLUSION: Adequate oxygenation can be maintained in the setting of hemorrhage and lung injury using a portable ventilator embedded with a CLC of FIO2 based on pulse oximetry. These devices may be valuable for providing advanced medical care in resource-limited environments.

Sphingolipids are a ubiquitous family of essential lipids with an increasingly understood role as biologically active mediators in numerous physiologic and pathologic processes. Two particular sphingolipid species, sphingosine-1-phosphate and ceramide, and their metabolites interact both directly and indirectly with endothelial cells to regulate vascular permeability. Sphingosine-1-phosphate generally augments endothelial integrity while ceramide tends to promote vascular leak, and a tight balance between the two is necessary to maintain normal physiologic function. The mechanisms by which sphingolipids regulate endothelial barrier function are complex and occur through multiple different pathways, and disruptions or imbalances in these pathways have been implicated in a number of specific disease processes. With improved understanding of sphingolipid biology, endothelial function, and the interactions between the two, several targets for therapeutic intervention have emerged and there is immense potential for further advancement in this field.

Pulmonary edema associated with increased vascular permeability is a severe complication of Staphylococcus aureus–induced sepsis and an important cause of human pathology and death. We investigated the role of the mammalian acid sphingomyelinase (Asm)/ceramide system in the development of lung edema caused by S. aureus. Our findings demonstrate that genetic deficiency or pharmacologic inhibition of Asm reduced lung edema in mice infected with S. aureus. The Asm/ceramide system triggered the formation of superoxide, resulting in degradation of tight junction proteins followed by lung edema. Treatment of infected mice with amitriptyline, a potent inhibitor of Asm, protected mice from lung edema caused by S. aureus, but did not reduce systemic bacterial numbers. In turn, treatment with antibiotics reduced bacterial numbers but did not protect mice from lung edema. In contrast, only the combination of antibiotics and amitriptyline inhibited both pulmonary edema and bacteremia protecting mice from lethal sepsis and lung dysfunction suggesting the combination of both drugs as novel treatment option for sepsis. Key messages Antibiotics are often insufficient to cure S. aureus–induced sepsis. S. aureus induces lung edema via the Asm/ceramide system. Genetic deficiency of Asm inhibits lung dysfunction upon infection with S. aureus. Pharmacologic inhibition of Asm reduces lung edema induced by S. aureus. Antibiotics plus amitriptyline protect mice from lung edema and lethal S. aureus sepsis. Electronic supplementary material The online version of this article (doi:10.1007/s00109-014-1246-y) contains supplementary material, which is available to authorized users.

Hemorrhagic shock is a leading cause of mortality within the trauma population, and blood transfusion is the standard of care. Leukoreduction filters remove donor leukocytes prior to transfusion of blood products. While the benefits of leukocyte depletion are well documented in scientific literature, these benefits do not translate directly to the clinical setting. This review summarizes current research regarding leukoreduction in the clinical arena, as well as studies performed exclusively in the trauma population.

Randomized, controlled trials have suggested that the transfusion of blood after prolonged storage does not increase the risk of adverse outcomes among patients, although most of these trials were restricted to high-risk populations and were not powered to detect small but clinically important differences in mortality. We sought to find out whether the duration of blood storage would have an effect on mortality after transfusion in a general population of hospitalized patients.In this pragmatic, randomized, controlled trial conducted at six hospitals in four countries, we randomly assigned patients who required a red-cell transfusion to receive blood that had been stored for the shortest duration (short-term storage group) or the longest duration (long-term storage group) in a 1:2 ratio. Only patients with type A or O blood were included in the primary analysis, since pilot data suggested that our goal of achieving a difference in the mean duration of blood storage of at least 10 days would not be possible with other blood types. Written informed consent was waived because all the patients received treatment consistent with the current standard of care. The primary outcome was in-hospital mortality, which was estimated by means of a logistic-regression model after adjustment for study center and patient blood type.From April 2012 through October 2015, a total of 31,497 patients underwent randomization. Of these patients, 6761 who did not meet all the enrollment criteria were excluded after randomization. The primary analysis included 20,858 patients with type A or O blood. Of these patients, 6936 were assigned to the short-term storage group and 13,922 to the long-term storage group. The mean storage duration was 13.0 days in the short-term storage group and 23.6 days in the long-term storage group. There were 634 deaths (9.1%) in the short-term storage group and 1213 (8.7%) in the long-term storage group (odds ratio, 1.05; 95% confidence interval [CI], 0.95 to 1.16; P=0.34). When the analysis was expanded to include the 24,736 patients with any blood type, the results were similar, with rates of death of 9.1% and 8.8%, respectively (odds ratio, 1.04; 95% CI, 0.95 to 1.14; P=0.38). Additional results were consistent in three prespecified high-risk subgroups (patients undergoing cardiovascular surgery, those admitted to intensive care, and those with cancer).Among patients in a general hospital population, there was no significant difference in the rate of death among those who underwent transfusion with the freshest available blood and those who underwent transfusion according to the standard practice of transfusing the oldest available blood. (Funded by the Canadian Institutes of Health Research and others; INFORM Current Controlled Trials number, ISRCTN08118744 .).

Critical Care Air Transport Teams (CCATTs) are a critical component of the United States Air Force evacuation paradigm. This study was conducted to assess the incidence of task saturation in simulated CCATT missions and to determine if there are predictable performance domains.Sixteen CCATTs were studied over a 6-month period. Performance was scored using a tool assessing eight domains of performance. Teams were also assessed during critical events to determine the presence or absence of task saturation and its impact on patient care.Sixteen simulated missions were reviewed and 45 crisis events identified. Task saturation was present in 22/45 (49%) of crisis events. Scoring demonstrated that task saturation was associated with poor performance in teamwork (odds ratio [OR] = 1.96), communication (OR = 2.08), and mutual performance monitoring (OR = 1.9), but not maintenance of guidelines, task management, procedural skill, and equipment management. We analyzed the effect of task saturation on adverse patient outcomes during crisis events. Adverse outcomes occurred more often when teams were task saturated as compared to non-task-saturated teams (91% vs. 23%; RR 4.1, p0.0001).Task saturation is observed in simulated CCATT missions. Nontechnical skills correlate with task saturation. Task saturation is associated with worsening physiologic derangements in simulated patients.

Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.

Acute lung injury following trauma resuscitation remains a concern despite recent advances. With the use of the PROMMTT study population, the risk of hypoxemia and potential modifiable risk factors are studied.Patients with survival for 24 hours or greater with at least one intensive care unit day were included in the analysis. Hypoxemia was categorized using the Berlin definition for adult respiratory distress syndrome: none (PaO₂-to-FIO₂ ratio [P/F]300 mm Hg), mild (P/F, 201-300 mm Hg), moderate (P/F, 101-200 mm Hg) or severe (P/F ≤ 100 mm Hg). The cohort was dichotomized into those with none or mild hypoxemia and those with moderate or severe injury. Early resuscitation was defined as that occurring 0 hour to 6 hours from arrival; late resuscitation was defined as that occurring 7 hours to 24 hours. Multivariate logistic regression models were developed controlling for age, sex, mechanisms of injury, arrival physiology, individual Abbreviated Injury Scale (AIS) scores, blood transfusions, and crystalloid administration.Of the patients 58.7% (731 of 1,245) met inclusion criteria. Hypoxemia occurred in 69% (mild, 24%; moderate, 28%; severe, 17%). Mortality was highest (24%) in the severe group. During early resuscitation (0-6 h), logistic regression revealed age (odd ratio [OR], 1.02; 95% confidence interval [CI], 1.00-1.04), chest AIS score (OR, 1.31; 95% CI, 1.10-1.57), and intravenously administered crystalloid fluids given in 500 mL increments (OR, 1.12; 95% CI, 1.01-1.25) as predictive of moderate or severe hypoxemia. During late resuscitation, age (OR, 1.02; 95% CI, 1.00-1.04), chest AIS score (OR, 1.33; 95% CI, 1.11-1.59), and crystalloids given during this period (OR, 1.05; 95% CI, 1.01-1.10) were also predictive of moderate-to-severe hypoxemia. Red blood cell, plasma, and platelet transfusions (whether received during early or late resuscitation) failed to demonstrate an increased risk of developing moderate/severe hypoxemia.Severe chest injury, increasing age, and crystalloid-based resuscitation, but not blood transfusions, were associated with increased risk of developing moderate-to-severe hypoxemia following injury.

Background/Aims: During storage, units of human red blood cells (pRBCs) experience membrane destabilization and hemolysis which may cause harm to transfusion recipients. This study investigates whether inhibition of acid sphingomyelinase could stabilize erythrocyte membranes and prevent hemolysis during storage. Methods: Human and murine pRBCs were stored under standard blood banking conditions with and without the addition of amitriptyline, a known acid sphingomyelinase inhibitor. Hemoglobin was measured with an electronic hematology analyzer and flow cytometry was used to measure erythrocyte size, complexity, phosphatidylserine externalization, and band 3 protein expression. Results: Cell-free hemoglobin, a marker of hemolysis, increased during pRBC storage. Amitriptyline treatment decreased hemolysis in a dose-dependent manner. Standard pRBC storage led to loss of erythrocyte size and membrane complexity, increased phosphatidylserine externalization, and decreased band 3 protein integrity as determined by flow cytometry. Each of these changes was reduced by treatment with amitriptyline. Transfusion of amitriptyline-treated pRBCs resulted in decreased circulating free hemoglobin. Conclusion: Erythrocyte storage is associated with changes in cell size, complexity, membrane molecular composition, and increased hemolysis. Acid sphingomyelinase inhibition reduced these changes in a dose-dependent manner. Our data suggest a novel mechanism to attenuate the harmful effects after transfusion of aged blood products.