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.

Direct red blood cell effect on thrombosis is dependent on the interaction of tissue factor and calcium with membrane phosphatidylserine.

BACKGROUND: Prior literature has implicated Red Blood Cells (RBCs) in the initiation of thrombosis and suggests that post-transfusion hypercoagulability may occur secondary to the effects of RBCs. Elevated serum tissue factor is a known sequelae of acute trauma. Phosphatidylserine is a pro-thrombotic phospholipid present within the RBC cell membrane. We hypothesized that RBC aggregation is dependent on the interaction between RBC membrane bound (exposed) PS, extracellular calcium, and tissue factor. METHODS: Human whole blood (WB) was separated into components including red blood cells (RBC) and platelet-rich plasma (PRP). WB, PRP, and RBCs underwent impedance aggregometry utilizing arachidonic acid (AA), ADP, collagen, calcium, and tissue factor (TF)-based agonists. RBCs then underwent impedance aggregometry utilizing combined calcium and TF agonists. RBCs were pre-treated with Annexin V, a known PS blocking agent, and underwent impedance aggregometry with combined calcium and TF agonists to determine if the mechanism of calcium/TF-induced RBC aggregability is dependent on PS. RBCs treated with calcium, TF, calcium+TF, and pre-treated with Annexin V followed by calcium+TF were perfused through an in vitro model of pulmonary microcirculatory flow. RESULTS: RBC aggregation was significantly higher than that of WB and PRP when utilizing a TF agonist, an effect unique to TF. The combination of calcium and TF demonstrated significantly higher RBC aggregation than either agonist alone. Pre-treatment with Annexin V resulted in a significantly reduced aggregability of RBC following treatment with TF + calcium. RBCs aged to 42 days did not exhibit significant change in aggregation. Exposure to calcium and TF significantly reduced time to thrombosis of RBCs perfused through a pulmonary microcirculatory model. CONCLUSION: Treatment with both TF and calcium synergistically induces RBC aggregation. PS appears to play an integral role in the TF/calcium-based, age-independent RBC aggregation response. RBCs treated with TF + calcium exhibit more rapid thrombus formation in an in vitro model of pulmonary microcirculatory perfusion.Study Type: human sample-based study. LEVEL OF EVIDENCE: basic science paper.

Contemporary Outcomes of Grade-C Postoperative Pancreatic Fistula in a Nationwide Database.

INTRODUCTION: Grade-C postoperative pancreatic fistulas (POPFs) are dreaded complications following pancreaticoduodenectomy. The aim of this study was to quantify the incidence and risk factors associated with grade C POPF in a national database. METHODS: The National Surgical Quality Improvement Program targeted user files were queried for patients who underwent elective pancreaticoduodenectomy (2014-2020). Outcomes were compared between clinically relevant (CR) grade B POPF and grade C POPF. RESULTS: Twenty-six thousand five hundred fifty-two patients were included, of which 90.1% (n = 23,714) had No CR POPF, 8.7% (n = 2287) suffered grade B POPF, and 1.2% (n = 327) suffered grade C POPF. There was no change in the rate Grade-C fistula overtime (m = 0.06, P = 0.63), while the rate of Grade-B fistula significantly increased (m = +1.40, P < 0.01). Fistula Risk Scores were similar between grade B and C POPFs (high risk: 34.9% versus 31.2%, P = 0.21). Associated morbidity was increased with grade C POPF, including delayed gastric emptying, organ space infections, wound dehiscence, respiratory complications, renal complications, myocardial infarction, and bleeding. On multivariate logistic regression, diabetes mellitus (odds ratio: 1.41 95% confidence interval: 1.06-1.87, P = 0.02) was associated with grade C POPF. CONCLUSIONS: This study represents the largest contemporary series evaluating grade C POPFs. Of those suffering CR POPF, the presence of diabetes mellitus was associated with grade C POPF. While modern management has led to grade C POPF in 1% of cases, they remain associated with alarmingly high morbidity and mortality, requiring further mitigation strategies to improve outcomes.

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.

Effectiveness of Negative Pressure Wound Therapy During Aeromedical Evacuation Following Soft Tissue Injury and Infection.

INTRODUCTION: Negative pressure wound therapy (NPWT) is utilized early after soft tissue injury to promote tissue granulation and wound contraction. Early post-injury transfers via aeromedical evacuation (AE) to definitive care centers may actually induce wound bacterial proliferation. However, the effectiveness of NPWT or instillation NPWT in limiting bacterial proliferation during post-injury AE has not been studied. We hypothesized that instillation NPWT during simulated AE would decrease bacterial colonization within simple and complex soft tissue wounds. METHODS: The porcine models were anesthetized before any experiments. For the simple tissue wound model, two 4-cm dorsal wounds were created in 34.9 ± 0.6 kg pigs and were inoculated with Acinetobacter baumannii (AB) or Staphylococcus aureus 24 hours before a 4-hour simulated AE or ground control. During AE, animals were randomized to one of the five groups: wet-to-dry (WTD) dressing, NPWT, instillation NPWT with normal saline (NS-NPWT), instillation NPWT with Normosol-R® (NM-NPWT), and RX-4-NPWT with the RX-4 system. For the complex musculoskeletal wound, hind-limb wounds in the skin, subcutaneous tissue, peroneus tertius muscle, and tibia were created and inoculated with AB 24 hours before simulated AE with WTD or RX-4-NPWT dressings. Blood samples were collected at baseline, pre-flight, and 72 hours post-flight for inflammatory cytokines interleukin (IL)-1ß, IL-6, IL-8 and tumor necrosis factor alpha. Wound biopsies were obtained at 24 hours and 72 hours post-flight, and the bacteria were quantified. Vital signs were measured continuously during simulated AE and at each wound reassessment. RESULTS: No significant differences in hemodynamics or serum cytokines were noted between ground or simulated flight groups or over time in either wound model. Simulated AE alone did not affect bacterial proliferation compared to ground controls. The simple tissue wound arm demonstrated a significant decrease in Staphylococcus aureus and AB colony-forming units at 72 hours after simulated AE using RX-4-NPWT. NS-NPWT during AE more effectively prevented bacterial proliferation than the WTD dressing. There was no difference in colony-forming units among the various treatment groups at the ground level. CONCLUSION: The hypoxic, hypobaric environment of AE did not independently affect the bacterial growth after simple tissue wound or complex musculoskeletal wound. RX-4-NPWT provided the most effective bacterial reduction following simulated AE, followed by NS-NPWT. Future research will be necessary to determine ideal instillation fluids, negative pressure settings, and dressing change frequency before and during AE.

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.

Blood component resuscitative strategies to mitigate endotheliopathy in a murine hemorrhagic shock model.

BACKGROUND: Resuscitation with plasma components has been shown to improve endotheliopathy induced by hemorrhagic shock, but the optimal resuscitation strategy to preserve the endothelial glycocalyx has yet to be defined. The aim of this study was to determine if resuscitation with lactated Ringer's (LR), whole blood (WB), packed red blood cells (RBCs), platelet-rich plasma (PRP), platelet poor plasma, balanced RBC:PRP (1:1), or day 14 (d14) RBC would best minimize endothelial damage following shock. METHODS: Male C57BL/6 mice were hemorrhaged to a goal mean arterial pressure of 25 mm Hg for 1 hour. Unshocked sham mice served as controls. Mice were then resuscitated with equal volumes of LR, WB, RBC, PRP, platelet poor plasma, 1:1, or d14 RBC and then sacrificed at 1, 4, or 24 hours (n = 5). Serum was analyzed for syndecan-1, ubiquitin C-terminal hydrolase L1, and cytokine concentrations. Lungs underwent syndecan-1 immunostaining, and lung injury scores were calculated after hematoxylin and eosin. Proteolytic cleavage of the endothelial glycocalyx was assessed by serum matrix metalloprotease 9 levels. RESULTS: Serum syndecan-1 and ubiquitin C-terminal hydrolase L1 levels were significantly increased following resuscitation with d14 RBC compared with other groups. Early elevation in lung syndecan-1 staining was noted in LR-treated mice, while d14 mice showed decreased staining compared with sham mice following shock. Lung injury scores were significantly elevated 4 hours after resuscitation with LR and d14 RBC compared with WB. Serum matrix metalloprotease 9 levels were significantly increased at 1 and 4 hours in d14 mice compared with sham mice. Systemic inflammation was increased in animals receiving LR, 1:1, or d14 RBC. CONCLUSION: Resuscitation with WB following hemorrhagic shock reduces endothelial syndecan-1 shedding and mitigates lung injury. Aged RBC and LR fail to attenuate endothelial injury following hemorrhagic shock. Further research will be necessary to determine the effect of each of these resuscitative fluids in a hemorrhagic shock model with the addition of tissue injury.

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.

Platelet dysfunction persists after trauma despite balanced blood product resuscitation.

BACKGROUND: Platelet activation and aggregation are critical to the initiation of hemostasis after trauma with hemorrhage. Platelet dysfunction is a well-recognized phenomenon contributing to trauma-induced coagulopathy. The goal of this study was to evaluate the timing and severity of platelet dysfunction in massively transfused, traumatically injured patients during the first 72 hours after injury and its association with 30-day survival. METHODS: A retrospective secondary cohort study of platelet count and function was performed using samples from the Pragmatic Randomized Optimal Platelet and Plasma Ratios trial. Platelet characteristics were measured at 8 timepoints during the first 72 hours of hospitalization and compared between 30-day survivors and nonsurvivors. Platelet counts were assessed via flow cytometry. Platelet function was analyzed with the use of serial thrombelastography and impedance aggregometry with agonists arachidonic acid, adenosine diphosphate, collagen, thrombin receptor activating peptide, and ristocetin. RESULTS: In total, 680 patients were included for analysis. Platelet counts were significantly lower from baseline to 72 hours after hospital admission with further 1.3 to 2-fold reductions noted in nonsurvivors compared to survivor patients. Platelet aggregation via adenosine diphosphate, arachidonic acid, collagen, thrombin receptor activating peptide, and ristocetin was significantly lower in nonsurvivors at all time points. The nadir of platelet aggregation was 2 to 6 hours after admission with significant improvements in viscoelastic maximum clot formation and agonist-induced aggregation by 12 hours without concomitant improvement in platelet count. CONCLUSION: Platelet aggregability recovers 12 hours after injury independent of worsening thrombocytopenia. Failure of platelet function to recover portends a poor prognosis.

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.

The Impact of Enhanced Recovery After Surgery on Persistent Opioid Use Following Pulmonary Resection.

BACKGROUND: Enhanced recovery after surgery (ERAS) has been associated with improved perioperative outcomes after thoracic surgery; however, the impact on long-term opioid use remains unknown. The aim of our study was to evaluate the effects of ERAS on long-term opioid use. METHODS: Patients who underwent pulmonary resection were identified from a prospectively maintained database and linked to the regional prescription drug monitoring program. Outcomes were compared between pre-ERAS (February 2016 to November 2018) and ERAS (December 2018 to June 2020) cohorts. Our ERAS protocol included regional anesthetic, multimodal pain control, and protocolized rehabilitation. RESULTS: We analyzed 240 pulmonary resections, 64.6% (n = 155) in the pre-ERAS era and 35.4% (n = 85) in the ERAS era. Baseline characteristics were similar; however, more patients in the ERAS cohort underwent minimally invasive surgery (67.7% vs 87.9%; P = .002). Median length of stay was reduced (5 days vs 4 days; P = .03) upon implementation of ERAS, with no change in perioperative complications or readmission rate. On multivariate analysis, ERAS was associated with decreased total inpatient morphine milligram equivalent and discharge morphine milligram equivalent. However, both long-term opioid use up to 1 year postoperatively and new persistent opioid use remained similar despite implementation of ERAS. On multivariate analysis, implementation of ERAS was not associated with a reduction in opioid use 14 to 90 days postoperatively or persistent opioid use 90 to 180 days postoperatively. CONCLUSIONS: Despite short-term opioid reduction, long-term opioid use persisted after implementation of ERAS. Additional strategies to monitor for and avoid opioid dependence are urgently needed to prevent chronic opioid use after pulmonary resection.

MULTIMODAL TREATMENT APPROACHES TO COMBINED TRAUMATIC BRAIN INJURY AND HEMORRHAGIC SHOCK ALTER POSTINJURY INFLAMMATORY RESPONSE.

ABSTRACT: 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-1ß 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.

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.

How Informed Is Your Informed Consent: Evaluating Differences Between Resident and Attending Obtained Consents for Cholecystectomy.

OBJECTIVE: There is considerable variability in surgeons' approach to write and obtain informed consent for surgery, particularly among resident trainees. We analyzed differences in procedures and complications described in documented surgical consents for cholecystectomy between residents and attendings. We hypothesized that attending consents would describe more comprehensive procedures and complications than those done by residents. DESIGN: This is a retrospective analysis of 334 patients who underwent cholecystectomy. Charts were queried for demographics, surgical approach, whether the consent was completed electronically, and which provider completed the consent. Specifically, consents were evaluated for inclusion of possible conversion to open procedure, intraoperative cholangiogram, bile duct injury, injury to nearby structures, reoperation, bile leak, as well as if the consent matched the actual procedure performed. SETTING: This study was conducted at an accredited general surgery training program at an academic tertiary care center in the Midwest. PARTICIPANTS: This was a review of 334 patients who underwent cholecystectomy over a 1 year period. RESULTS: Of all documented consents analyzed, 153 (47%) specifically included possible intraoperative cholangiogram, 156 (47%) included bile duct injury, 76 (23%) included injury to nearby structures, 22 (7%) included reoperation, and 62 (19%) included bile leak. In comparing residents and attendings, residents were more likely to consent for bile duct injury (p = 0.002), possible intraoperative cholangiogram (p = 0.0007), injury to nearby structures (p < 0.0001), reoperation (p < 0.0001), and bile leak (p < 0.0001). CONCLUSIONS: Significant variation exists between documentation between resident and attending cholecystectomy consents, with residents including more complications than attendings on their consent forms. These data suggest that experience alone does not predict content of written consents, particularly for common ambulatory procedures. Education regarding the purpose of informed consent and what should be included in one may lead to a reduction in variability between providers.

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.

Low Volume Blood Product Transfusion Patterns And Ratios After Injury.

BACKGROUND: The benefit of a balanced resuscitation in low volume transfusions remains unclear This study is aimed at characterizing blood product ratios in this cohort. METHODS: A retrospective analysis (2017-2019) of the ACS TQIP was performed to identify adult trauma patients who received ≥1 unit of packed red blood cells (pRBCs) 4 and 24 h after admission. Blood products received were used to calculate plasma and platelet ratios. RESULTS: Plasma and platelet ratios were closer to the target 1:1 ratio for ≤4 units pRBCs. Plasma and platelet ratios increased for those receiving ≤10 units pRBCs, demonstrating increasingly unbalanced resuscitation. Transfusion ratios were unbalanced for those receiving ≥5 units pRBC. CONCLUSION: Transfusion ratios were closer to the desired transfusion ratio for low volume blood product resuscitation. In those receiving ≥5 units pRBC, plasma and platelet ratios were not balanced. The optimal transfusion ratio in low volume trauma resuscitation is unknown.

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.

Defining Endotheliopathy in Murine Polytrauma Models.

INTRODUCTION: "Endotheliopathy of trauma" is recognized as endothelial dysfunction following traumatic injury leading to poor patient outcomes. Acute post-traumatic disruptions in endothelial cell function have been associated with profound physiologic, hemodynamic, and coagulation derangements. The goal of this study was to define the generation and extent of endotheliopathy in murine polytrauma models by evaluating the post-traumatic release of serum biomarkers of ongoing cellular injury. METHODS: Mice were randomized to undergo moderately severe concussive TBI by weight drop, 60-min hemorrhagic shock to MAP 25 mmHg with subsequent resuscitation with Lactated Ringer's, submandibular bleed (SMB), and/or midline laparotomy with rectus muscle crush. Mice were sacrificed at 1, 4, or 24 h for serum biomarker evaluation. RESULTS: Serum biomarkers revealed differential timing of elevation and injury-dependent release.At 24 h, soluble thrombomodulin was significantly elevated in combined TBI + shock + lap crush compared to untouched, and shock alone. Syndecan-1 levels were significantly elevated after shock 1 to 24 h compared to untouched cohorts with a significant elevation in TBI + shock + lap crush 24 h after injury compared to shock alone. UCHL-1 was significantly elevated in shock mice at 1 to 24 h post-injury compared to untouched mice. UCHL-1 was also significantly elevated in the TBI + shock cohort 24 h after injury compared to shock alone. Hyaluronic acid release at 4 h was significantly elevated in shock alone compared to the untouched cohort with further elevations in TBI + shock + lap crush and TBI + shock compared to shock alone at 24 h. Hyaluronic acid was also increased in lap crush and laparotomy only cohort compared to untouched mice 24 h after injury. CONCLUSIONS: A murine model of polytrauma including TBI, hemorrhagic shock, and laparotomy abdominal crush is a reliable method for evaluation of endotheliopathy secondary to trauma as indicated by differential changes in serum biomarkers.

Tracheostomy decreases continuous analgesia and sedation requirements.

BACKGROUND: The goals of sedation in the critically ill surgical patient are to minimize pain, anxiety, and agitation without hindering cardiopulmonary function. One potential benefit of tracheostomy during endotracheal intubation is the reduction of sedation and analgesia; however, there are little data to support this supposition. We hypothesized that patients undergoing tracheostomy would have a rapid reduction in sedation and analgesia following tracheostomy. METHODS: A retrospective review of tracheostomies performed at a single Level I trauma center from January 2013 to June 2018 was completed. An evaluation of Glasgow Coma Scale, Richmond Agitation-Sedation Scale, and Confusion Assessment Method for the intensive care unit 72 hours pretracheostomy to 72 hours posttracheostomy was performed. The total daily dose of sedation, anxiolytic, and analgesic medications administered were recorded. Mixed-effects models were used to evaluate longitudinal drug does over time (hours). RESULTS: Four hundred sixty-eight patients included for analysis with a mean age of 58.8 ± 18.3 years. There was a significant decrease in propofol and fentanyl utilization from 24 hours pretracheostomy to 24 hours posttracheostomy in both dose and number of patients receiving these continuous intravenous medications. Similarly, total morphine milligram equivalents (MME) use and continuous midazolam significantly decreased from 24 hours pretracheostomy to 24 hours posttracheostomy. By contrast, intermittent enteral quetiapine and methadone administration increased after tracheostomy. Importantly, Richmond Agitation-Sedation Scale, Glasgow Coma Scale, and Confusion Assessment Method scoring were also significantly improved as early as 24 hours posttracheostomy. Total MME use was significantly elevated in patients younger than 65 years and in male patients pretracheostomy compared with female patients. Patients admitted to the medical intensive care unit had significantly higher MME use compared with those in the surgical intensive care unit pretracheostomy. CONCLUSION: Tracheostomy allows for a rapid and significant reduction in intravenous sedation and analgesia medication utilization. Posttracheostomy sedation can transition to intermittent enteral medications, potentially contributing to the observed improvements in postoperative mental status and agitation. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.