Murine Traumatic Brain Injury Model Comparison: Closed Head Injury Versus Controlled Cortical Impact.

INTRODUCTION: Various murine models have been utilized to study TBI, including closed head injury (CHI) and controlled cortical impact (CCI), without direct comparison. The aim of our study was to evaluate these models to determine differences in neurological and behavioral outcomes postinjury. METHODS: Male C57B/6 mice (9-10 wk) were separated into six groups including: untouched, sham craniotomy (4 mm), CCI 0.9 mm depth of impact, CCI 1.6 mm, CCI 2.2 mm, and CHI. CCI was performed using a 3 mm impact tip at a velocity of 5 m/s, dwell time of 250 ms, and depth as noted above. CHI was completed with a centered 400 g weight drop from 1 cm height. Mice were survived to 14-d (n = 5 per group) and 30-d (n = 5 per group) respectively for histological analysis of p-tau within the hippocampus. These mice underwent Morris Water Maze memory testing and Rotarod motor testing. Serum was collected from a separate cohort of mice (n = 5 per group) including untouched, isoflurane only, CCI 1.6 mm, CHI at 1, 4, 6, and 24 h for analysis of neuron specific enolase and glial fibrillary acidic protein (GFAP) via ELISA. Laser speckle contrast imaging was analyzed prior to and after impact in the CHI and CCI 1.6 mm groups. RESULTS: There were no significant differences in Morris Water Maze or Rotarod testing times between groups at 14- or 30-d. P-tau was significantly elevated in all groups except CCI 1.6 mm contralateral and CCI 2.2 mm ipsilateral compared to untouched mice at 30-d. P-tau was also significantly elevated in the CHI group at 30 d compared to CCI 1.6 mm contralateral and CCI 2.2 mm on both sides. GFAP was significantly increased in mice undergoing CHI (9959 ± 91 pg/mL) compared to CCI (2299 ± 1288 pg/mL), isoflurane only (133 ± 75 pg/mL), and sham (86 ± 58 pg/mL) at 1-h post TBI (P < 0.0001). There were no differences in serum neuron specific enolase levels between groups. Laser doppler imaging demonstrated similar decreases in cerebral blood flow between CHI and CCI; however, CCI mice had a reduction in blood flow with craniotomy only that did not significantly decrease further with impact. CONCLUSIONS: Based on our findings, CHI leads to increased serum GFAP levels and increased p-tau within the hippocampus at 30-d postinjury. While CCI allows the comparison of one cerebral hemisphere to the other, CHI may be a better model of TBI as it requires less technical expertise and has similar neurological outcomes in these murine models.

Aberrant Oxygen Concentrations Induce Systemic Inflammation in a Murine Model.

INTRODUCTION: Hypoxia is a significant cause of secondary insult in the critically ill trauma or surgical patient. The cause of increased mortality following a brief period of hypoxia is not well understood. The aim of this study is to determine the effect of acute, isolated deviations in oxygen concentration on proinflammatory cytokine release and markers of endothelial stress in a murine model. METHODS: Mice were randomized to either control, hypoxia, or hyperoxia group. The control group was exposed to room air for 60 min, the hyperoxia group was exposed to 70% fraction of inspired oxygen, and the hypoxia group was exposed to 10% fraction of inspired oxygen for 60 min. Whole blood collection was completed via cardiac puncture. Serum concentrations of proinflammatory cytokines and endothelial stress markers were analyzed via enzyme-linked immunosorbent assay. RESULTS: Following exposure to hypoxic conditions, there was a significant increase in interleukin (IL)-1α (IL-1 α), IL-1 ß, IL-3, IL-4, IL-6, IL-10, tumor necrosis factor α . Following exposure to hyperoxic conditions, there was a significant increase in monocyte chemoattractant protein-1 and regulated upon activation normal T cell expressed and presumably secreted, as well as a significant decrease in IL-12, and IL-17. No clinically significant difference was noted in serum concentration of endothelial stress markers between the treatment groups. DISCUSSION: Exposure to oxygen extremes induces systemic inflammation as measured by proinflammatory cytokines in a murine model. Hyperoxia also demonstrates the ability to downregulate certain inflammatory pathways while inducing others. No effect on serum concentration of endothelial stress markers is observed following acute, isolated hypoxic or hyperoxic conditions.

Need for Blood Transfusion Volume Is Associated With Increased Mortality in Severe Traumatic Brain Injury.

INTRODUCTION: Many patients suffering from isolated severe traumatic brain injury (sTBI) receive blood transfusion on hospital arrival due to hypotension. We hypothesized that increasing blood transfusions in isolated sTBI patients would be associated with an increase in mortality. METHODS: We performed a trauma quality improvement program (TQIP) (2017-2019) and single-center (2013-2021) database review filtering for patients with isolated sTBI (Abbreviated Injury Scale head ≥3 and all other areas ≤2). Age, initial Glasgow Coma Score (GCS), Injury Severity Score (ISS), initial systolic blood pressure (SBP), mechanism (blunt/penetrating), packed red blood cells (pRBCs) and fresh frozen plasma (FFP) transfusion volume (units) within the first 4 h, FFP/pRBC ratio (4h), and in-hospital mortality were obtained from the TQIP Public User Files. RESULTS: In the TQIP database, 9257 patients had isolated sTBI and received pRBC transfusion within the first 4 h. The mortality rate within this group was 47.3%. The increase in mortality associated with the first unit of pRBCs was 20%, then increasing approximately 4% per unit transfused to a maximum mortality of 74% for 11 or more units. When adjusted for age, initial GCS, ISS, initial SBP, and mechanism, pRBC volume (1.09 [1.08-1.10], FFP volume (1.08 [1.07-1.09]), and FFP/pRBC ratio (1.18 [1.08-1.28]) were associated with in-hospital mortality. Our single-center study yielded 138 patients with isolated sTBI who received pRBC transfusion. These patients experienced a 60.1% in-hospital mortality rate. Logistic regression corrected for age, initial GCS, ISS, initial SBP, and mechanism demonstrated no significant association between pRBC transfusion volume (1.14 [0.81-1.61]), FFP transfusion volume (1.29 [0.91-1.82]), or FFP/pRBC ratio (6.42 [0.25-164.89]) and in-hospital mortality. CONCLUSIONS: Patients suffering from isolated sTBI have a higher rate of mortality with increasing amount of pRBC or FFP transfusion within the first 4 h of arrival.

Desmopressin, Misoprostol, nor Carboprost Affect Platelet Aggregability Following Traumatic Brain Injury and Aspirin.

INTRODUCTION: Desmopressin (DDAVP) has been utilized clinically in patients taking aspirin (ASA) to improve drug-induced platelet dysfunction. Misoprostol and carboprost, prostaglandin analogs commonly used for postpartum hemorrhage, may also induce platelet aggregation. The aim of this study was to determine the effects of DDAVP, misoprostol, and carboprost administration on platelet aggregability following traumatic brain injury (TBI) in mice treated with ASA. METHODS: Male C57BL/6 mice were randomized into seven groups (n = 5 each): untouched, ASA only, Saline/TBI, ASA/TBI, ASA/TBI/DDAVP 0.4 µg/kg, ASA/TBI/misoprostol 1 mg/kg, and ASA/TBI/carboprost 100 µg/kg. TBI was induced via a weight drop model 4-h after ASA (50 mg/kg) gavage. Mice were given an intraperitoneal injection of DDAVP, misoprostol, or carboprost 10 minutes after TBI. In vivo testing was completed utilizing tail vein bleed. Mice were sacrificed 30-min posttreatment and blood was collected via cardiac puncture. Whole blood was analyzed via Multiplate impedance aggregometry, rotational thromboelastometry, and TEG6s. RESULTS: Mice receiving misoprostol after ASA/TBI demonstrated decreased tail vein bleeding times compared to ASA only treated mice. However, mice treated with misoprostol following ASA and TBI demonstrated decreased platelet aggregability compared to untouched mice and TBI only mice within the arachidonic acid agonist pathway. By contrast, DDAVP and carboprost did not significantly change platelet aggregability via adenosine diphosphate or arachidonic acid following ASA and TBI. However, DDAVP did decrease the platelet contribution to clot via rotational thromboelastometry. CONCLUSIONS: Reversal of medication-induced platelet inhibition has become increasingly controversial after TBI. Based on these results, DDAVP, misoprostol, nor carboprost consistently improve platelet aggregability following TBI in those also treated with ASA.

Syndecan-1 as the Effect or Effector of the Endothelial Inflammatory Response?

INTRODUCTION: Syndecan-1 is a heparan sulfate proteoglycan found in the glycocalyx of vascular endothelial cells. Serum levels of syndecan-1 have repeatedly been demonstrated to increase following traumatic injury and shock, but it is unclear whether syndecan-1 plays an active role in the inflammatory response or is simply a biomarker of a state of hypoperfusion. The aim of this study was to identify the role of syndecan-1 role in the inflammatory process in the absence of trauma. METHODS: Male mice were randomized into five groups (n = 3). Four groups received increasing concentrations of syndecan-1 (1, 10, 100, and 1000pg/mL per blood volume) and a fifth group was given normal saline as a control via intravenous injection. These concentrations were selected based on previous syndecan-1 enzyme-linked immunosorbent assay data acquired following induced hemorrhagic shock in mice resulting in serum levels of 10-6000 pg/mL. Mice from each group were sacrificed at 1-, 4-, and 24-h time points for serum biomarker evaluation. A multiplex enzyme-linked immunosorbent assay was performed to analyze proinflammatory cytokines and chemokines including interleukin (IL)-1a, IL-1b, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, IL-17, monocyte chemoattractant protein-1, TNF-α, macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor, and normal T cell expressed and presumably secreted levels. Whole blood was analyzed via rotational thromboelastometry in a separate group of mice dosed with syndecan-1 at 1000 pg/mL and compared to sham mice at 1 h. RESULTS: Tumor necrosis factor-α was significantly elevated in the 1000 pg/mL group compared to sham animals. There were no significant changes in IL-1a, IL-1b, IL-2, IL-3, IL-4, IL-6, IL-10, IL-12, monocyte chemoattractant protein--1, macrophage inflammatory protein-1α, granulocyte-macrophage colony-stimulating factor, or normal T cell expressed and presumably secretedat 1, 4, and 24 h for any group when compared to mice receiving saline alone. No significant differences were noted in coagulability between the 1000 pg/mL syndecan-1 group and shams at 1 h CONCLUSIONS: Inflammatory cytokine concentrations did not change with increasing dosage of syndecan-1 within mice at any timepoint, except for an acute change in tumor necrosis factor-α which was transient. Based on our results, syndecan-1 appears to be a biomarker for inflammation rather than an active participant in eliciting an inflammatory response. Further research will focus on the role of syndecan-1 following hemorrhagic shock.

Microvesicles from stored red blood cells induce P-selectin and von Willebrand factor release from endothelial cells via a protein kinase C-dependent mechanism.

INTRODUCTION: The use of packed red blood cells (pRBCs) for resuscitation is limited by the red blood cell storage lesion, a series of biochemical and physiological changes that occur during the storage and aging of blood. Microvesicles (MVs) shed from pRBCs during this process are one component of the red blood cell storage lesion and lead to acute lung injury and pulmonary vascular microthrombi. We hypothesized that MVs from stored pRBCs lead to the release of P-selectin and von Willebrand factor (vWF) from endothelial cells and that this mechanism is mediated via activation of protein kinase C (PKC) or protein kinase A (PKA). METHODS: Leukoreduced, platelet-poor murine pRBCs were isolated from C57BL/6 8-12 week-old male mice via cardiac puncture, prepared via centrifugation using a Ficoll gradient, and stored for up to 14 days, the equivalent of 42 days of storage in humans. MVs were isolated from the stored pRBC units via sequential high-speed centrifugation. Murine lung endothelial cells (MLECs) were cultured and grown to confluence, then treated with MVs and either calphostin C, a PKC inhibitor (10 µg/mL), or PKI 14-22 amide, a PKA inhibitor (10 µM). The supernatant was collected after 1 h. P-selectin and vWF A2 concentrations were quantified via ELISA. Immunofluorescent staining for vWF was performed on MLECs. Statistical analysis was performed via unpaired t-test or ANOVA as indicated and reported as mean ± SD. Concentration is reported as pg/mL. RESULTS: MLECs treated with MVs isolated from stored pRBCs demonstrated increased release of P-selectin and vWF A2 in a dose-dependent fashion. MLECs treated with MVs prepared from stored as compared to fresh pRBCs demonstrated increased release of P-selectin (3751 ± 726 vs 359 ± 64 pg/mL, p < 0.0001) and vWF A2 (3141 ± 355 vs 977 ± 75 pg/mL, p < 0.0001) with increasing duration of storage. The treatment of MVs with calphostin C decreased the amount of P-selectin (1471 ± 444 vs 3751 ± 726 pg/mL, p < 0.0001) and VWF A2 (2401 ± 289 vs 3141 ± 355 pg/mL, p = 0.0017) released into the supernatant by MLECs compared to MVs alone. The treatment of MVs with PKI 14-22 increased the amount of P-selectin released compared to MVs alone (1999 ± 67 vs 1601 ± 135 pg/mL, p = 0.0018). CONCLUSIONS: MVs from stored pRBCs stimulate the release of P-selectin and VWF A2 from endothelial cells. The effect of MVs increases with both dose of MVs and age of stored pRBCs from which they are formed. This mechanism is dependent on activation of PKC and inhibition of this enzyme represents a potentially significant strategy to modulate the inflammatory response to resuscitation with stored pRBCs.

Predictive Value of Early Inflammatory Markers in Trauma Patients Based on Transfusion Status.

INTRODUCTION: Seven key inflammatory biomarkers were recently found to be associated with the risk of mortality in a multicenter study of massively transfused patients. The aim of this prospective single-center study was to determine which of these early inflammatory markers could predict 30-d mortality among all critically injured trauma patients. METHODS: Serum samples were collected at 6, 24, and 72 h from 238 consecutive patients admitted to the intensive care unit following traumatic injury. Inflammatory markers syndecan-1, eotaxin, IL-1ra, IL-6, IL-8, IL-10, IP-10, and MCP-1 were analyzed via multiplex enzyme-linked immunosorbent assay. Subgroup analysis was performed for patients undergoing massive transfusion (≥5 red blood cells), submassive transfusion (1-4 red blood cells), or no transfusion during the first 4 h postinjury. The primary outcome of 30-d survival was modeled as a function of each biomarker and confounders using repeat measures logistic regression. RESULTS: Patients had a median age of 51.3 y [33.7, 70.2], 70.6% were male, 17.4% experienced penetrating trauma, and had a median injury severity score of 22 [14, 33]. IL-1ra, IL-8, IL-10, and MCP-1 were significantly increased during the first 72 h in nonsurvivors (n = 31). Elevated IL-1ra, IL-8, IL-10, and MCP-1 at 6 h postinjury were associated with 30-d mortality. By contrast, serum syndecan-1 and eotaxin levels were not associated with mortality at any time point. IL-8 and lactate were increased at 6 h in 30-d nonsurvivors for patients receiving submassive transfusion (n = 78). CONCLUSIONS: Early evaluations of IL-1ra, IL-8, IL-10, and IP-10 within 6 h of injury are useful predictors of 30-d mortality. Subgroup analysis suggests that transfusion status does not significantly affect early inflammatory markers. LEVEL OF EVIDENCE: Level III, prognostic/epidemiological.

Aspirin Administration Mitigates Platelet Hyperaggregability After Splenectomy in a Murine Model.

INTRODUCTION: Patients who undergo splenectomy (SPLN) have an estimated 10%-35% risk of venous thromboembolic events; however, the underlying mechanism and strategy for prevention have yet to be identified. The goals of this study were to 1) investigate platelet aggregation after SPLN, 2) examine if aspirin administration could mitigate this effect, and 3) determine if concomitant hemorrhage would affect post-SPLN platelet function and response to aspirin. METHODS: Murine models of operative SPLN and submandibular bleed (SMB) were utilized. Mice were randomized to eight groups as follows: untouched, SPLN, sham (laparotomy only), SMB, SPLN + SMB, SPLN + aspirin (ASA), SMB + ASA, and SPLN + SMB + ASA. Aspirin (50 mg/kg) was administered on postoperative days (PODs) one and two via oral gavage. Mice were euthanized on POD 3, platelet counts were obtained, and blood samples were analyzed via rotational thromboelastometry and impedance aggregometry with adenosine diphosphate (ADP) and arachidonic acid (AA) as agonists. RESULTS: By POD 3, SPLN mice displayed a significant thrombocytosis compared to untouched, SMB, and sham SPLN mice. Clotting time and clot formation time were significantly decreased in SPLN and SPLN + SMB cohorts compared to untouched and sham controls with elevated mean clot firmness. SPLN mice also displayed a significant increase in ADP- and AA-mediated platelet aggregability compared to untouched controls, SMB, and SPLN + SMB. ASA significantly decreased platelet aggregation via both ADP and AA signaling in SPLN and SPLN + SMB cohorts without affecting viscoelastic coagulation testing. CONCLUSIONS: Platelet hyperaggregability after SPLN is mediated by both ADP and AA signaling. Early aspirin administration may prevent increased platelet aggregation exacerbated after polytrauma.

The Association of Norepinephrine Utilization With Mortality Risk in Trauma Patients.

INTRODUCTION: While the pillars of trauma resuscitation are surgical hemostasis and blood product administration, norepinephrine (NE) can be used as an adjunct. The goal of this study was to evaluate the relationship between the maximum dose of NE, timing of NE administration, and mortality in trauma patients. METHODS: Patients admitted between January 2013 and January 2021 treated with NE were reviewed. Univariate and multivariate logistic regression were used to assess whether maximum NE dose was independently associated with mortality. Optimal dosage rates for NE were determined via Youden Index. Subgroup analyses comparing those who received NE within versus after the first 24 h of admission were conducted. RESULTS: Three hundred fifty-first trauma patients were included, with 217 (62%) surviving. Patients who died received an average maximum dose of 16.7 mcg/min compared to 9.1 mcg/min in survivors (P = 0.0003). Mortality rate increased with dosage (P < 0.0001), with doses greater than 20 mcg/min having 79% mortality. Those who received NE within the first 24 h had an inflection point in mortality at 16 mcg/min (Youden = 0.45) (OR 1.06; 95% CI 1.03-1.10). For patients who received NE after the first 24 h, an inflection point in mortality was at 10 mcg/min (Youden = 0.34) (OR 1.09; 95% CI 1.04-1.14). CONCLUSIONS: Higher maximum doses of NE were associated with increased mortality. Patients initiated on NE more than 24 h into their admission displayed an inflection point at a lower dose than those initiated later. This suggests that trauma patients initiated on NE after 24 h from injury may have a dire prognosis.

Acute and Chronic Hematologic Implications of Emergency and Elective Splenectomy.

INTRODUCTION: Thrombocytosis and leukocytosis are common after splenectomy. The potential effect of emergency surgery on these postoperative findings is unknown. We hypothesized that emergency splenectomy leads to a more profound and persistent hematologic change as compared to elective splenectomy. METHODS: A retrospective review was conducted of patients who underwent elective or trauma splenectomy. Records were queried for platelet (PLT) and white blood cell (WBC) count prior to splenectomy, on postoperative days 1-5, and at day 14, 1 month, 3 months, 6 months, and 1 year. Complications, including thromboembolic events, infection, need for repeat operation, and readmission within 30 days of discharge, were recorded. RESULTS: 463 patients were identified as being eligible for the study, with 173 patients in the elective cohort and 145 patients in each of the isolated trauma splenectomy and polytrauma cohorts. Both cohorts had peak thrombocytosis at week 2 postoperatively. However, polytrauma patients had a significantly higher peak platelet count (P < 0.01). The PLT:WBC ratio was lower in both trauma cohorts pre-operatively and postoperative day 1. Trauma splenectomy had a higher PLT:WBC ratio on days 2 and 3 whereas polytrauma had a lower ratio on days 4 and 5. Emergency cases had greater reoperation and infection rates, whereas elective cases were more likely to require readmission. Postoperative thromboembolic events were only higher in the polytrauma cohort. CONCLUSIONS: While trauma splenectomy resulted in more profound postoperative leukocytosis and thrombocytosis, there was no correlation with timing of infection or risk of thromboembolic events. These findings suggest that thrombocytosis and leukocytosis may be associated with thrombotic and infectious events but their presence alone does not indicate direct risks of concomitant infection or thrombosis.

Hitting the Vasopressor Ceiling: Finding Norepinephrine Associated Mortality in the Critically Ill.

BACKGROUND: There is no consensus on what dose of norepinephrine corresponds with futility. The purpose of this study was to investigate the maximum infusion and cumulative doses of norepinephrine associated with survival for patients in medical and surgical intensive care units (MICU and SICU). MATERIALS AND METHODS: A retrospective review was conducted of 661 critically ill patients admitted to a large academic medical center who received norepinephrine. Univariate, multivariate, and area under the curve analyses with optimal cut offs for maximum infusion rate and cumulative dosage were determined by Youden Index. RESULTS: The population was 54.9% male, 75.8% white, and 58.7 ± 16.1 y old with 384 (69.8%) admitted to the MICU and 166 (30.2%) admitted to the SICU, including 38 trauma patients. Inflection points in mortality were seen at 18 mcg/min and 17.6 mg. The inflection point was higher in MICU patients at 21 mcg/min and lower in SICU patients at 11 mcg/min. MICU patients also had a higher maximum cumulative dosage of 30.7 mg, compared to 2.7 mg in SICU patients. In trauma patients, norepinephrine infusions up to 5 mcg/min were associated with a 41.7% mortality rate. CONCLUSION: A maximum rate of 18 mcg/min and cumulative dose of 17.6 mg were the inflection points for mortality risk in ICU patients, with SICU patients tolerating lower doses. In trauma patients, even low doses of norepinephrine were associated with higher mortality. These data suggest that MICU, SICU, and trauma patients differ in need for, response to, and outcome from escalating norepinephrine doses.

IFNγ and TNFα mediate CCL22/MDC production in alveolar macrophages after hemorrhage and resuscitation.

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.

Emerging Therapies for Prehospital Control of Hemorrhage.

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.

Hepatic Pseudoaneurysm Incidence After Liver Trauma.

BACKGROUND: Posttraumatic hepatic artery pseudoaneurysm is a potentially devastating complication after complex liver injury. Increasing computed tomography (CT) use may lead to more frequent identification of posttraumatic hepatic complications. This study was designed to determine the rate of hepatic pseudoaneurysm after traumatic liver injury. METHODS: We conducted a retrospective review of patients at an urban level 1 trauma center over 5 y (2012-2016). Injury characteristics, patient management, and complications were extracted from trauma registry data and chart review. RESULTS: Six hundred thirty-four hepatic injuries (11 no grade/no CT, 159 grade I, 154 grade II, 165 grade III, 93 grade IV, and 52 grade V) were identified from our trauma registry. No patient with a grade I or II injury had a subsequent bleeding complication. Eighteen patients had a documented hepatic pseudoaneurysm: grade III n = 3 (1.8%), grade IV n = 6 (6.5%), grade V n = 9 (17.3%). The median time to pseudoaneurysm identification was 6.5 d. Seven pseudoaneurysms were found on asymptomatic surveillance CT-angiography on average 5 d after injury. Eleven patients were symptomatic at the time of CT-angiography performed at a median of 9 d after admission. Of the 11 symptomatic patients, four were in hemorrhagic shock, and two died from hepatic-related complications. CONCLUSIONS: The incidence of hepatic artery pseudoaneurysm increases with higher grade liver injury. Aggressive surveillance for hepatic pseudoaneurysm with interval CT-angiography 5-7 d postinjury may be warranted, especially for grade IV and V injuries.

Characterizing Early Inpatient Death After Trauma.

BACKGROUND: There is a paucity of data to predict early death or futility after trauma. The objective of this study was to characterize the laboratory values, blood product administration, and hospital disposition for patients with trauma who died within 72 h of admission. METHODS: All deaths within 72 h of admission over a 5-y period at a level I trauma center were reviewed. Blood transfusion within the first 4 h of arrival and patient disposition from the emergency department to the operating room (OR), surgical intensive care unit, or the neuroscience intensive care unit (NSICU) were analyzed. Kaplan-Meier curves were generated to determine time to death. RESULTS: A total of 622 subjects were identified; 39.5% died in the emergency department, 10.6% went directly to the OR, 13.6% were admitted to the surgical intensive care unit, and 29.7% admitted to the NSICU. Of these subjects, 201 (32.2%) patients received blood within the first 4 h. By 24 h, early blood transfusion was associated with more rapid death for patients who were admitted to the NSICU (80% versus 60% mortality, P = 0.01) but not for patients taken directly to the OR (80% versus 70% mortality, P = 0.2). Admission coagulopathy by international normalized ratio (P < 0.01), but not anemia (P = 0.64) or acidosis (P = 0.45), correlated with a shorter time to death. In contrast, laboratory values obtained at 4 h after admission did not correlate with time to death. CONCLUSIONS: Our data demonstrate that admission coagulation derangement and need for early blood product transfusion are the two factors most associated with early death after injury, particularly in those patients with traumatic brain injury. These data will help construct future models for futility of continued care in patients with trauma.

Death by Decade: Establishing a Transfusion Ceiling for Futility in Massive Transfusion.

BACKGROUND: Age and massive transfusion are predictors of mortality after trauma. We hypothesized that increasing age and high-volume transfusion would result in progressively elevated mortality rates and that a transfusion "ceiling" would define futility. METHODS: The Trauma Quality Improvement Program (TQIP) database was queried for 2013-2016 records and our level I trauma registry was reviewed from 2013 to 2018. Demographic, mortality, and blood transfusion data were collected. Patients were grouped by decade of life and by packed red blood cell (pRBC) transfusion requirement (zero units, 1-3 units, or ≥4 units) within 4 h of admission. RESULTS: TQIP analysis demonstrated an in-hospital mortality risk that increased linearly with age, to an odds ratio of 10.1 in ≥80 y old (P < 0.01). Mortality rates were significantly higher in older adults (P < 0.01) and those with more pRBCs transfused. In massively transfused patients, the transfusion "ceiling" was dependent on age. Owing to the lack granularity in the TQIP database, 230 patients from our institution who received ≥4 units of pRBCs within 4 h of admission were reviewed. On arrival, younger patients had significantly higher heart rates and more severe derangements in lactate levels, base deficits, and pH compared with older patients. There were no differences among age groups in injury severity score, systolic blood pressure, or mortality. CONCLUSIONS: In massively transfused patients, mortality increased with age. However, a significant proportion of older adults were successfully resuscitated. Therefore, age alone should not be considered a contraindication to high-volume transfusion. Traditional physiologic and laboratory criteria indicative of hemorrhagic shock may have reduced reliability with increasing age, and thus providers must have a heightened suspicion for hemorrhage in the elderly. Early transfusion requirements can be combined with age to establish prognosis to define futility to help counsel families regarding mortality after traumatic injury.

Early Identification of Acute Lung Injury in a Porcine Model of Hemorrhagic Shock.

BACKGROUND: Acute lung injury (ALI) is a frequent complication after severe trauma. Lung-protective ventilation strategies and damage control resuscitation have been proposed for the prevention of ALI; however, there are no clinical or laboratory parameters to predict who is at risk of developing ALI after trauma. In the present study, we explored pulmonary inflammatory markers as a potential predictor of ALI using a porcine model of hemorrhagic shock. MATERIALS AND METHODS: Female swine were randomized to mechanical ventilation with low tidal volume (VT) (6 mL/kg) or high VT (12 mL/kg). After equilibration, animals underwent pressure-controlled hemorrhage (mean arterial pressure [MAP] 35 ± 5 mmHg) for 1 h, followed by resuscitation with fresh whole blood or Hextend. They were maintained at MAP of 50 ± 5 mmHg for 3 h in the postresuscitation phase. Bronchoalveolar lavage fluids were collected hourly and analyzed for inflammatory markers. Lung samples were taken, and porcine neutrophil antibody staining was used to evaluate the presence of neutrophils. ELISA evaluated serum porcine surfactant protein D levels. Sham animals were used as negative controls. RESULTS: Pigs that underwent hemorrhagic shock had higher heart rates, lower cardiac output, lower MAPs, and worse acidosis compared with sham at the early time points (P < 0.05 each). There were no significant differences in central venous pressure or pulmonary capillary wedge pressure between groups. Pulmonary neutrophil infiltration, as defined by neutrophil antibody staining on lung samples, was greater in the shock groups regardless of resuscitation fluid (P < 0.05 each). Bronchoalveolar lavage fluid neutrophil levels were not different between groups. There were no differences in levels of porcine surfactant protein D between groups at any time points, and the levels did not change over time in each respective group. CONCLUSIONS: Our study demonstrates the reproducibility of a porcine model of hemorrhagic shock that is consistent with physiologic changes in humans in hemorrhagic shock. Pulmonary neutrophil infiltration may serve as an early marker for ALI; however, the practicality of this finding has yet to be determined.

Amitriptyline Reduces Inflammation and Mortality in a Murine Model of Sepsis.

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.

Lower Extremity Duplex Ultrasound Screening Protocol for Moderate- and High-Risk Trauma Patients.

BACKGROUND: Deep vein thrombosis (DVT) remains a significant cause of morbidity after injury. Lower extremity duplex ultrasound screening (LEDUS) is designed to identify early, asymptomatic DVTs in moderate and high risk patients. We sought to describe when thrombus is detected and identify which trauma patients benefit from LEDUS. MATERIALS AND METHODS: A retrospective review was conducted on trauma patients who were moderate or high risk for venous thromboembolism based on risk assessment profile (RAP) scoring. Patients with RAP scores ≥5 underwent LEDUS on hospital Day 4 and then weekly. We defined moderate venous thromboembolism risk as an RAP score of 5-9 and high risk as an RAP score of ≥10. Demographics, injury characteristics, and chemoprophylaxis type and timing were analyzed. RESULTS: A total of 579 trauma patients underwent a total of 820 ultrasounds in 1 y. Eighty-eight acute DVTs were identified. There was only one progression of a below- to above-the-knee DVT. Patients with RAP scores ≥10 had significantly higher rates of DVTs compared with patients with lower RAP scores in addition to longer lengths of stay and time to DVT prophylaxis. Moderate- and high-risk patients had similar rates of pulmonary embolism. Two-thirds of all DVTs were diagnosed on the first screening examination. The rate of DVTs in patients with RAP scores 7-9 was 15.4% compared with 6.1% of those with RAP scores of 5-6. CONCLUSIONS: LEDUS allows for early identification of asymptomatic DVTs. Moderate-risk patients with RAP scores of ≥7 should be considered for LEDUS, given higher rates of DVT.

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.