Succinate Activation of SUCNR1 Predisposes Severely Injured Patients to Neutrophil-mediated ARDS.

OBJECTIVES: Identify the metabolites that are increased in the plasma of severely injured patients that developed ARDS versus severely injured patients that did not, and assay if these increased metabolites prime pulmonary sequestration of neutrophils (PMNs) and induce pulmonary sequestration in an animal model of ARDS. We hypothesize that metabolic derangement due to advanced shock in critically injured patients leads to the PMNs, which serves as the first event in the ARDS. Summary of Background Data: Intracellular metabolites accumulate in the plasma of severely injured patients. METHODS: Untargeted metabolomics profiling of 67 critically injured patients was completed to establish a metabolic signature associated with ARDS development. Metabolites that significantly increased were assayed for PMN priming activity in vitro. The metabolites that primed PMNs were tested in a 2-event animal model of ARDS to identify a molecular link between circulating metabolites and clinical risk for ARDS. RESULTS: After controlling for confounders, 4 metabolites significantly increased: creatine, dehydroascorbate, fumarate, and succinate in trauma patients who developed ARDS ( P < 0.05). Succinate alone primed the PMN oxidase in vitro at physiologically relevant levels. Intravenous succinate-induced PMN sequestration in the lung, a first event, and followed by intravenous lipopolysaccharide, a second event, resulted in ARDS in vivo requiring PMNs. SUCNR1 inhibition abrogated PMN priming, PMN sequestration, and ARDS. Conclusion: Significant increases in plasma succinate post-injury may serve as the first event in ARDS. Targeted inhibition of the SUCNR1 may decrease ARDS development from other disease states to prevent ARDS globally.

Rotational thromboelastometry thresholds for patients at risk for massive transfusion.

BACKGROUND: Goal-directed hemostatic resuscitation based on thrombelastography has a survival benefit compared to conventional coagulation assays. While thrombelastography transfusion thresholds for patients at risk for massive transfusion (MT) have been defined, similar cutoffs do not exist for the other commonly used viscoelastic assay, rotational thromboelastometry (ROTEM). The purpose of this study was to develop ROTEM blood product thresholds in patients at risk for MT. METHODS: ROTEM was assessed in trauma activation patients admitted from 2010 to 2016 (n = 222). Receiver operating characteristic curve analyses were performed to test the predictive performance of ROTEM measurements in patients requiring MT. The Youden Index defined optimal thresholds for ROTEM-based resuscitation. RESULTS: Patients who required MT (n = 37, 17%) were more severely injured. EXTEM clotting time (CT) was longer in patients with MT compared to non-MT (87 versus 64 s, P < 0.0001). EXTEM angle was shallower in MT patients compared to non-MT (54° versus 69°, P < 0.0001). Clot amplitude after 10 min (CA10) was less in MT compared to non-MT patients (30.5 versus 50 mm, P < 0.0001). Clot lysis index 60 min (CLI60) was lower in patients who had MT than non-MT (47 versus 94%, P = 0.0006). EXTEM CT yielded an area under the receiver operating characteristic curve (AUROC) = 0.7116 and a cut point of >78.5 s. EXTEM angle had an AUROC = 0.865 and a cut point of <64.5°. EXTEM CA10 had an AUROC = 0.858, with a cut point of <40.5 mm. CLI60 had an AUROC = 0.6788 with a cut point at <74%. CONCLUSIONS: We have identified ROTEM thresholds for transfusion of blood components in severely injured patients requiring an MT. Based on our analysis, we propose plasma transfusion for EXTEM CT > 78.5 s, fibrinogen for angle <64.5°, platelet transfusion for CA10 < 40.5 mm, and antifibrinolytics for CLI60 < 74%.

Hemoglobin-based oxygen carriers promote systemic hyperfibrinolysis that is both dependent and independent of plasmin.

BACKGROUND: Hyperfibrinolysis plays an integral role in the genesis of trauma-induced coagulopathy. Recent data demonstrate that red blood cell lysis promotes fibrinolysis; however, the mechanism is unclear. Hemoglobin-based oxygen carriers (HBOCs) have been developed for resuscitation and have been associated with coagulopathy. We hypothesize that replacement of whole blood (WB) using an HBOC results in a coagulopathy because of the presence of free hemoglobin. MATERIALS AND METHODS: WB was sampled from healthy donors (n = 6). The clotting profile of each citrated sample was evaluated using native thromboelastography. Serial titrations were performed using both HBOC (PolyHeme) and normal saline (NS; 5%, 25%, and 50%) and evaluated both with and without a 75-ng/mL tissue plasminogen activator (tPA) challenge. Tranexamic acid (TXA) was added to inhibit plasmin-dependent fibrinolysis. Fibrinolysis was measured and recorded as lysis at 30 min (LY30), the percentage of clot LY30 after maximal clot strength. Dilution of WB with NS or HBOC was correlated using LY30 via Spearman rho coefficients. Groups were also compared using a Friedman test and post hoc analysis with a Bonferroni adjustment. RESULTS: tPA-provoked fibrinolysis was enhanced by both HBOC (median LY30 at 5%, 25%, and 50% titrations: 11%, 21%, and 44%, respectively; Spearman = 0.94; P < 0.001) and NS (11%, 28%, and 58%, respectively; Spearman = 0.790; P < 0.001). However, HBOC also enhanced fibrinolysis without the addition of tPA (1%, 4%, 5%; Spearman = 0.735; P = 0.001) and NS did not (1%, 2%, 1%; r = 0.300; P = 0.186. Moreover, addition of TXA did not alter or inhibit this fibrinolysis (WB versus 50% HBOC: 1.8% versus 5.7%, P = 0.04). There was no significant difference in fibrinolysis of HBOC with or without TXA (50% HBOC versus 50% HBOC + TXA: 5.6% versus 5.7%, P = 0.92). In addition, the increased fibrinolysis seen with NS was reversed when TXA was present (WB versus 50% NS: 1.8% versus 1.7%, P = 1.0). CONCLUSIONS: HBOCs enhance fibrinolysis both with and without addition of tPA; moreover, this mechanism is independent of plasmin as the phenomenon persists in the presence of TXA. Our findings indicate the hemoglobin molecule or its components stimulate fibrinolysis by both tPA-dependent and innate mechanisms.

Trauma/hemorrhagic shock instigates aberrant metabolic flux through glycolytic pathways, as revealed by preliminary (13)C-glucose labeling metabolomics.

BACKGROUND: Metabolic derangement is a key hallmark of major traumatic injury. The recent introduction of mass spectrometry-based metabolomics technologies in the field of trauma shed new light on metabolic aberrations in plasma that are triggered by trauma and hemorrhagic shock. Alteration in metabolites associated with catabolism, acidosis and hyperglycemia have been identified. However, the mechanisms underlying fluxes driving such metabolic adaptations remain elusive. METHODS: A bolus of U-(13)C-glucose was injected in Sprague-Dawley rats at different time points. Plasma extracts were analyzed via ultra-high performance liquid chromatography-mass spectrometry to detect quantitative fluctuations in metabolite levels as well as to trace the distribution of heavy labeled carbon isotopologues. RESULTS: Rats experiencing trauma did not show major plasma metabolic aberrations. However, trauma/hemorrhagic shock triggered severe metabolic derangement, resulting in increased glucose levels, lactate and carboxylic acid accumulation. Isotopologue distributions in late Krebs cycle metabolites (especially succinate) suggested a blockade at complex I and II of the electron transport chain, likely due to mitochondrial uncoupling. Urate increased after trauma and hemorrhage. Increased levels of unlabeled mannitol and citramalate, metabolites of potential bacterial origin, were also observed in trauma/hemorrhagic shock rats, but not trauma alone or controls. CONCLUSIONS: These preliminary results are consistent with observations we have recently obtained in humans, and expand upon our early results on rodent models of trauma and hemorrhagic shock by providing the kinetics of glucose fluxes after trauma and hemorrhage. Despite the preliminary nature of this study, owing to the limited number of biological replicates, results highlight a role for shock, rather than trauma alone, in eliciting systemic metabolic aberrations. This study provides the foundation for tracing experiments in rat models of trauma. The goal is to improve our understanding of substrate specific metabolic derangements in trauma/hemorrhagic shock, so as to design resuscitative strategies tailored toward metabolic alterations and the severity of trauma.

A modern, multicenter evaluation of hepatic angioembolization - Complications and readmissions persist.

BACKGROUND: Indications for angioembolization (AE) following liver injury are not clearly defined. This study evaluated the outcomes and complications of hepatic AE. We hypothesize hepatic angioembolization is a useful adjunct to non-operative management of liver injury but with significant morbidity. METHODS: Subjects were identified utilizing trauma registries from centers in a regional trauma network from 2010 to 2017 with an Abbreviated Injury Scale (AIS) coded hepatic injury and an ICD9/10 for hepatic angiography (HA). RESULTS: 1319 patients with liver injuries were identified, with 30 (2.3%) patients undergoing HA: median ISS was 26, and median liver AIS was 4. Twenty-three subjects required AE. 81% had extravasation on CT from a liver injury. 63% underwent HA as initial intervention. 43% of AE subjects had liver-related complications with 35% 30-day readmission but with zero 30-day mortality. CONCLUSIONS: While there were zero reported deaths, a high rate of morbidity and readmission was found. This may be due to the angioembolization or the liver injury itself.

Preventable death and interpersonal violence in the United States: Who can be saved?

BACKGROUND: Public health initiatives to reduce mortality from penetrating trauma have largely developed from patterns of injury observed in military casualties, with a focus on hemorrhage control and use of tourniquets. Recent efforts show that injury patterns differ between civilian mass casualty events and combat settings, and no studies characterize wounding patterns in all types of civilian homicide. We hypothesize that many homicide deaths are due to nonsurvivable injuries, and that an effective strategy to reduce mortality must focus on both primary prevention as well as improvement in trauma prehospital care. METHODS: We analyzed homicides from the National Violent Death Reporting System from 2012 to 2015. We excluded deaths due to poisoning, intentional neglect, or unknown weapon. Deaths were classified as "dead on scene" (DOS), "dead on arrival" (DOA), or "dead at or after hospital" (DAH) if the patient was admitted to a hospital. Injury patterns for penetrating weapons (firearms and sharp instruments) were further categorized. RESULTS: We included 18,051 homicides, the vast majority of which were due to firearms (n = 12,901 or 71.5%) or sharp instruments (n = 2,265 or 12.5%). The most common injury patterns included wounds to the chest or head, with isolated extremity injuries representing a minority of both firearms deaths (n = 397 of 12,901, 3.1%) and deaths from sharp instruments (n = 50 of 2,265, 2.2%). Furthermore, over half of all deaths occurred prehospital, with only 13.3% of victims admitted prior to death. CONCLUSION: The vast majority of deaths from interpersonal violence are due to firearm injuries. Few deaths appear to be related to extremity hemorrhage alone, and over half of all fatally injured died at the scene. Strategies to decrease mortality from interpersonal violence must go beyond treating injuries that have already occurred, and must address violence prevention directly. LEVEL OF EVIDENCE: Epidemiological study, level IV.

The Extremity/Mechanism/Shock Index/GCS (EMS-G) score: A novel pre-hospital scoring system for early and appropriate MTP activation.

BACKGROUND: Numerous in-hospital scoring systems to activate massive transfusion protocols (MTP) have been proposed; however, to date, pre-hospital scoring systems have not been robustly validated. Many trauma centers do not have blood or pre-thawed plasma available in the trauma bay, leading to delays in balanced transfusion. This study aims to assess pre-hospital injury and physiologic parameters to develop a pre-hospital scoring system predictive of need for massive transfusion (MT) prior to patient arrival. METHODS: A retrospective review of all adult full and partial trauma team activations from July 2014-July 2018 from an urban level 2 trauma center was performed utilizing our trauma registry. Stepwise logistic regression analysis was performed to develop a new scoring system, with point totals assigned proportional to the odds ratios of requiring MT for each variable. Internal validation of the EMS-G score was performed using a subset of the data which was not utilized for development of the scoring system, and sensitivity and specificity were compared to previously validated in-hospital scoring systems applied in the pre-hospital setting. RESULTS: 763 patients were included with 94 patients (12.3%) receiving early MT, defined as 4 units pRBC in 4 h or ED death. In-hospital models for predicting MT such as Assessment of Blood Consumption (ABC) or Shock Index (SI) have sensitivities and specificities of 46/85% and 94/79% respectively for early MTP utilization based on pre-hospital data. Pre-hospital variables found to be predictive of MT were used to develop the EMS-G (Extremity, Mechanism, Shock Index, GCS) score. This system assigns obvious extremity injury-1-point, penetrating mechanism -2 points, shock index ≥0.9-2 points, GCS ≤8-3 points. A score of 3 or greater was chosen to maximize sensitivity and specificity for pre-hospital MT activation. EMS-G score based on pre-hospital report is 89% sensitive, 84% specific, with a PPV of 44% and NPV of 98% for early MT. Using this system, 25% of full and partial trauma team activations met criteria for pre-hospital MTP activation. CONCLUSION: The EMS-G Score has increased sensitivity and specificity compared to the ABC Score in the pre-hospital setting and appears more appropriate than shock index alone at predicting massive transfusion. This scoring system allows trauma centers to activate MTP prior to patient arrival to ensure early and appropriate blood product administration without blood product wastage.

Obstruction reduction: Use of water-soluble contrast challenge to differentiate between partial and complete small bowel obstruction.

Differentiating SBO that will resolve conservatively from those requiring surgery remains challenging. Water-soluble contrast administration may be diagnostic and therapeutic. Our study evaluated use of a WSC challenge protocol. We hypothesize that protocol use discriminates between surgical SBO and obstructions which can be managed non-operatively. Demographics, prior surgeries, time to operation, complications, and LOS were analyzed. 108 patients were admitted with SBO. 13% underwent immediate laparotomy with concern for bowel compromise; these had a median LOS of 8.5 days. 91 received WSC protocol. Of these, 77% had contrast passage to the colon. Of the 48 in whom contrast passed between 0 and 12 h, LOS was 2 days. Of the 22 patients in whom contrast passed between 12 and 24 h, LOS was 4.5 days. 21 had failure of contrast passage; 18 of those underwent surgery after 24 h as a result. Of the 21 patients who failed WSC challenge, median LOS was 8 days. WSC protocol implementation facilitates early recognition of partial from complete obstruction and may decrease LOS. Our findings warrant further evaluation with a multicenter trial.

Trauma Resuscitation Consideration: Sex Matters.

BACKGROUND: Sex dimorphisms in coagulation have been recognized, but whole blood assessment of these dimorphisms and their relationship to outcomes in trauma have not been investigated. This study characterizes the viscoelastic hemostatic profile of severely injured patients by sex, and examines how sex-specific coagulation differences affect clinical outcomes, specifically, massive transfusion (MT) and death. We hypothesized that severely injured females are more hypercoagulable and therefore, have lower rates of MT and mortality. STUDY DESIGN: Hemostatic profiles and clinical outcomes from all trauma activation patients from 2 level I trauma centers were examined, with sex as an experimental variable. As part of a prospective study, whole blood was collected and thrombelastography (TEG) was performed. Coagulation profiles were compared between sexes, and association with MT and mortality were examined. Poisson regression with robust standard errors was performed. RESULTS: Overall, 464 patients (23% female) were included. By TEG, females had a more hypercoagulable profile, with a higher angle (clot propagation) and maximum amplitude (MA, clot strength). Females were less likely to present with hyperfibrinolysis or prolonged activating clotting time than males. In the setting of depressed clot strength (abnormal MA), female sex conferred a survival benefit, and hyperfibrinolysis was associated with higher case-fatality rate in males. CONCLUSIONS: Severely injured females have a more hypercoagulable profile than males. This hypercoagulable status conferred a protective effect against mortality in the setting of diminished clot strength. The mechanism behind these dimorphisms needs to be elucidated and may have treatment implications for sex-specific trauma resuscitation.

Effect of Pre-Hospital Use of the Assessment of Blood Consumption Score and Pre-Thawed Fresh Frozen Plasma on Resuscitation and Trauma Mortality.

BACKGROUND: Early blood product resuscitation reduces trauma patient mortality from hemorrhage. This mortality benefit depends on a system that can rapidly identify actively bleeding patients, initiate massive transfusion protocol (MTP), and mobilize resources to the bedside. We hypothesized that process improvement efforts that identify patients early and mobilize appropriate blood products to the bedside for immediate use would improve mortality. STUDY DESIGN: Pre-implementation, MTP activation was at the discretion of the trauma surgeon, and only PRBCs were immediately available. In June 2016, the Assessment of Blood Consumption (ABC) score was incorporated in our pre-hospital triage process, and a process for thawed plasma to be available was developed. We performed a retrospective review of patients who were hypotensive on arrival or had MTP activated. We compared mortality and MTP component ratios 15 months pre- vs 15 months post-implementation. RESULTS: Activations of MTP increased 6-fold, while the specificity of the process remained the same. In patients receiving MTP, appropriate blood product transfusion ratios increased 44%. Overall and penetrating trauma mortality improved by 23% and 41%, respectively. When divided by the Injury Severity Score (ISS), penetrating trauma mortality decreased by 65% for the ISS subgroup 15 to 24 and by 38% for ISS subgroup ≥ 25. Length of stay, ICU length of stay, and readmission rates were not significantly different. CONCLUSIONS: Delivery of balanced blood product resuscitation is essential to confer mortality benefits. Process improvement directed at early recognition of the hemorrhagic patient, immediate product availability, and product delivery to the bedside for transfusion allows for mortality reduction without increased resource use.

Female platelets have distinct functional activity compared with male platelets: Implications in transfusion practice and treatment of trauma-induced coagulopathy.

BACKGROUND: Females are hypercoagulable and have survival benefit in trauma-induced coagulopathy (TIC). The mechanism for this sex-specific hypercoagulability is unknown. Platelets and platelet function are central in providing hemostatic potential and are the largest contributor to clot strength. Ligands (adenosine diphosphate [ADP] and platelet-activating factor [PAF]) bind distinct platelet receptors to potentiate activation and aggregation. We hypothesize that female platelets have a differential response to ADP and PAF, resulting in greater aggregation and activation compared to males, and that estradiol pretreatment of male or female platelets enhances this activity. METHODS: Platelets were collected from healthy volunteers: premenopausal/postmenopausal females (≤54 years, >54 years) and similarly aged males. Platelet aggregometry and flow cytometry (fibrinogen binding capacity) were examined. After treatment with ADP or PAF, platelet aggregation was assessed with Chronolog and activation assessed by CD41 receptor surface expression using flow cytometry. Aggregation and activation were again assessed after platelet pretreatment with estradiol. RESULTS: Healthy volunteers included 12 premenopausal and 13 postmenopausal females and 18 similarly aged males. Female platelets (combined premenopausal and postmenopausal) had increased aggregation with ADP stimulation, as compared to male platelets. Male and female platelets had differential fibrinogen receptor expression, with female platelets (combined premenopausal and postmenopausal) demonstrating robust activation with ADP versus male platelets with PAF. In the presence of estradiol incubation, male platelets' activation with PAF approximated that of females (combined premenopausal and postmenopausal) and activation with PAF was enhanced in both male and female platelets. CONCLUSION: Male and female platelets have differential response to stimuli, suggesting sex-dependent signaling and cellular activation. Female platelets have both increased aggregation and activation potential, and estradiol pretreatment feminizes male platelets to approximate female platelet activation with PAF. These findings offer potential explanation for sex-based differences in hemostatic potential in TIC and question whether donor sex of transfused platelets should be considered in resuscitation. Estradiol may also serve as a novel therapeutic adjunct in TIC.

Evaluation of a water-soluble contrast protocol for small bowel obstruction: A southwestern surgical congress multicenter trial.

Differentiation between SBO that will resolve with supportive measures and those requiring surgery remains challenging. WSC administration may be diagnostic and therapeutic. The purpose of this study was to evaluate use of a SBO protocol using WSC challenge. A protocol was implemented at five tertiary care centers. Demographics, prior surgical history, time to operation, complications, and LOS were analyzed. 283 patients were admitted with SBO; 13% underwent immediate laparotomy; these patients had a median LOS of 7.5 days. The remaining 245 were candidates for WSC challenge. Of those, 80% received contrast. 139 (71%) had contrast passage to the colon. LOS in these patients was 4 days. Sixty-five patients (29%) failed contrast passage within 24 h and underwent surgery. LOS was 9 days. 8% of patients in whom contrast passage was observed at 24 h nevertheless subsequently underwent surgery. 4% of patients who failed WSC challenge did not proceed to surgery. Our multicenter trial revealed that implementation of a WSC protocol may facilitate early recognition of partial from complete obstruction.

Selective organ ischaemia/reperfusion identifies liver as the key driver of the post-injury plasma metabolome derangements.

BACKGROUND: Understanding the molecular mechanisms in perturbation of the metabolome following ischaemia and reperfusion is critical in developing novel therapeutic strategies to prevent the sequelae of post-injury shock. While the metabolic substrates fueling these alterations have been defined, the relative contribution of specific organs to the systemic metabolic reprogramming secondary to ischaemic or haemorrhagic hypoxia remains unclear. MATERIALS AND METHODS: A porcine model of selected organ ischaemia was employed to investigate the relative contribution of liver, kidney, spleen and small bowel ischaemia/reperfusion to the plasma metabolic phenotype, as gleaned through ultra-high performance liquid chromatography-mass spectrometry-based metabolomics. RESULTS: Liver ischaemia/reperfusion promotes glycaemia, with increases in circulating carboxylic acid anions and purine oxidation metabolites, suggesting that this organ is the dominant contributor to the accumulation of these metabolites in response to ischaemic hypoxia. Succinate, in particular, accumulates selectively in response to the hepatic ischemia, with levels 6.5 times spleen, 8.2 times small bowel, and 6 times renal levels. Similar trends, but lower fold-change increase in comparison to baseline values, were observed upon ischaemia/reperfusion of kidney, spleen and small bowel. DISCUSSION: These observations suggest that the liver may play a critical role in mediating the accumulation of the same metabolites in response to haemorrhagic hypoxia, especially with respect to succinate, a metabolite that has been increasingly implicated in the coagulopathy and pro-inflammatory sequelae of ischaemic and haemorrhagic shock.

The why and how our trauma patients die: A prospective Multicenter Western Trauma Association study.

BACKGROUND: Historically, hemorrhage has been attributed as the leading cause (40%) of early death. However, a rigorous, real-time classification of the cause of death (COD) has not been performed. This study sought to prospectively adjudicate and classify COD to determine the epidemiology of trauma mortality. METHODS: Eighteen trauma centers prospectively enrolled all adult trauma patients at the time of death during December 2015 to August 2017. Immediately following death, attending providers adjudicated the primary and contributing secondary COD using standardized definitions. Data were confirmed by autopsies, if performed. RESULTS: One thousand five hundred thirty-six patients were enrolled with a median age of 55 years (interquartile range, 32-75 years), 74.5% were male. Penetrating mechanism (n = 412) patients were younger (32 vs. 64, p < 0.0001) and more likely to be male (86.7% vs. 69.9%, p < 0.0001). Falls were the most common mechanism of injury (26.6%), with gunshot wounds second (24.3%). The most common overall primary COD was traumatic brain injury (TBI) (45%), followed by exsanguination (23%). Traumatic brain injury was nonsurvivable in 82.2% of cases. Blunt patients were more likely to have TBI (47.8% vs. 37.4%, p < 0.0001) and penetrating patients exsanguination (51.7% vs. 12.5%, p < 0.0001) as the primary COD. Exsanguination was the predominant prehospital (44.7%) and early COD (39.1%) with TBI as the most common later. Penetrating mechanism patients died earlier with 80.1% on day 0 (vs. 38.5%, p < 0.0001). Most deaths were deemed disease-related (69.3%), rather than by limitation of further aggressive care (30.7%). Hemorrhage was a contributing cause to 38.8% of deaths that occurred due to withdrawal of care. CONCLUSION: Exsanguination remains the predominant early primary COD with TBI accounting for most deaths at later time points. Timing and primary COD vary significantly by mechanism. Contemporaneous adjudication of COD is essential to elucidate the true understanding of patient outcome, center performance, and future research. LEVEL OF EVIDENCE: Epidemiologic, level II.

Delayed presentation of complete arterial transection treated with interposition graft: A case report.

INTRODUCTION: Traumatic arterial injuries have a high degree of morbidity if left untreated. Frequently, arterial injuries are found soon after injury due to either subjective complaints or objective findings. Opportunity for delayed repair of vascular injury is a rare event as irreversible ischemia occurs at such early time points. CASE REPORT: We report a case of delayed presentation of complete arterial transection of the brachial artery due to penetrating trauma, but without classical hard signs of vascular injury. Trajectory, symptoms, and pulse exam prompted further evaluation. Successful reverse saphenous vein interposition grafting of the transected artery returned normal blood flow to the affected extremity with preserved function. CONCLUSION: This case of delayed presentation of arterial transection is significant as delayed identification of arterial injury is rare. Furthermore, it demonstrates the need for clinicians to have a high index of suspicion in patients with traumatic limb injuries who present in a subacute or delayed fashion with increasing pain and worsening of initial physical exam findings.

Defining the criteria for intubation of the patient with thermal burns.

OBJECTIVES: Recent studies demonstrate that burn patients are undergoing unnecessary intubations. We sought to determine the clinical criteria that predict intubations with benefit. METHODS: This was a retrospective review of intubated adults admitted to our center with thermal burns 2008-2013. Criteria for intubation were defined as traditional criteria (suspected smoke inhalation, oropharynx soot, hoarseness, dysphagia, singed facial hair, oral edema, oral burn, non-full thickness facial burns), or ABA criteria as defined by the 2011 ABA guidelines (full thickness facial burns, stridor, respiratory distress, swelling on laryngoscopy, upper airway trauma, altered mentation, hypoxia/hypercarbia, hemodynamic instability). Patients with <26days free from mechanical ventilation (ventilator-free days (VFD)) out of 28, were deemed indicated long-term intubations. Those with ≥26 VFD were deemed unnecessary short-term intubations. RESULTS: Of 218 patients, 151 had long-term and 67 had short-term intubations. Long-term intubation was strongly associated with ABA criteria (77.5%) compared to traditional criteria (22.5%) (p<0.001). Sensitivity of ABA criteria for long-term intubation was 77% and specificity 46%. Traditional criteria associated with long-term intubation included suspected smoke inhalation (OR 2.45 [95% CI, 1.18-5.11]), and singed facial hair (OR 2.53 [95% CI, 1.25-5.09]). The addition of these to ABA criteria created the Denver criteria, which exhibited an increased sensitivity for long-term intubations (95%), but decreased specificity (24%). CONCLUSIONS: Intubation should be considered for patients displaying the Denver criteria, which includes full thickness facial burns, stridor, respiratory distress, swelling on laryngoscopy, upper airway trauma, altered mentation, hypoxia/hypercarbia, hemodynamic instability, suspected smoke inhalation, and singed facial hair. Patients lacking these criteria should not be intubated.

The Metabolopathy of Tissue Injury, Hemorrhagic Shock, and Resuscitation in a Rat Model.

INTRODUCTION: The metabolic consequences of trauma induce significant clinical pathology. In this study, we evaluate the independent, metabolic contributions of tissue injury (TI) and combined tissue injury and hemorrhagic shock (TI/HS) using mass spectrometry (MS) metabolomics in a controlled animal model of critical injury. METHODS: Sprague-Dawley rats (n = 14) underwent TI alone or TI/HS, followed by resuscitation with normal saline and shed blood. Plasma was collected (baseline, post-laparotomy, post-HS, post-resuscitation) for ultra-high pressure liquid chromatography MS-metabolomics. Repeated-measures ANOVA with Tukey multiple column comparison test compared the fold change of metabolite concentration among the animal groups at corresponding time points. RESULTS: Four hundred forty metabolites were identified. TI alone did not change the metabolite levels versus baseline. TI/HS induced changes in metabolites from glycolysis, the tricarboxylic acid cycle, the pentose phosphate, fatty acid and glutathione homeostasis pathways, sulfur metabolism, and urea cycle versus TI alone. Following resuscitation many metabolites normalized to TI alone levels, including lactate, most tri-carboxylic acid metabolites, most urea cycle metabolites, glutathione disulfide, and some metabolites from both the pentose phosphate pathway and sulfur metabolism. CONCLUSIONS: Significant changes occur immediately following TI/HS versus TI alone. These metabolic changes are not explained by dilution as a number of metabolites remained unchanged or even increased following resuscitation. The differential metabolic changes resulting from TI alone and TI/HS provide foundation for future investigations severe injury in humans, where TI and HS are often concurrent. This investigation provides a foundation to evaluate metabolic-related outcomes and design-targeted resuscitation strategies.

Systemic hyperfibrinolysis after trauma: a pilot study of targeted proteomic analysis of superposed mechanisms in patient plasma.

BACKGROUND: Viscoelastic measurements of hemostasis indicate that 20% of seriously injured patients exhibit systemic hyperfibrinolysis, with increased early mortality. These patients have normal clot formation with rapid clot lysis. Targeted proteomics was applied to quantify plasma proteins from hyperfibrinolytic (HF) patients to elucidate potential pathophysiology. METHODS: Blood samples were collected in the field or at emergency department arrival and thrombelastography (TEG) was used to characterize in vitro clot formation under native and tissue plasminogen activator (tPA)-stimulated conditions. Ten samples were taken from injured patients exhibiting normal lysis time at 30 min (Ly30), "eufibrinolytic" (EF), 10 from HF patients, defined as tPA-stimulated TEG Ly30 >50%, and 10 from healthy controls. Trauma patient samples were analyzed by targeted proteomics and ELISA assays for specific coagulation proteins. RESULTS: HF patients exhibited increased plasminogen activation. Thirty-three proteins from the HF patients were significantly decreased compared with healthy controls and EF patients; 17 were coagulation proteins with anti-protease consumption (p < 0.005). The other 16 decreased proteins indicate activation of the alternate complement pathway, depletion of carrier proteins, and four glycoproteins. CXC7 was elevated in all injured patients versus healthy controls (p < 0.005), and 35 proteins were unchanged across all groups (p > 0.1 and fold change of concentrations of 0.75-1.3). CONCLUSION: HF patients had significant decreases in specific proteins and support mechanisms known in trauma-induced hyperfibrinolysis and also unexpected decreases in coagulation factors, factors II, X, and XIII, without changes in clot formation (SP, R times, or angle). Decreased clot stability in HF patients was corroborated with tPA-stimulated TEGs. LEVEL OF EVIDENCE: Prognostic, level III.

The hypercoagulability paradox of chronic kidney disease: The role of fibrinogen.

BACKGROUND: Chronic kidney disease (CKD) patients have increased rates of bleeding as well as thrombosis. Fibrinogen and platelets combine to generate a mature clot, but in CKD platelets are dysfunctional. Therefore, we hypothesize that CKD patients have increased clot strength due to elevated fibrinogen levels. METHODS: Retrospective review of CKD patients (n = 84) who had rTEG and fibrinogen levels measured. They were compared to healthy controls (n = 134). RESULTS: CKD patients had statistically significant increases in ACT, angle, MA and decreases in LY30 compared to controls. Fibrinogen levels were increased in CKD patients compared to reference range. Fibrinogen levels had a positive correlation with MA (rho = 0.709, p < 0.0001) in CKD patients. CONCLUSIONS: Patients with CKD manifest a coagulopathy consisting of delayed clot formation, but increased final clot strength and decreased clot breakdown. Furthermore, the elevated clot strength is mediated by increased fibrinogen levels in CKD patients.