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Background: Tibial plateau fractures (TPFs) are frequently associated with motor vehicle accidents, auto-pedestrian crashes and falls. However, hospitals near ski resorts commonly treat TPF resulting from skiing. The soft tissue envelope and original mechanism of injury are important determinants in the decision to proceed with immediate or delayed fixation of the fracture. Our objective was to assess whether immediate (≤24 hours) versus delayed (>24 hours) open reduction internal fixation (ORIF) affected in-hospital outcomes among snow sport participants., Methods: This was a retrospective study of patients with isolated TPF who were injured while skiing or snowboarding and treated at a Level III Trauma Center that serves four major ski resorts between 2010 and 2013. Clinical characteristics and in-hospital outcomes were obtained from an existing trauma database. Imaging was reviewed to classify the fracture as high (Schatzker IV-VI) or low (Schatzker I-III) energy. Differences in clinical characteristics and outcomes between immediate and delayed ORIF patients were analyzed with χ 2 and Wilcoxon two-sample tests. These analyses were also performed in the high-energy and low-energy fracture populations., Results: ORIF was performed on 119 snow sport patients, 93 (78%) immediately. Patients had a median age of 49 years (range 19-70) and were predominantly male (66%). Forty percent sustained a high-energy TPF. No differences were observed between the demographic characteristics, injury severity, Schatzker scores or time from injury to hospital arrival for patients treated immediately versus delayed treatment. Compared with delayed fixation, patients treated immediately had less compartment syndrome (3% vs 27%), needed fewer fasciotomies (6% vs 31%) and had a shorter length of stay (3 vs 6.5 days), p<0.05 for all. These results persisted in the stratified analysis of high-energy fracture patients., Discussion: Treating patients immediately led to more favorable in-hospital outcomes compared with delayed treatment, even among the patients with a high-energy fracture., Level of Evidence: Level IV, Therapeutic/Care Management., Competing Interests: Competing interests: None declared.

Introduction: Statin discontinuation has been investigated in a wide range of diseases and injuries, but there is a paucity of data in the older adult population with traumatic brain injury (TBI). The purpose of this study was to re-examine the extent to which early discontinuation of pre-injury statin (PIS) therapy increases the risk of poor patient outcomes in older adult patients suffering a TBI., Methods: This was a retrospective observational cohort study of adult trauma patients with a blunt TBI across three trauma centres over four years. Patients were excluded because of no PIS use, age <55years, or a hospital length of stay (LOS) less than three days. Patients found to be intentionally discontinued from statin therapy within 48h of hospital admission for injury-related reasons were excluded. The primary and secondary outcomes were in-hospital mortality and a hospital LOS ≥1 week. Outcomes were analysed using logistic regression., Results: There were 266 patients in the continuation group, and 131 in the discontinuation group. The statin discontinuation group had a significantly higher proportion of patients with a moderate or severe head injury, intubation in emergency department (ED), and disposition to the intensive care unit or operating room. Overall, 23 (6%) patients died while in the hospital. After adjusting for ED Glasgow coma scale, the odds of dying in the hospital were not significantly larger for patients having been discontinued from PIS, compared to those who were continued (OR=1.75, 95%CI=0.71-4.31, p=0.22). Among patients who received an in-hospital statin, the median (interquartile range) time between hospital admission and first administration of statin medication did not differ between patients who died and those who survived (22.8h [10.96-28.91] vs. 22.9h [11.67-39.80], p=0.94). There were no significant differences between study groups in the proportion of patients with a hospital length of stay >1 week (continuation=29% vs. discontinuation=36%, p=0.19)., Conclusion: We did not observe a significantly increased odds of in-hospital mortality following PIS discontinuation, compared to PIS continuation, in an older adult population with TBI. It remains to be seen whether statin discontinuation is a proxy variable for injury severity, or whether it exerts deleterious effects after injury., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To characterize trends and prognosis of severe traumatic brain injury (TBI)., Methods: This 5-year multicenter retrospective study included patients with TBI and Glasgow Coma Scale of 3. We analyzed demographic and clinical characteristics and mortality using Pearson χ 2 tests, Cochran-Armitage trend tests, and stepwise logistic regression. Analyses were stratified by vehicular and fall etiologies; other etiologies were excluded (24%)., Results: Included were 481 patients. Fall-related injuries increased 58% (P=.001) but vehicular etiology did not change (P=.63). The characteristics of the populations changed over time; with falls, the population became older and increasingly presented with normal vital signs, whereas with vehicular etiology, the population became younger, with more alcohol-related injury (P<.05 for all). Mortality from falls increased substantially from 25% to 63% (P<.001), whereas death from vehicular injures remained statistically unchanged but with a downward trend (50%-38%, P=.28). Predictors of mortality included injury severity and age at least 65 years for both groups. Additional variables that were prognostic were abnormal vital signs and subdural hematoma for vehicular injuries, and sex for fall injuries., Conclusions: The epidemiology of severe TBI is changing. These epidemiologic data may be used for management and resource decisions, monitoring, and directing injury prevention measures., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Venous thromboembolism (VTE) remains a clinically significant complication after trauma even though screening and prophylaxis strategies for at-risk patients have substantially reduced incidence. Our study sought to determine if diabetes, a condition that promotes thrombi formation, is associated with developing a VTE in trauma patients., Methods: The registries of 2 level I and a level II trauma centers were retrospectively reviewed for consecutively admitted trauma patients over a 6-year period. Demographics, VTE risk factors, injury characteristics, and VTE incidence were univariately compared between patients with insulin-dependent diabetes mellitus (IDDM), non-insulin-dependent diabetes mellitus (NIDDM), and no diabetes. Stepwise logistic regression was performed to identify independent predictors of VTE; results were further stratified by age (<65 and ≥65 years) and presented as adjusted ORs (AOR)., Results: Of the 26 934 total patients, 779 (2.9%) had IDDM, 2052 (7.6%) had NIDDM, and the remaining 89.5% were without diabetes. VTE incidence was 3.6%, 2.4%, and 2.2%, in IDDM, NIDDM, and non-diabetes, respectively (p=0.02). After adjustment for established and significant risk factors, neither IDDM (AOR=1.43, 95% CI 0.95 to 2.15, p=0.09) nor NIDDM (AOR=1.03, 95% CI 0.75 to 1.40, p=0.88) was associated with increased odds of developing a VTE. Patients ≥65 years developed VTE more frequently than those <65 years (2.5% vs 2.1%, p=0.04). Among patients <65 years, IDDM was significantly predictive of VTE (AOR=1.86, 95% CI 1.01-3.41, p=0.045), but NIDDM was not. For patients ≥65 years, neither type of diabetes was predictive of VTE., Conclusions: VTE incidence was ∼2 times higher among injured patients <65 years with IDDM versus no diabetes. Overall, we did not find an increased risk of VTE in patients with any diabetes. Additional studies are needed before a recommendation on VTE screening or prophylaxis in IDDM can be made., Level of Evidence: Level III, therapeutic/care management., Competing Interests: Competing interests: DB-O has held various leadership roles within Ampio Pharmaceuticals and has been issued close to 300 patents.

Introduction: Prognosis in patients with traumatic brain injury (TBI) and Glasgow Coma Scale (GCS) score of 3 is poor, raising concern regarding the utility of aggressive operative neurosurgical management. Our purpose was to describe outcomes in a propensity matched population with TBI and GCS3 treated with operative neurosurgical procedures of craniotomy or craniectomy (CRANI)., Methods: We conducted a five-year, multicenter retrospective cohort study of patients with an ED GCS 3 and a positive head CT identified by ICD-9CM diagnosis codes. Two populations were examined: (1) patients with extra-axial mass lesion (subdural or epidural haematoma), (2) patients without mass lesion (subarachnoid and intraparenchymal haemorrhage including contusion, other intracerebral haemorrhage or intracranial injury including diffuse axonal injury). In patients with extra-axial mass lesion, propensity score techniques were used to match patients 1:1 by CRANI, and the following outcomes were analysed with conditional logistic regression: survival, favourable hospital disposition to home or rehabilitation, and development of complications., Results: There were 541 patients with TBI and GCS3; 19% had a CRANI, 83% were initiated within 4h. In those with mass lesion, 27% (91/338) had a CRANI; after matching, a significant survival benefit was observed with CRANI vs. without CRANI (65% vs. 34% survival, OR: 3.9 (1.6-10.5) p<0.001). There was borderline increased odds of favourable disposition (43% vs. 26%, OR: 2.4 (0.99-6.3, p=0.052) with CRANI vs. without CRANI, and no difference in developing a complication (58% vs. 48%, OR: 1.5 (0.7-3.4), p=0.30)., Conclusions: Survival was achieved in 65% of patients that underwent surgical intervention for subdural and epidural haematoma, despite a presenting GCS of 3. These results demonstrate prompt operative neurosurgical management of mass lesion is warranted for selected patients with a GCS of 3, contributing to a significant 4-fold survival benefit. In the absence of mass lesion the effect of immediate neurosurgery on outcomes is inconclusive., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

There are few reliable markers for assessing traumatic brain injury (TBI). Elevated levels of oxidative stress have been observed in TBI patients. We hypothesized that oxidation-reduction potential (ORP) could be a potent biomarker in TBI. Two types of ORP were measured in patient plasma samples: the static state of oxidative stress (sORP) and capacity for induced oxidative stress (icORP). Differences in ORP values as a function of time after injury, severity, and hospital discharge were compared using ANOVAs with significance at p ≤ 0.05. Logit regression analyses were used to predict acute outcome comparing ORP, Injury Severity Score (ISS), Abbreviated Injury Scale (AIS), and Glasgow Coma Scale (GCS). Antioxidant capacity (icORP) on day 4 was prognostic for acute outcomes (p < 0.05). An odds ratio of 4.08 was associated with poor acute outcome when icORP > 7.25 μC. IcORP was a better predictor than ISS, AIS, or GCS scores. sORP increased in those with the highest ISS values (p < 0.05). Based on these findings ORP is useful biomarker for severity and acute outcome in TBI patients. Changes in ORP values on day 4 after injury were the most prognostic, suggesting that patients' response to brain injury over time is a factor that determines outcome.

Hemorrhagic shock is a principal cause of death among trauma patients within the first 24 hours after injury. Optimal fluid resuscitation strategies have been examined for nearly a century, more recently with several randomized controlled trials. Hypotensive resuscitation, also called permissive hypotension, is a resuscitation strategy that uses limited fluids and blood products during the early stages of treatment for hemorrhagic shock. A lower-than-normal blood pressure is maintained until operative control of the bleeding can occur. The randomized controlled trials examining restricted fluid resuscitation have demonstrated that aggressive fluid resuscitation in the prehospital and hospital setting leads to more complications than hypotensive resuscitation, with disparate findings on the survival benefit. Since the populations studied in each randomized controlled trial are slightly different, as is the timing of intervention and targeted vitals, there is still a need for a large, multicenter trial that can examine the benefit of hypotensive resuscitation in both blunt and penetrating trauma patients.

Electrolyte imbalances are common among patients with traumatic brain injury (TBI). Cerebral salt wasting (CSW) is an electrolyte imbalance characterized by hyponatremia and hypovolemia. Differentiating the syndrome of inappropriate antidiuretic hormone and CSW remains difficult and the pathophysiological mechanisms underlying CSW are unclear. Our intent was to review the literature on CSW within the TBI population, in order to report the incidence and timing of CSW after TBI, examine outcomes, and summarize the biochemical changes in patients who developed CSW. We searched MEDLINE through 2014, hand-reviewed citations, and searched abstracts from the American Association for the Surgery of Trauma (2003-2014). Publications were included if they were conducted within a TBI population, presented original data, and diagnosed CSW. Publications were excluded if they were review articles, discussed hyponatremia but did not differentiate the etiology causing hyponatremia, or presented cases with chronic disease. Fifteen of the 47 publications reviewed met the selection criteria; nine (60%) were case reports, five (33%) were prospective and 1 (7%) was a retrospective study. Incidence of CSW varied between 0.8 - 34.6%. The populations studied were heterogeneous and the criteria used to define hyponatremia and CSW varied. Though believed to play a role in the development of CSW, increased levels of natriuretic peptides in patients diagnosed with CSW were not consistently reported. These findings reinforce the elusiveness of the CSW diagnosis and the need for strict and consistent diagnostic criteria.

Background: Do-Not-Resuscitate (DNR) orders in patients with traumatic injury are insufficiently described. The objective is to describe the epidemiology and outcomes of DNR orders in trauma patients., Methods: We included all adults with trauma to a community Level I Trauma Center over 6 years (2008-2013). We used chi-square, Wilcoxon rank-sum, and multivariate stepwise logistic regression tests to characterize DNR (established in-house vs. pre-existing), describe predictors of establishing an in-house DNR, timing of an in-house DNR (early [within 1 day] vs late), and outcomes (death, ICU stay, major complications)., Results: Included were 10,053 patients with trauma, of which 1523 had a DNR order in place (15%); 715 (7%) had a pre-existing DNR and 808 (8%) had a DNR established in-house. Increases were observed over time in both the proportions of patients with DNRs established in-house (p = 0.008) and age ≥65 (p < 0.001). Over 90% of patients with an in-house DNR were ≥65 years. The following covariates were independently associated with establishing a DNR in-house: age ≥65, severe neurologic deficit (GCS 3-8), fall mechanism of injury, ED tachycardia, female gender, and comorbidities (p < 0.05 for all). Age ≥65, female gender, non-surgical service admission and transfers-in were associated with a DNR established early (p < 0.05 for all). As expected, mortality was greater in patients with DNR than those without (22% vs. 1%), as was the development of a major complication (8% vs. 5%), while ICU admission was similar (19% vs. 17%). Poor outcomes were greatest in patients with DNR orders executed later in the hospital stay., Conclusions: Our analysis of a broad cohort of patients with traumatic injury establishes the relationship between DNR and patient characteristics and outcomes. At 15%, DNR orders are prevalent in our general trauma population, particularly in patients ≥65 years, and are placed early after arrival. Established prognostic factors, including age and physiologic severity, were determinants for in-house DNR orders. These data may improve physician predictions of outcomes with DNR and help inform patient preferences, particularly in an environment with increasing use of DNR and increasing age of patients with trauma.

Importance: The Glasgow Coma Scale (GCS) is used frequently to define the extent of neurologic injury in patients with a traumatic brain injury (TBI). Whether age affects the predictive ability of the GCS for severity of TBI (determined by the Abbreviated Injury Scale [AIS] score) remains unknown., Objective: To investigate the effect of age on the association between the GCS and anatomic TBI severity., Design, Setting, and Participants: We examined all patients with a TBI, defined by diagnostic codes 850 to 854 from the International Classification of Diseases, Ninth Revision, Clinical Modification, who were admitted to 2 level I trauma centers from January 1, 2008, through December 31, 2012., Exposures: We compared elderly (≥65 years) and younger (18-64 years) adults with TBI., Main Outcomes and Measures: We examined differences by age in GCS category (defined by emergency department GCS as severe [3-8], moderate [9-12], or mild [13-15]) at each level of TBI severity (head AIS score, 1 [minor] to 5 [critical]). Cochran-Armitage χ² trend tests and stepwise multivariate linear and logistic regression models were used., Results: During the study period, 6710 patients had a TBI (aged <65 years, 73.17%). Significant differences in GCS category by age occurred at each AIS score (P ≤ .01 for all). In particular, among patients with an AIS score of 5, most of the elderly patients (56.33%) had a mild neurologic deficit (GCS score, 13-15), whereas most of the younger patients (63.28%) had a severe neurologic deficit (GCS score, 3-8). After adjustment, the younger adults had increased odds of presenting with a severe neurologic deficit (GCS score, 3-8) at each of the following AIS scores: 1, 4.2 (95% CI, 1.0-17.6; P = .05); 2, 2.0 (1.0-3.7; P = .04); 3, 2.0 (1.2-3.5; P = .01); 4, 4.6 (2.8-7.5; P < .001); and 5, 3.1 (2.1-4.6; P < .001). The interaction between age and GCS for anatomic TBI severity remained significant after adjustment (estimate, -0.11; P = .005)., Conclusions and Relevance: Age affects the relationship between the GCS score and anatomic TBI severity. Elderly TBI patients have better GCS scores than younger TBI patients with similar TBI severity. These findings have implications for TBI outcomes research and for protocols and research selection criteria that use the GCS.

Objective: To synthesise published and unpublished findings examining the relationship between institutional trauma centre volume or trauma patient volume per surgeon and mortality., Background: Evidence on the relationship between patient volume and survival in trauma patients is inconclusive in the literature and remains controversial., Methods: A literature search was performed to identify studies published between 1976 and 2013 via MEDLINE (Pubmed) and the Cumulative Index to Nursing and Allied Health Literature (EbscoHost) as well as footnote chasing. Abstracts from appropriate conferences and ProQuest Dissertations and Theses were also searched. Inclusion criteria required studies to be original research published in English that examined the relationship between mortality and either institutional or per surgeon volume in American trauma centres. We employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement checklist and flowchart. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was employed to rate the quality of the evidence., Results: Of 1392 studies reviewed, 19 studies met defined inclusion criteria; all studies were retrospective. The definition of volume was heterogeneous across the studies. Patient population and analysis methods also varied across the studies. Sixteen studies (84%) examined the relationship between institutional trauma centre volume and mortality. Of the 16 studies, 12 examined the volume of severely injured patients and eight examined overall trauma patient volume. High institutional volume was associated with at least somewhat improved mortality in ten of 16 studies (63%); however, nearly half of these studies found only some subpopulations experienced benefits. In the remaining six studies, volume was not associated with any benefits. Four studies (25%) analysed the impact of surgeon volume on mortality. High volume per surgeon was associated with improved mortality in only one of four studies (25%)., Conclusions: The studies were extremely heterogeneous, thus definitive conclusions cannot be drawn regarding optimal volume before a clear advantage in survival is observed. A prospective study defining volume as a continuous variable is warranted to support current admission criteria for American trauma patients., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Standard bacteriologic culture techniques offer results within 2 days to 3 days, precluding a focused and timely antibiotic therapy in ventilated trauma patients. Our laboratory developed a real-time quantitative polymerase chain reaction (qPCR) test that can detect 25 different bacteria and fungi and methicillin resistance and offers results within 3 hours. The objective of this study was to compare the qPCR method to standard culture techniques., Methods: This was a prospective observational cohort study at a Level I trauma center from 2009 to 2012. Adult trauma patients on ventilation, receiving at least one bronchoalveolar lavage (BAL) with culture results were eligible for inclusion. DNA was isolated from the BAL samples and analyzed in 96-well plates using qPCR. Student's t tests were used to examine differences in mean qPCR cycle counts. Sensitivities, specificities, negative predictive values, and positive predictive values were calculated for the qPCR primer sets., Results: There were 28 BALs in the study. The qPCR method detected a total of 165 organisms, and culture methods found 54. The qPCR test had an overall sensitivity of 85%, specificity of 74%, negative predictive value of 98%, and positive predictive value of 27%. Those organisms that were only identified through qPCR had significantly less DNA than those identified through both qPCR and quantitative culture (28.8 vs. 23.3, p < 0.001). Concurrent antibiotic therapy was found to decrease the qPCR specificity in some primer sets, and methicillin resistance was only found in BAL samples that were concurrent with antibiotics., Conclusion: The qPCR method shows promising initial diagnostic value. Many of the organisms not identified by quantitative culture had late cycle calls, suggesting that they might have been in quantities too low to result in culture identification. Once refined, our qPCR method has the potential to identify pathogens faster and earlier than standard quantitative culture methods, allowing for targeted antibiotic therapy within 3 hours., Level of Evidence: Diagnostic test, level II.

Due to the heterogeneous nature of commercial human serum albumin (cHSA), other components, such as the protease dipeptidyl peptidase IV (DPP-IV), possibly contribute to the therapeutic effect of cHSA. Here, we provide evidence for the first time that DPP-IV activity contributes to the formation of aspartate-alanine diketopiperazine (DA-DKP), a known immunomodulatory molecule from the N terminus of human albumin. cHSA was assayed for DPP-IV activity using a specific DPP-IV substrate and inhibitor. DPP-IV activity was assayed at 37 and 60°C because cHSA solutions are pasteurized at 60°C. DPP-IV activity in cHSA was compared with other sources of albumin such as a recombinant albumin (rHSA). In addition, the production of DA-DKP was measured by negative electrospray ionization/liquid chromatography mass spectrometry (ESI(-)/LCMS). Significant levels of DPP-IV activity were present in cHSA. This activity was abolished using a specific DPP-IV inhibitor. Fully 70 to 80% DPP-IV activity remained at 60°C compared with the 37°C incubate. No DPP-IV activity was present in rHSA, suggesting that DPP-IV activity is present only in HSA produced using the Cohn fractionation process. The formation of DA-DKP at 60°C was observed with the DPP-IV inhibitor significantly decreasing this formation. DPP-IV activity in cHSA results in the production of DA-DKP, which could account for some of the clinical effects of cHSA., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The abrupt discontinuation of statin therapy has been suggested as being deleterious to patient outcomes. Although pre-injury statin (PIS) therapy has been shown to have a protective effect in elderly trauma patients, no study has examined how this population is affected by its abrupt discontinuation. This study examined the effects of in-hospital statin discontinuation on patient outcomes in elderly traumatic brain injury (TBI) patients., Methods: This was a multicenter, retrospective cohort study on consecutively admitted elderly (≥ 55) PIS patients who were diagnosed with a blunt TBI and who had a hospital length of stay (LOS) ≥ 3 days. Patients who received an in-hospital statin within 48 hours of admission were considered continued, and patients who never received an in-hospital statin were considered discontinued. Differences in in-hospital mortality, having at least one complication, and LOS > 1 week were examined between those who continued and discontinued PIS., Results: Of 93 PIS patients, 46 continued and 15 discontinued statin therapy. The two groups were equivalent vis-a-vis demographic and clinical characteristics. Those who discontinued statin therapy had a 4-fold higher mortality rate than those who continued (n = 4, 27% vs. n = 3, 7%, P = 0.055). Statin discontinuation did not have a higher complication rate, compared to statin continuation (n = 3, 20% vs. n = 7, 15%, P = 0.70), and no difference was seen in the proportion with a hospital LOS > 1 week (P > 0.99)., Conclusions: Though our study is not definitive, it does suggest that the abrupt, unintended discontinuation of statin therapy is associated with increased mortality in the elderly TBI population. Continuing in-hospital statin therapy in PIS users may be an important factor in the prevention of in-hospital mortality in this elderly TBI population.

Background: Level I trauma centers have requirements on the percentage of trauma patients admitted to either a trauma surgeon or surgical subspecialist; however, surgical resources are in steady decline. Therefore, a trauma system might better utilize its surgical resources if trained hospitalists admitted a larger percentage of mild to moderately injured trauma patients. The objective of this report is to provide a 5-year evaluation of a trauma medical service (TMED) at treating mild to moderately injured trauma patients., Methods: Adult trauma patients consecutively admitted to a Level I trauma center between January 2006 and December 2010 were analyzed. Patients admitted to trauma surgical services were matched 1:1 to those admitted to TMED, via propensity scores. Paired t tests examined differences in hospital duration of stay (DOS), and exact conditional logistic regression examined differences in the odds of having a delayed diagnosis, developing a complication, and dying., Results: Of 1,202 TMED patients, 494 were matched; matched TMED patients had similar patient outcomes to nonmatched TMED patients. There were no differences between study groups in the mean hospital DOS, the proportion having a delayed diagnosis, or in the odds of dying in the hospital (P > .05 for all). The TMED group had a nominally higher complication rate (P = .12) owing to a higher rate of urinary tract infections., Conclusion: Since its inception, the TMED service has successfully and safely treated mild to moderately injured trauma patients, and decreased the dependency on trauma surgical services. Trauma centers might utilize declining surgical services more efficiently with the addition of trauma medical hospitalists., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Breakdown of endothelial barrier function is a hallmark event across a variety of pathologies such as inflammation, cancer, and diabetes. It has also been appreciated that steroid hormones impart direct biological activity on endothelial cells at many levels. The purpose of this investigation was to explore the effect of the androgen-like steroid, danazol, on endothelial cell barrier function in vitro. Primary human endothelial cells exposed to 0.01-50 μM danazol were evaluated for changes in permeability. We found that danazol altered endothelial permeability in a biphasic manner in which nanomolar concentrations enhance barrier function while micromolar concentrations are detrimental. Monitoring of trans-endothelial electrical resistance demonstrated that these barrier enhancing effects were rapid (within 5 min) and lasted for over 24h. Analysis of intracellular f-actin organization showed that barrier enhancement also correlated with the formation of a submembranous cortical actin ring. Conversely, at higher danazol concentrations, contractile cell phenotypes were observed, represented by stress fiber formation. Competitive binding studies performed using steroid hormone receptor antagonists proved that this activity is the result of androgen and estrogen receptor ligation. These findings suggest that low dose danazol may provide a therapeutic window for diseases involving vascular leakage., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: In critical injury, the occurrence of increased oxidative stress or a reduced antioxidant status has been observed. The purpose of this study was to correlate the degree of oxidative stress, by measuring the oxidation-reduction potential (ORP) of plasma in the critically injured, with injury severity and serum amyloid A (SAA) levels., Methods: A total of 140 subjects were included in this retrospective study comprising 3 groups: healthy volunteers (N = 21), mild to moderate trauma (ISS < 16, N = 41), and severe trauma (ISS >or= 16, N = 78). For the trauma groups, plasma was collected on an almost daily basis during the course of hospitalization. ORP analysis was performed using a microelectrode, and ORP maxima were recorded for the trauma groups. SAA, a sensitive marker of inflammation in critical injury, was measured by liquid chromatography/mass spectrometry., Results: ORP maxima were reached on day 3 (+/- 0.4 SEM) and day 5 (+/- 0.5 SEM) for the ISS < 16 and ISS >or= 16 groups, respectively. ORP maxima were significantly higher in the ISS < 16 (-14.5 mV +/- 2.5 SEM) and ISS >or= 16 groups (-1.1 mV +/- 2.3 SEM) compared to controls (-34.2 mV +/- 2.6 SEM). Also, ORP maxima were significantly different between the trauma groups. SAA was significantly elevated in the ISS >or= 16 group on the ORP maxima day compared to controls and the ISS < 16 group., Conclusion: The results suggest the presence of an oxidative environment in the plasma of the critically injured as measured by ORP. More importantly, ORP can differentiate the degree of oxidative stress based on the severity of the trauma and degree of inflammation.

Background: The pyruvate dehydrogenase complex (PDC) catalyzes the conversion of pyruvate to acetyl CoA, effectively controlling the entrance of glycolysis products into aerobic metabolism. Because hyperlactatemia is one of the hallmarks of sepsis, we hyphothesized that gram-positive and negative bacterial toxin treatment will interfere with mRNA levels of regulatory enzymes of the PDC and overall enzyme activity in hepatocytes., Methods: HEP G2 hepatocarcinoma cells were incubated for 24 hours in the presence of lipopolysaccaride (LPS) or lipoteichoic acid. Total RNA was then isolated and message RNA levels for both pyruvate dehydrogense kinase 4 and phosphatase 2 were determined by RTPCR. Amplified DNA fragments were visualized by ethidium bromide in agarose gels and densitometry of the bands was performed. Data were then normalized to the housekeeping gene, GAPDH. Enzyme activity was then determined by capturing intact PDC on nitrocellulose membranes then determining PDC-dependent production of NADH., Results: LPS treatment led to a time dependent increase in PDK4 message while decreasing PDP2 levels. Enzyme activity, in these cells, also significantly decreased 24 hours after exposure to LPS. Cells cultured in the presence of lipoteichoic acid and insulin exhibited differing message ratios and activity levels when evaluated at 4 hours, but at 24 hours shifted to mimic those observed in LPS treated cells., Conclusion: This data may indicate that exposure to bacterial cell wall components and insulin could create cellular environments that result in a build-up of lactate.

Background: The abbreviated injury scale (AIS) was updated in 2005 from the AIS 1998 version. The purpose of this study is to describe the effects of this change on injury severity scoring and outcome measures., Materials and Methods: Analyses were performed on all trauma patients consecutively admitted over a 6-month period at two geographically separate Level I trauma centers. Injuries were manually double-coded according to the AIS 05 and the AIS 98. Changes in AIS, ISS, and new ISS (NISS) were analysed using paired t-tests. Apparent differences in outcome by ISS strata (<16, 16-24, >24) were compared for AIS 05 versus AIS 98 using the Wald-type statistic. Lastly, the percent of patients with a change in ISS strata are reported., Results: There were 2250 patients included in the study. Nearly half (46.4%) of AIS codes changed, resulting in a different AIS score for 18.9% of all codes. The mean ISS was significantly lower using the AIS 05 (11.7) versus the AIS 98 (13.3, p<0.001). Similarly, the mean NISS was significantly lower (16.3 versus 18.7, p<0.001). In the ISS strata 16-24 an apparent increase in mortality, length of stay, and percent of patients not discharged home was observed for the AIS 05 versus AIS 98. Changes in outcome measures for this stratum were as follows (AIS 98 versus AIS 05): mortality, 4.3% versus 7.7% (p=0.002); hospital length of stay, 5.2 days versus 7.3 days (p<0.001); percent of patients not discharged home, 39.2% versus 49.3% (p<0.001). Finally, there was a 20.5% reduction in patients with an ISS>or=16 and a 26.2% reduction in patients with an ISS>or=25 using the AIS 05., Conclusions: The AIS revision had a significant impact on overall injury severity measures, clinical outcome measures, and percent of patients in each ISS strata. Therefore, the AIS revision affects the ability to directly compare data generated using AIS 05 and AIS 98 which has implications in trauma research, reimbursement and ACS accreditation.

The amount of oxidative stress in patients with an isolated traumatic brain injury (ITBI) can be estimated by measuring several biochemical parameters, such as total antioxidants, lipid peroxidation, protein oxidation, and others. Unfortunately, measuring these parameters is time-consuming, impractical in a clinical setting, and may miss important factors contributing to the overall redox balance. Here we suggest that the overall oxidative status in ITBI patients can be assessed by measuring plasma oxidation-reduction potential (ORP). Daily whole blood samples were obtained from severe ITBI patients (abbreviated injury score [AIS] >or=3, n = 32), and demographically similar non-head injury traumatized patients (n = 26) until discharge. Whole blood was also collected from patients with minor to moderate ITBI (AIS

Phthalate esters (PE's) are plasticizers used to soften PVC-based medical devices. PE's are the most abundant man-made pollutants and increase the risk of developing an allergic respiratory disease or a malignancy. The leaching of PE's in donated packed red blood cells (PRBC) during storage was assessed. PRBC transfusion bags containing CPD/AS-1 (ADSOL) buffer were analyzed. Samples were collected on storage day 1 and day 42. Two PE's, di-(2-ethylhexyl) phthalate (DEHP) and mono-(2-ethylhexyl) phthalate (MEHP), were measured by liquid chromatography coupled to mass spectrometry (LCMS). Interleukin-8 (IL-8) was measured by standard ELISA techniques. DEHP significantly increased from 34.3 microM (+/-20.0 SD) on day 1 to 433.2 microM (+/-131.2 SD) on day 42, a 12.6-fold increase. Similarly, MEHP significantly increased from 3.7 microM (+/-2.8 SD) on day 1 to 74.0 microM (+/-19.1 SD) on day 42, a 20.2-fold increase. Also, DEHP and MEHP increased the release of IL-8 from human umbilical vein endothelial cells (HUVEC). The transfusion of older units of PRBC could lead to an accumulation of PE's possibly resulting in inflammation and other effects. This accumulation could be exacerbated due to the decreased metabolism of PE's since trauma patients have a lower esterase activity, the enzymes responsible for metabolizing PE's. The effect of oxidative stress caused by PE's is discussed as a potential mechanism for increases in inflammation caused by older units of PRBC.

Background: The American College of Surgeons criteria for Level I trauma centers calls for >90% of trauma patients to be admitted directly by a trauma surgeon or surgical subspecialist; however, the efficiency of the trauma system may be increased if patients presenting with comorbid conditions and minor injuries are treated by a hospitalist team (nonsurgical Trauma MEDical [TMED] service). We hypothesized outcomes would be equivalent for patients treated under TMED versus a surgical service., Methods: This retrospective review compared mortality, hospital length of stay (LOS), Emergency Department (ED) LOS, placement to rehabilitation facilities, and complication rates for patients who could have been treated by TMED as identified by an algorithm. The study population for 2003 (pre-TMED) was compared with the study population for 2006 (post-TMED). Univariate analyses and multivariate logistic and linear regression were used to identify outcomes that were different for patients treated in 2003 versus 2006. Sensitivity, specificity, and percent kappa agreement were calculated for patients who were treated by the TMED team in 2006 versus patients in 2006 who were identified using the algorithm., Results: The algorithm had reasonable sensitivity (78%) and specificity (90%); the kappa agreement was excellent (0.88). No differences were found in mortality (P = .31), rate of complications (P = .08), ED LOS (P = .77), or placement to rehabilitation facilities (P = .29) for patients identified in 2003 versus 2006. Hospital LOS was increased in 2006 (3.7 vs 4.1 days; P = .02)., Conclusion: These data support admission of trauma patients with nonsevere, single-system injuries to a nonsurgical hospitalist service. We hypothesize that overall system efficiency may be improved by applying this alternative model in other trauma centers.

Objective: To quantify the cumulative effective dose of radiation received during hospitalization after traumatic injury and to compare the computed tomography (CT) utilization practices for two time periods in patients with trauma., Design: A retrospective analysis of radiologic and medical data., Setting: A level I trauma center., Patients: Consecutively admitted adult patients with trauma with moderate to severe injuries (injury severity score >8), an intensive care unit (ICU) length of stay of one or more days, who were directly admitted and not transferred to another acute care center., Measurements and Main Results: CT examination means and utilization were compared for April through August, 2003 and April to August, 2007. Cumulative effective doses were calculated for the 2007 period, and patients with a high radiation dose (>100 mSv) were identified. One hundred sixty-five adult patients with trauma were included. An increase in mean CT examinations per patient was observed in the 2007 period compared with the 2003 period, overall (4.41 vs. 3.44, p = 0.002) and among subsets of patients. The overall increase remained significant after adjustment for patient demographics (p = 0.05). The mean cumulative effective dose per patient was 11.13 mSv in 2007; 9% of patients received a dose >or=100 mSv., Conclusions: Patients with trauma are at an increased risk of adverse effects from CT studies, because they receive high doses of radiation, and the number of CT examinations that patients receive is increasing with time. We recommend that risk of radiation be prospectively monitored and estimated by hospitals through the use of CT examination count per patient.

Biomarkers for the early detection of liver toxicity are crucial in drug development for assessing the safety of a new drug. Oxidation reduction potential (ORP) is an overall measure of the oxidative stress to which a biological component is subjected and correlates with organ dysfunction. Raman spectroscopy is a non-invasive method that we employed to analyze the perfusates of five normothermic human livers perfused with the known toxin α-naphthylisothiocyanate. Spectral signatures were generated using principle component analysis (PCA) coupled with stepwise linear regression of the first several PCA coefficients to the ORP. The Raman signatures correlated to the measured ORP with an r2 of 0.854. This study demonstrated the utility of this technique in determining the presence of liver toxicity as reflected by increasing ORP. Real-time, non-invasive monitoring of normothermic perfusates of human livers using processed Raman spectra has the potential to predict drug toxicity and organ viability for transplantation.

Background: Transfusion-related acute lung injury (TRALI) is a life-threatening condition characterized by oxidative stress. Longer storage times of packed red blood cells (PRBC) and other blood products have been implicated with an increased risk in developing TRALI in transfused patients., Methods: A total of 10 units of blood containing PRBC stored in citrate-phosphate-dextrose buffer at 4 degrees C were included in the study. At Bonfils Blood Center (Denver, CO), samples were collected on storage day 1 and day 42. Samples were immediately centrifuged, and the supernatants were collected and stored at -80 degrees C until further analysis. Oxidation-reduction potential and protein oxidation were measured in both the day 1 and day 42 samples., Results: Oxidation-reduction potential significantly increased (p < 0.05) in the day 42 sample (98.1 mV +/- 21.9 SD) versus the day 1 sample (62.6 mV +/- 21.5 SD). The oxidation of human serum albumin increased by 63.6% during the storage time. Other serum proteins such as apolipoprotein A1 and transthyretin demonstrated similar increases in oxidation. Also, proteins with a cleaved C-terminal amino acid were observed indicating the presence of carboxypeptidase activity, a marker of inflammation., Conclusions: The presence of an oxidative environment in transfused PRBC increases with storage time. This could partially explain the increased risk of developing TRALI related to the transfusion of older blood products.

Background: The cytotoxic effects of antiseptics on pivotal cell types of the healing process have been well documented. The purpose of our investigation was to explore the ability of subcytotoxic levels of antiseptics to interfere with fibroblast function., Methods: Cell proliferation assays were performed by culturing fibroblasts in the presence of commonly used antiseptics. Migration was evaluated using scratch assays in which monolayers were "wounded" and cellular movement was monitored by digital photography. Matrix metalloproteinase (MMP) release was analyzed by zymography., Results: H2O2 and povidone-iodine reduced both migration and proliferation of fibroblasts in a dose-dependent fashion. Treatment with silver-containing antiseptics and chlorhexidine exhibited reductions in proliferation at high concentrations, but enhanced growth at lower doses. Silver-containing compounds and chlorhexidine also proved to be the least detrimental to migration in these assays. metalloproteinase release from the cells was differently affected depending on the dosage and class of antiseptic applied., Conclusions: When debridement of the wound bed is not sufficient to reduce bacterial loads, the application of broad-spectrum antiseptics maybe indicated. Our data would suggest that H2O2 and iodine are poor choices, potentially retarding the contribution of fibroblasts to the healing process. Silver sulfadiazine and chlorhexidine, at levels still proven to be bactericidal, had fewer detrimental effects on fibroblast activity in these assays. The silver-containing antiseptics may even increase the proliferative potential of these cells in culture.

Background: We previously hypothesized that the N-terminus of human serum albumin (HSA) is altered during ischemic events, thus establishing the foundation for the cobalt-HSA binding assay phenomenon. In this investigation, we attempt to clarify the mode of action of the cobalt-HSA binding assay by direct observations of cobalt binding to HSA., Methods: High pressure liquid chromatography coupled to positive electrospray ionization mass spectrometry (HPLC/MS) was used to study cobalt binding to HSA in the plasma of patients with and without evidence of myocardial ischemia., Results: Strong binding of cobalt to the N-terminus of HSA occurs at pH>7.0. No differences in cobalt binding to the N-terminus of HSA are observed in ischemic versus non-ischemic patients' plasma despite differences in the cobalt-HSA binding assay. Plasma free cysteine/cystine ratio appears to play a role in the quantitative response of the cobalt-HSA binding assay., Conclusions: The main determinants of the cobalt-HSA binding assay mechanism of action include but are not limited to: the proportion of intact N-terminus of HSA, HSA concentration, plasma cysteine/cystine ratio, plasma pH, and the state of oxidation of cys34 of HSA. Assay improvements that consider and take these factors into account could lead to an improved cobalt-HSA binding assay with greater clinical utility.

Objective: To determine if a change in trauma designation from level II (L2) to level I (L1) in the same institution reduces mortality., Design, Setting, and Patients: A retrospective cohort study of all patients consecutively admitted to a community hospital trauma center., Intervention: The upgrade to trauma L1 designation (January 1, 2003-March 31, 2007) (n = 7902) from trauma L2 designation (January 1, 1998-December 31, 2002) (n = 9511)., Main Outcome Measures: Adjusted overall mortality and adjusted mortality for severely injured patients, patients with complications, and patients with severe sites of injury., Results: After adjusting for age, sex, Injury Severity Score, mechanism of injury, hypotension on admission, respirations, and comorbidities, there was a significant decrease in overall mortality during L1 designation compared with L2 designation (2.50% vs 3.48%; P = .001). Severely injured patients (Injury Severity Score of >/= 15) admitted during an L1 trauma designation had a significant reduction in mortality compared with patients admitted during an L2 designation (8.99% vs 14.11%; P < .001). Patients admitted during an L1 designation with a severe head, chest, or abdominal or pelvic injury diagnosis had a significant decrease in mortality (9.96% vs 14.51% [P = .005], 7.14% vs 11.27% [P = .01], and 6.76% vs 17.05% [P = .002], respectively), as did patients who developed acute respiratory distress syndrome during their hospital stay (9.51% vs 26.87%; P = .02)., Conclusion: The significant reduction in mortality of trauma patients with severe or specific injuries after the change to a higher trauma level designation may justify direct triage of these patients to L1 facilities, when available.

Background: Aspartyl-alanyl- diketopiperazine (DA-DKP) is generated by cleavage and cyclization from the N-terminus of human albumin during the preparation of commercial serum albumin product. Antigen-stimulated human T lymphocytes produce significantly lower quantities of interferon-gamma and tumor necrosis factor-alpha after stimulation in vitro in the presence of DA-DKP., Methods: T lymphocytes activated in the presence of DA-DKP were analyzed by pull-down western blot assay for the activation of the guanosine triphosphatase Rap1 and by quantitative immunoassay for the phosphorylated transcription factors ATF-2 (activating transcription factor-2) and c-jun, which regulate the production of interferon-gamma and tumor necrosis factor-alpha., Results: Exposure of human T lymphocytes to DA-DKP resulted in increased levels of active Rap1 and decreased activation factors relevant to the T-cell receptor signal transduction pathway and subsequently, decreased phosphorylated ATF-2 and c-jun expression., Conclusion: The cyclized N- terminal fragment of human serum albumin, DA-DKP, can modulate the inflammatory immune response through a molecular pathway implicated in T- lymphocyte anergy.

The amount of oxidative stress in severely traumatized patients is usually based on various individual parameters such as total antioxidants and lipid peroxidation. Serial measurements of plasma oxidation-reduction potential (ORP) in severely traumatized patients as a simple mean of assessing overall oxidative stress is described. Serial whole blood samples were obtained from multi-trauma patients (N=39) and healthy individuals (N=10). Plasma ORP in multi-trauma patients increased during the first few days of hospitalization and approached normal ORP levels upon discharge. On the ORP maxima day (5.8 days+/-0.5 SEM), a statistically significant decrease (p<0.05) was observed for negative acute phase reactants such as plasma paraoxonase-arylesterase (PON-AE) activity and total plasma protein in comparison with admission plasma levels. Monitoring ORP could be a useful tool for assessing the degree of oxidative stress, inflammation, severity of injury, and potential efficacy of treatment.

Introduction: Gaucher's disease (GD) is an inborn error, autosomal recessive lysosomal lipid storage disorder characterized by the lack of the enzyme glucocerebrosidase. We observed some abnormalities in the plasma of a traumatized patient with GD., Case Report: We report of a traumatized patient with GD that developed a severe systemic immune response during the course of an extended hospital stay. Plasma paraoxonase (PON) activity was assayed and found to be extremely low possibly due to the existence of GD in this particular patient. Also, a potentially novel post-translational modification (PTM) of albumin was noticed in the patient's plasma that coincided with enzyme replacement therapy (ERT) with Cerezyme., Conclusions: The decreased plasma PON activity measured might be a contributive factor in the development of an accentuated systemic immune response in a traumatized patient with GD. A modified albumin species could serve as a biomarker for ERT in Gaucher patients.

Introduction: Hypoalbuminemia is known to occur in critically ill patients and is associated with increased mortality. We observed a potentially novel, partial explanation for the hypoalbuminemia noticed in a severely traumatized patient., Case Report: We report of a severely, multi-system traumatized patient in whom hypoalbuminemia was present (1-2 g/dl). The plasma albumin (HSA) was analyzed by liquid chromatography/positive electrospray ionization mass spectrometry. A high percentage of a truncated albumin that lost its carboxy terminal amino acid leucine (HSA-L) associated with a 10-fold increase in plasma carboxypeptidase A (CPA) activity (R(2)=0.994) were found. We estimated the half life of this truncated albumin species to be <80 h., Conclusions: The increased CPA activity encountered following a traumatic event and subsequent rapid clearance of the resulting HSA-L from plasma might be a contributing factor to the hypoalbuminemia observed in the critically ill patients.

Objective: Human serum albumin is indicated for the treatment of shock, acute restoration of blood volume, and in hypoalbuminemia. Conflicting reports are found in the literature for the clinical safety and efficacy of human serum albumin administration to critically ill patients. We sought to analyze various commercially available albumin preparations for common, posttranslational modifications., Design: Analysis of six commercially available albumin preparations for clinical use., Setting: Trauma research laboratory., Subjects: Commercially available human serum albumin preparations and healthy volunteers., Interventions: Six commercially available human serum albumin preparations were analyzed by high-performance liquid chromatography. The presence of various posttranslational modifications was identified by positive electrospray ionization, time-of-flight mass spectrometry. Three different lots from three preparations were also analyzed to assess variability within lots from the same manufacturer. Also, for the purpose of comparison, human serum albumin was analyzed in the plasma of healthy volunteers., Measurements and Main Results: The six human serum albumin preparations analyzed contained a high percentage (57.2 +/- 3.3%) of bound Cys34 (oxidation of cysteine in position 34 on the human serum albumin molecule) in comparison to the plasma human serum albumin from healthy volunteers (22.9 +/- 4.8%). Lot-to-lot variability in native human serum albumin ranged between 4.8% and 11.2% in three separate commercial albumins. Significant differences existed among the various commercial preparations in other posttranslational modifications of albumin., Conclusions: Human serum albumin species with a bound Cys34 account for a large percentage of the composition of human serum albumin preparations used for the treatment of critically ill patients. Also, the variability within lots from the same manufacturer is significant. Consequences of the administration of these oxidized forms of human serum albumin to critically ill patients warrants further investigation.

The understanding of the importance of nutrition, particularly in the critically ill patient, is based on the known physiologic consequences of malnutrition. It includes respiratory muscle function, cardiac function, the coagulation cascade balance, electrolyte and hormonal balance, and renal function. Nutrition affects emotional and behavioral responses, functional recovery, and the overall cost of health care. The need to identify and treat the malnourished or potentially malnourished patient is a critical aspect of patient management. Much is known of catabolic and hypermetabolic state caused by trauma and burns. The response to injury needs to be mediated. There is much to learn about the intervention of that response through adjuvant nutritional therapy.