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.

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.

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.

Validation of Preload Assessment Technologies at Altitude in a Porcine Model of Hemorrhage.

INTRODUCTION: Dynamic preload assessment measures including pulse pressure variation (PPV), stroke volume variation (SVV), pleth variability index (PVI), and hypotension prediction index (HPI) have been utilized clinically to guide fluid management decisions in critically ill patients. These values aid in the balance of correcting hypotension while avoiding over-resuscitation leading to respiratory failure and increased mortality. However, these measures have not been previously validated at altitude or in those with temporary abdominal closure (TAC). METHODS: Forty-eight female swine (39 ± 2 kg) were separated into eight groups (n = 6) including all combinations of flight versus ground, hemorrhage versus no hemorrhage, and TAC versus no TAC. Flight animals underwent simulated aeromedical evacuation via an altitude chamber at 8000 ft. Hemorrhagic shock was induced via stepwise hemorrhage removing 10% blood volume in 15-min increments to a total blood loss of 40% or a mean arterial pressure of 35 mmHg. Animals were then stepwise transfused with citrated shed blood with 10% volume every 15 min back to full blood volume. PPV, SVV, PVI, and HPI were monitored every 15 min throughout the simulated aeromedical evacuation or ground control. Blood samples were collected and analyzed for serum levels of serum IL-1ß, IL-6, IL-8, and TNF-α. RESULTS: Hemorrhage groups demonstrated significant increases in PPV, SVV, PVI, and HPI at each step compared to nonhemorrhage groups. Flight increased PPV (P = 0.004) and SVV (P = 0.003) in hemorrhaged animals. TAC at ground level increased PPV (P < 0.0001), SVV (P = 0.0003), and PVI (P < 0.0001). When TAC was present during flight, PPV (P = 0.004), SVV (P = 0.003), and PVI (P < 0.0001) values were decreased suggesting a dependent effect between altitude and TAC. There were no significant differences in serum IL-1ß, IL-6, IL-8, or TNF-α concentration between injury groups. CONCLUSIONS: Based on our study, PPV and SVV are increased during flight and in the presence of TAC. Pleth variability index is slightly increased with TAC at ground level. Hypotension prediction index demonstrated no significant changes regardless of altitude or TAC status, however this measure was less reliable once the resuscitation phase was initiated. Pleth variability index may be the most useful predictor of preload during aeromedical evacuation as it is a noninvasive modality.

Platelet Function is Independent of Sphingolipid Manipulation.

INTRODUCTION: Previous literature suggests that sphingolipids may impact systemic coagulation and platelet aggregation, thus modulating the risks of thrombotic events. The goal of this investigation was to evaluate the role of serum sphingolipids on intrinsic platelet function to assess whether pharmacologic manipulation of sphingolipid metabolites would impact platelet aggregability. METHODS: C57BL/6J mice were injected with either normal saline, 1 mg/kg FTY720 (synthetic sphingosine-1-phosphate [S1P] receptor analog), or 5 mg/kg SLM6031434 (sphingosine kinase two inhibitor). Mice were sacrificed at 6 h and whole blood (WB) was collected for impedance aggregometry assessing platelet responsiveness to arachidonic acid or adenosine diphosphate. Ex vivo studies utilized WB or platelet-rich plasma that was pretreated with S1P, FTY720, amitriptyline, or d-sphingosine then analyzed by aggregability and flow cytometry for platelet and platelet-derived microvesicle characteristics. RESULTS: FTY720 and SLM6031434 pretreated induced similar arachidonic acid and adenosine diphosphate-mediated platelet aggregation as controls. Ex vivo WB and platelet-rich plasma treatment with S1P, FTY720, amitriptyline and d-sphingosine did not impact platelet aggregation. The percentages of CD41+, CD62P+ and CD41+/ceramide+, CD62P+/ceramide + platelets, and platelet-derived microvesicle were not significantly different between amitriptyline-treated and normal saline-treated cohorts. CONCLUSIONS: Sphingolipid modulating agents, such as FTY720, SLM6031434, S1P, amitriptyline, ceramide, and d-sphingosine do not appear to independently impact platelet aggregation in murine models.

Re-Evaluating the Use of High Sensitivity Troponin to Diagnose Blunt Cardiac Injury.

INTRODUCTION: Blunt cardiac injury (BCI) can be challenging diagnostically, and if misdiagnosed, can lead to life-threatening complications. Our institution previously evaluated BCI screening with troponin and electrocardiogram (EKG) during a transition from troponin I to high sensitivity troponin (hsTnI), a more sensitive troponin I assay. The previous study found an hsTnI of 76 ng/L had the highest capability of accurately diagnosing a clinically significant BCI. The aim of this study was to determine the efficacy of the newly implemented protocol. METHODS: Patients diagnosed with a sternal fracture from March 2022 to April 2023 at our urban level-1 trauma center were retrospectively reviewed for EKG findings, hsTnI trend, echocardiogram changes, and clinical outcomes. The BCI cohort and non-BCI cohort ordinal measures were compared using Wilcoxon's two-tailed rank sum test and categorical measures were compared with Fisher's exact test. Youden indices were used to evaluate hsTnI sensitivity and specificity. RESULTS: Sternal fractures were identified in 206 patients, of which 183 underwent BCI screening. Of those screened, 103 underwent echocardiogram, 28 were diagnosed with clinically significant BCIs, and 15 received intervention. The peak hsTnI threshold of 76 ng/L was found to have a Youden index of 0.31. Rather, the Youden index was highest at 0.50 at 40 ng/L (sensitivity 0.79 and specificity 0.71) for clinically significant BCI. CONCLUSIONS: Screening patients with sternal fractures for BCI using hsTnI and EKG remains effective. To optimize the hsTnI threshold, this study determined the hsTnI threshold should be lowered to 40 ng/L. Further improvements to the institutional protocol may be derived from multicenter analysis.

Just Say NO: Inhaled Nitric Oxide Effect on Respiratory Parameters Following Traumatic Brain Injury in Humans and a Porcine Model.

INTRODUCTION: The mechanism of post-traumatic brain injury (TBI) hypoxemia involves ventilation/perfusion mismatch and loss of pulmonary hypoxic vasoconstriction. Inhaled nitric oxide (iNO) has been studied as an adjunct treatment to avoid the use of high positive end-expiratory pressure and inspired oxygen in treatment-refractory hypoxia. We hypothesized that iNO treatment following TBI would improve systemic and cerebral oxygenation via improved matching of pulmonary perfusion and ventilation. METHODS: Thirteen human patients with isolated TBI were enrolled and randomized to receive either placebo or iNO with measured outcomes including pulmonary parameters, blood gas data, and intracranial pressure (ICP) /perfusion. To complement this study, a porcine model of TBI (including 10 swine) was utilized with measured outcomes of brain tissue blood flow and oxygenation, ventilator parameters, and blood gas data both after administration and following drug removal and clearance. RESULTS: There were no clinically significant changes in pulmonary parameters in either the human or porcine arm following administration of iNO when compared to either the placebo group (human arm) or the internal control (porcine arm). Analysis of pooled human data demonstrated the preservation of alveolar recruitment in TBI patients. There were no clinically significant changes in human ICP or cerebral perfusion pressure following iNO administration compared to controls. CONCLUSIONS: iNO had no significant effect on clinically relevant pulmonary parameters or ICPs following TBI in both human patients and a porcine model. The pressure-based recruitment of the human lungs following TBI was preserved. Further investigation will be needed to determine the degree of utility of iNO in the setting of hypoxia after polytrauma.

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.

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.

Partial Resuscitative Endovascular Balloon Occlusion of the Aorta Limits Ischemia-Reperfusion Injury After Simulated Aeromedical Evacuation.

INTRODUCTION: One of the advantages of partial Resuscitative Endovascular Balloon Occlusion of the Aorta (pREBOA) compared to the original model is the mitigation of reperfusion injury. The safety and efficacy of pREBOA have not been demonstrated in the setting of aeromedical evacuation. We hypothesized that the pREBOA would result in less ischemia-reperfusion injury after altitude exposure. METHODS: Twenty-four swine underwent femur fracture with hemorrhage for 20 min, followed by resuscitative endovascular balloon occlusion of the aorta (REBOA) deployment to Zone 1 and were randomized to pREBOA-PRO (Prytime Medical Devices Inc) full inflation, partial inflation, or sham inflation and then an altitude exposure of ground level or 8000 ft for 15 min. The primary endpoint was to examine if the balloon functioned at altitude. Our secondary endpoint was investigating evidence of ischemia-reperfusion by hemodynamic instability, electrolyte derangements, and acidosis. Comparisons were made by ANOVA. RESULTS: After deflation, the partially inflated group maintained a higher mean arterial pressure (MAP) compared to fully inflated group (P = 0.026). Full REBOA pigs were more tachycardic compared to sham pREBOA at ground (P < 0.001) and this was exacerbated at altitude (P < 0.001). Full REBOA pigs were more acidotic than sham and pREBOA at ground pigs (P = 0.0006 and P = 0.0002, respectively). Altitude increased the acidosis in full REBOA pigs, resulting in a greater base deficit (P < 0.0001), lactate (P < 0.0001), and IL-6 (P = 0.006). CONCLUSIONS: PREBOA resulted in less severe ischemia-reperfusion injury at both altitude and ground, while full balloon inflation at altitude exacerbated acidosis and ischemia-reperfusion injury. Efforts should therefore be made to utilize partial balloon occlusion when employing the REBOA catheter.

Evaluating the Utility of High Sensitivity Troponin in Blunt Cardiac Injury.

INTRODUCTION: Screening for blunt cardiac injury (BCI) includes obtaining a serum troponin level and an electrocardiogram for patients diagnosed with a sternal fracture. Our institution has transitioned to the use of a high sensitivity troponin I (hsTnI). The aim of this study was to determine whether hsTnI is comparable to troponin I (TnI) in identifying clinically significant BCI. MATERIALS AND METHODS: Trauma patients presenting to a level I trauma center over a 24-mo period with the diagnosis of sternal fracture were screened for BCI. Any initial TnI more than 0.04 ng/mL or hsTnI more than 18 ng/L was considered positive for potential BCI. Clinically significant BCI was defined as a new-bundle branch block, ST wave change, echocardiogram change, or need for cardiac catheterization. RESULTS: Two hundred sixty five patients with a sternal fracture were identified, 161 underwent screening with TnI and 104 with hsTnI. For TnI, the sensitivity and specificity for detection of clinically significant BCI was 0.80 and 0.79, respectively. For hsTnI, the sensitivity and specificity for detection of clinically significant BCI was 0.71 and 0.69, respectively. A multivariate analysis demonstrated the odds ratio for significant BCI with a positive TnI was 14.4 (95% confidence interval, 3.9-55.8, P < 0.0001) versus an odds ratio of 5.48 (95% confidence interval 1.9-15.7, P = 0.002) in the hsTnI group. CONCLUSIONS: The sensitivity of hsTnI is comparable to TnI for detection of significant BCI. Additional investigation is needed to determine the necessity and interval for repeat testing and the need for additional diagnostic testing.

Acute Pain Management in Traumatically Injured Patients With Outpatient Buprenorphine Therapy.

INTRODUCTION: Acute pain management is challenging in trauma patients undergoing outpatient buprenorphine therapy at the time of injury due to the high binding affinity of this partial agonist. The purpose of this study was to evaluate acute pain management in admitted trauma patients with discontinued versus continued outpatient buprenorphine therapy. MATERIALS AND METHODS: This retrospective study included adult trauma patients admitted to a level-1 trauma center between January 2017 and August 2020 who were receiving buprenorphine prior to admission. Groups were defined as buprenorphine discontinued (BD) or continued (BC) during hospitalization. The primary outcome compared median daily morphine milligram equivalents between groups. Secondary outcomes utilized patient-reported numeric rating scale (NRS) scores to compare incidences of no pain (NRS 0), mild (NRS 1-3), moderate (NRS 4-6), and severe (NRS 7-10) pain. RESULTS: A total of 57 patients were included (BD 37 [64.9%] and BC 20 [35.1%]). The median (interquartile range) outpatient daily buprenorphine dose was similar between groups (8 [8-16] mg versus 16 [8-16], P = 0.25). Median daily morphine milligram equivalents was significantly higher during admission in the BD group (103.7 [80.7-166] versus 67 [30.8-97.4], P = 0.002). Incidence of no pain (7.1% versus 5.7%, P = 0.283), mild (5.5% versus 4.3%, P = 0.295), moderate (20.2%, 19.8%, P = 0.855), or severe (67.2% versus 70.2%, P = 0.185) pain was similar between BD and BC groups, respectively. CONCLUSIONS: Continuation of outpatient buprenorphine therapy in acute trauma patients is associated with decreased daily opioid requirements and similar analgesic efficacy compared to patients with BD. Based on our findings, trauma patients receiving outpatient buprenorphine and not requiring ventilator support may benefit from buprenorphine continuation within 48 h of initial presentation.

Propranolol Reduces p-tau Accumulation and Improves Behavior Outcomes in a Polytrauma Murine Model.

INTRODUCTION: Traumatic brain injury (TBI) can lead to neurocognitive decline, in part due to phosphorylated tau (p-tau). Whether p-tau accumulation worsens in the setting of polytrauma remains unknown. Propranolol has shown clinical benefit in head injuries; however, the underlying mechanism is also unknown. We hypothesize that hemorrhagic shock would worsen p-tau accumulation but that propranolol would improve functional outcomes on behavioral studies. METHODS: A murine polytrauma model was developed to examine the accumulation of p-tau and whether it can be mitigated by early administration of propranolol. TBI was induced using a weight-drop model and hemorrhagic shock was achieved via controlled hemorrhage for 1 h. Mice were given intraperitoneal propranolol 4 mg/kg or saline control. The animals underwent behavioral testing at 30 d postinjury and were sacrificed for cerebral histological analysis. These studies were completed in male and female mice. RESULTS: TBI alone led to increased p-tau generation compared to sham on both immunohistochemistry and immunofluorescence (P < 0.05). The addition of hemorrhage led to greater accumulation of p-tau in the hippocampus (P < 0.007). In male mice, p-tau accumulation decreased with propranolol administration for both polytrauma and TBI alone (P < 0.0001). Male mice treated with propranolol also outperformed saline-control mice on the hippocampal-dependent behavioral assessment (P = 0.0013). These results were not replicated in female mice; the addition of hemorrhage did not increase p-tau accumulation and propranolol did not demonstrate a therapeutic effect. CONCLUSIONS: Polytrauma including TBI generates high levels of hippocampal p-tau, but propranolol may help prevent this accumulation to improve both neuropathological and functional outcomes in males.

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.

General Surgery Residency Virtual Recruitment During the Pandemic: An Analysis of Applicant Surveys.

INTRODUCTION: The COVID-19 pandemic forced a sudden change from in-person to virtual interviews for the general surgery residency match. General surgery programs and applicants adopted multiple strategies to best mimic in-person recruitment. The purpose of this study was to evaluate applicant opinions of the virtual recruitment format. MATERIALS AND METHODS: Postinterview survey responses for applicants interviewing at a single general surgery residency program in the 2020-2021 and 2021-2022 cycles were evaluated. All interviewed applicants were sent an anonymous survey assessing the virtual interview structure, their impression of the program, and their opinions on recruitment in the future. RESULTS: The response rate was 31.2% (n = 60). Most (88.4%) respondents reported a more favorable view of the program after a virtual interview. Factors that were most likely to create a favorable impression were residents (89.6%) and culture (81.0%). 50.8% of applicants favored virtual-only interviews. The majority of applicants (60.3%), however, preferred the virtual interview remain a component of the application process, 34.4% recommended that virtual interviews be used as an initial screen before in-person invites, while 19.0% suggested applicants should interview in-person or virtually without penalty. 62.1% favored capping the number of interviews offered by programs and accepted by applicants. CONCLUSIONS: The virtual interview format for general surgery residency allows applicants to effectively evaluate a residency program. Applicants are in favor of a combination of virtual and in-person interviews in the future. Innovation in the recruitment process, including limiting the number of applications and incorporating virtual events, is supported by applicants.

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.

Postinjury Treatment to Mitigate the Effects of Aeromedical Evacuation After Traumatic Brain Injury in a Porcine Model.

INTRODUCTION: Early aeromedical evacuation after traumatic brain injury (TBI) has been associated with worse neurologic outcomes in murine studies and military populations. The goal of this study was to determine if commonly utilized medications, including allopurinol, propranolol, or tranexamic acid (TXA), could mitigate the secondary traumatic brain injury experienced during the hypobaric and hypoxic environment of aeromedical evacuation. METHODS: Porcine TBI was induced via controlled cortical injury. Twenty nonsurvival pigs were separated into four groups (n = 5 each): TBI+25 mL normal saline (NS), TBI+4 mg propranolol, TBI+100 mg allopurinol, and TBI+1g TXA. The pigs then underwent simulated AE to an altitude of 8000 ft for 4 h with an SpO2 of 82-85% and were sacrificed 4 h later. Hemodynamics, serum cytokines, and hippocampal p-tau accumulation were assessed. An additional survival cohort was partially completed with TBI/NS (n = 5), TBI/propranolol (n = 2) and TBI/allopurinol groups (n = 2) survived to postinjury day 7. RESULTS: There were no significant differences in hemodynamics, tissue oxygenation, cerebral blood flow, or physiologic markers between treatment groups and saline controls. Transient differences in IL-1b and IL-6 were noted but did not persist. Neurological Severity Score (NSS) was significantly lower in the TBI + allopurinol group on POD one compared to NS and propranolol groups. P-tau accumulation was decreased in the nonsurvival animals treated with allopurinol and TXA compared to the TBI/NS group. CONCLUSIONS: Allopurinol, propranolol, and TXA, following TBI, do not induce adverse changes in systemic or cerebral hemodynamics during or after a simulated postinjury flight. While transient changes were noted in systemic cytokines and p-tau accumulation, further investigation will be needed to determine any persistent neurological effects of injury, flight, and pharmacologic treatment.

Surprising neutral effect of shorter staple cartridges in laparoscopic sleeve gastrectomy.

BACKGROUND: Consensus agreements regarding laparoscopic sleeve gastrectomy (LSG) advise against using staple loads less than 1.5 mm in closed staple height. However, few data exist to support this recommendation. We hypothesized that using staples with a shorter closed height would actually decrease incidence of intraoperative and postoperative bleeding during LSG, while not increasing the incidence of leak. METHODS: All LSG cases for a single institution from 1/1/2014 to 12/31/2019 were exported for analysis. Two cohorts were established: 1. 'Green/Blue' group was cases in which no white cartridges were used and 2. 'White' group was cases in which any white cartridges were used. Demographic variables, procedural characteristics, hospital length of stay, and postoperative outcomes were compared between groups. RESULTS: The study populations included 1710 patients, 974 in the green/blue group and 736 in the white cartridge group. There were no significant differences in postoperative leak, bleed, stricture, readmission, or death while using white staple loads as compared with the standard combination of blue and green loads. CONCLUSION: Using staples with a shorter closed height during LSG did not impact the postoperative bleeding or leak rate. The impact from selection of shorter staples to achieve more tissue compression may be limited.

Multisite study of Titan SGS stapler in longitudinal gastric resection.

BACKGROUND: Standardization of the laparoscopic sleeve gastrectomy procedure is needed to improve patient outcomes. A single-fire 23 cm stapler was developed to streamline the operation. Comparative testing conducted on excised human tissue has demonstrated the superiority of the novel Titan SGS stapler to two commonly utilized commercial devices in both staple line integrity and burst pressure. We hypothesized that the stapler would be safe and effective in creating longitudinal gastric resections in human patients. METHODS: 61 patients were enrolled to undergo gastric resection with the Titan SGS stapler. Perioperative interventions and post-operative adverse events were recorded. Upper GI study was completed on post-operative day 1, and patients were followed for 6 weeks post-operatively to determine any subacute device-related adverse events. RESULTS: Surgeon feedback for intraoperative device utilization and post-operative gastric pouch shape were positive. Adverse events were found to be mild, limited, and generally well-known effects of bariatric surgery. One episode of post-operative hemorrhage required surgical takeback, with no criminal bleeding vessel identified. CONCLUSION: The Titan SGS stapler is both safe and effective in sleeve gastrectomy pouch creation.