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Abstract: Introduction: Traumatic shock and hemorrhage (TSH) is a leading cause of preventable death in military and civilian populations. Using a TSH model, we compared plasma with whole blood (WB) as prehospital interventions, evaluating restoration of cerebral tissue oxygen saturation (CrSO 2 ), systemic hemodynamics, colloid osmotic pressure (COP) and arterial lactate, hypothesizing plasma would function in a noninferior capacity to WB, despite dilution of hemoglobin (Hgb). Methods: Ten anesthetized male rhesus macaques underwent TSH before randomization to receive a bolus of O(-) WB or AB(+) plasma at T0. At T60, injury repair and shed blood (SB) to maintain MAP > 65 mm Hg began, simulating hospital arrival. Hematologic data and vital signs were analyzed via t test and two-way repeated measures ANOVA, data presented as mean ± SD, significance = P < 0.05. Results: There were no significant group differences for shock time, SB volume, or hospital SB. At T0, MAP and CrSO 2 significantly declined from baseline, though not between groups, normalizing to baseline by T10. Colloid osmotic pressure declined significantly in each group from baseline at T0 but restored by T30, despite significant differences in Hgb (WB 11.7 ± 1.5 vs. plasma 6.2 ± 0.8 g/dL). Peak lactate at T30 was significantly higher than baseline in both groups (WB 6.6 ± 4.9 vs. plasma 5.7 ± 1.6 mmol/L) declining equivalently by T60. Conclusions: Plasma restored hemodynamic support and CrSO 2 , in a capacity not inferior to WB, despite absence of additional Hgb supplementation. This was substantiated via return of physiologic COP levels, restoring oxygen delivery to microcirculation, demonstrating the complexity of restoring oxygenation from TSH beyond simply increasing oxygen carrying capacity., Competing Interests: This work was funded by the Office of Naval Research (Work Unit Number: G1904). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. The authors report no conflict of interest., (Copyright © 2023 by the Shock Society.)

Background: Severe burn injury activates shock, inflammation, and blood cell system, but inappropriate reactions may lead to adverse outcomes. Soluble Fas ligand (sFasL) participates in apoptosis and inflammatory response. The circulating sFasL levels we investigated in association with the burn severity, shock, inflammation, blood cells, and mortality in patients with severe burns., Methods: A total of 56 patients with severe burns were recruited. The levels of sFasL and the biomarkers reflecting shock, organ damage, inflammation, and blood cells at 48 h postburn were analyzed. We compared the practical situation of patients that stratified by median sFasL levels and investigated the predictive value of sFasL for mortality., Results: High circulating sFasL levels were associated with the higher degrees of burn index, shock index, lactate, N-terminal probrain natriuretic peptide, total bilirubin, blood urea nitrogen, creatinine, tumor necrosis factor-α, interleukin-1β, interleukin-8, intercellular adhesion molecule 1, and complement 3, and the lower degrees of oxygenation index, lymphocytes, and platelets. Multiple linear regression analysis showed that the higher tumor necrosis factor-α (P < 0.001) and the lower oxygenation index (P = 0.031) and lymphocytes (P = 0.043) were associated with the higher sFasL. High sFasL (a unit is 50 ng/L) (odds ratio [OR] 5.50 [95% CI 1.04-29.20], P = 0.045) was an independent predictor of increased mortality by multivariate logistic regression analysis., Conclusions: High circulating sFasL at 48 h postburn in patients with severe burns reflect shock, proinflammatory response, organ damage, and lymphocyte reductions and predict 30-day mortality., (Copyright © 2021. Published by Elsevier Inc.)

Background: ABG samples are often obtained in trauma patients to assess shock severity. Venous blood gas (VBG) sampling, which is less invasive, has been widely used to assess other forms of shock. The study aim was to determine the agreement between VBG and ABG measurements in trauma., Methods: Patients were enrolled at an Australian trauma centre between October 2016 and October 2018. Bland-Altman limits of agreement (LOA) between paired blood gas samples taken <30 min apart were used to quantify the extent of agreement. The impact of using only VBG measurements was considered using an a priori plan. Cases where venous sampling failed to detect 'concerning levels' were flagged using evidence-based cut-offs: pH ≤7.2, base deficit (BD) ≤-6, bicarbonate <21 and lactate ≥4. Case summaries of these patients were assessed by independent trauma clinicians as to whether an ABG would change expected management., Results: During the study period 176 major trauma patients had valid paired blood gas samples available for analysis. The median time difference between paired measurements was 11 min (IQR 6-17). There was a predominance of men (81.8%) and blunt trauma (92.0%). Median Injury Severity Score was 13 (range 1-75) and inpatient mortality was 6.3%. Mean difference (ABG-VBG) and LOA between paired arterial and venous measurements were 0.036 (LOA -0.048 to 0.120) for pH, -1.27 mmol/L (LOA -4.35 to 1.81) for BD, -0.64 mmol/L (LOA -1.86 to 0.57) for lactate and -1.97 mmol/L (LOA -5.49 to 1.55) for bicarbonate. Independent assessment of the VBG 'false negative' cases (n=20) suggested an ABG would change circulatory management in two cases., Conclusions: In trauma patients VBG and ABG parameters displayed suboptimal agreement. However, in cases flagged as VBG 'false negative' independent review indicated that the availability of an ABG was unlikely to change management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Randomized clinical trials (RCTs) support the use of prehospital plasma in traumatic hemorrhagic shock, especially in long transports. The citrate added to plasma binds with calcium, yet most prehospital trauma protocols have no guidelines for calcium replacement. We reviewed the experience of two recent prehospital plasma RCTs regarding admission ionized-calcium (i-Ca) blood levels and its impact on survival. We hypothesized that prehospital plasma is associated with hypocalcemia, which in turn is associated with lower survival., Methods: We studied patients enrolled in two institutions participating in prehospital plasma RCTs (control, standard of care; experimental, plasma), with i-Ca collected before calcium supplementation. Adults with traumatic hemorrhagic shock (systolic blood pressure ≤70 mm Hg or 71-90 mm Hg + heart rate ≥108 bpm) were eligible. We use generalized linear mixed models with random intercepts and Cox proportional hazards models with robust standard errors to account for clustered data by institution. Hypocalcemia was defined as i-Ca of 1.0 mmol/L or less., Results: Of 160 subjects (76% men), 48% received prehospital plasma (median age, 40 years [interquartile range, 28-53 years]) and 71% suffered blunt trauma (median Injury Severity Score [ISS], 22 [interquartile range, 17-34]). Prehospital plasma and control patients were similar regarding age, sex, ISS, blunt mechanism, and brain injury. Prehospital plasma recipients had significantly higher rates of hypocalcemia compared with controls (53% vs. 36%; adjusted relative risk, 1.48; 95% confidence interval [CI], 1.03-2.12; p = 0.03). Severe hypocalcemia was significantly associated with decreased survival (adjusted hazard ratio, 1.07; 95% CI, 1.02-1.13; p = 0.01) and massive transfusion (adjusted relative risk, 2.70; 95% CI, 1.13-6.46; p = 0.03), after adjustment for confounders (randomization group, age, ISS, and shock index)., Conclusion: Prehospital plasma in civilian trauma is associated with hypocalcemia, which in turn predicts lower survival and massive transfusion. These data underscore the need for explicit calcium supplementation guidelines in prehospital hemotherapy., Level of Evidence: Therapeutic, level II.

Background aim: Reperfusion after hemorrhagic traumatic shock (HTS) is often associated with complications that are partly ascribed to the formation of reactive oxygen species (ROS). The aim of our study was to compare the effects of restrictive reperfusion (RR) to rapid full reperfusion (FR) on ROS formation and/or oxidative events., Materials and Methods: Anesthetized male rats were randomly subjected to HTS followed by FR (75 mL/kg/h) or RR (30 mL/kg/h for 40 min, followed by 75 mL/kg/h) with Ringer's solution (n = 8/group). Compartment-specific ROS formation was determined by infusion of ROS scavenger 1-hydroxy-3-carboxy-2,2,5,5-tetramethyl-pyrrolidine hydrochloride (CP-H) during resuscitation, followed by electron paramagnetic resonance spectroscopy. Sham-operated animals (n = 8) served as controls. The experiment was terminated 100 min post-shock., Results: Mean arterial pressure was significantly higher in the FR compared to the RR group during early reperfusion. Only RR animals, not FR animals, showed significantly higher ROS concentrations in erythrocytes (1951 ± 420 vs. 724 ± 75 AU) and in liver (474 ± 57 vs. 261 ± 21 AU) compared to sham controls. This was accompanied by elevated alanine aminotransferase and creatinine levels in RR animals compared to both shams and FR animals, while lipid peroxidation products (thiobarbituric acid reactive substances) were significantly increased only in the kidney in the FR group ( p < 0.05). RR animals showed significantly higher plasma peroxiredoxin-4 values when compared to the FR group (20 ± 2 vs. 14 ± 0.5 RLU)., Conclusion: Restrictive reperfusion after HTS is associated with increased ROS formation in erythrocytes and liver compared to sham controls. Moreover, the restrictive reperfusion is associated with a more pronounced injury to the liver and kidney, which is likely mediated by other than lipid peroxidation process and/or oxidative stress reactions.

Background: Deranged glucose metabolism after moderate to severe trauma with either high or low concentrations of blood glucose is associated with poorer outcome. Data on prehospital blood glucose concentrations and trauma are scarce., Objectives: The primary aim was to describe the relationship between traumatic shock and prehospital blood glucose concentrations. The secondary aim was to determine the additional predictive value of prehospital blood glucose concentration for traumatic shock when compared with vital parameters alone., Design: Retrospective analysis of the predefined, observational database of a nationwide Helicopter Emergency Medical Service (34 bases)., Setting: Emergency trauma patients treated by Helicopter Emergency Medical Service between 2005 and 2013 were investigated., Patients: All adult trauma patients (≥18 years) with recorded blood glucose concentrations were enrolled., Outcomes: Primary outcome: upper and lower thresholds of blood glucose concentration more commonly associated with traumatic shock. Secondary outcome: additional predictive value of prehospital blood glucose concentrations when compared with vital parameters alone., Results: Of 51 936 trauma patients, 20 177 were included. In total, 220 (1.1%) patients died on scene. Hypoglycaemia (blood glucose concentration 2.8 mmol l or less) was observed in 132 (0.7%) patients, hyperglycaemia (blood glucose concentration exceeding 15 mmol l) was observed in 265 patients (1.3%). Blood glucose concentrations more than 10 mmol l (n = 1308 (6.5%)) and 2.8 mmol l or less were more common in patients with traumatic shock (P < 0.0001). The Youden index for traumatic shock ((sensitivity + specificity) - 1) was highest when blood glucose concentration was 3.35 mmol l (P < 0.001) for patients with low blood glucose concentrations and 7.75 mmol l (P < 0.001) for those with high blood glucose concentrations. In logistic regression analysis of patients with spontaneous circulation on scene, prehospital blood glucose concentrations (together with common vital parameters: Glasgow Coma Scale, heart rate, blood pressure, breathing frequency) significantly improved the prediction of traumatic shock in comparison with prediction by common vital parameters alone (P < 0.0001)., Conclusion: In adult trauma patients, low and high blood glucose concentrations were more common in patients with traumatic shock. Prehospital blood glucose concentration measurements in addition to common vital parameters may help identify patients at risk of traumatic shock.

Background: During traumatic hemorrhage, the ability to identify shock and intervene before decompensation is paramount to survival. Lactate is extremely sensitive to shock, and its clearance has been demonstrated a useful gauge of shock and resuscitation status. Though lactate can be measured in the field, logistical constraints render it impractical in certain environments. The compensatory reserve represents a new clinical measurement reflecting the remaining capacity to compensate for hypoperfusion. We hypothesized the compensatory reserve index (CRI) would be an effective surrogate marker of shock and resuscitation compared to lactate., Methods: The CRI device was placed on consecutive patients meeting trauma center activation criteria and remained on the patient until discharge, admission, or transport to operating suite. All subjects had a lactate level measured as part of their routine admission metabolic analysis. Time-corresponding CRI and lactate values were matched in regards to initial and subsequent lactate levels. Mean time from lactate sample collection to data availability in the electronic medical record was calculated. Predictive capacity of CRI and lactate in predicting hemorrhage was determined by receiver-operator characteristic curve analysis. Correlation analysis was performed to determine if any association existed between changing CRI and lactate values., Results: Receiver-operator characteristic (ROC) curves were generated and area under the curve was 0.8052 and 0.8246 for CRI and lactate, respectively. There was no significant difference in each parameter's ability to predict hemorrhage (p = 0.8015). The mean duration from lactate sample collection to clinical availability was 44 minutes whereas CRI values were available immediately. Analysis of the concomitant change in serial CRI and lactate levels revealed a Spearman's correlation coefficient of -0.73 (p < 0.01)., Conclusion: CRI performed with equivalent predictive capacity to lactate with respect to identifying initial perfusion status associated with hemorrhage and subsequent resuscitation., Level of Evidence: Diagnostic, Level II.

Introduction: Arterial base excess is an established marker of shock and predictor of survival in trauma patients. However, venous blood is more quickly and easily obtained. This study aimed to determine if venous base excess could replace arterial base excess as a marker in trauma patients at presentation and if venous base excess is predictive of survival at 24 hours and one week., Methods: This was a prospective study of 394 trauma patients presenting to the emergency department of a tertiary hospital over a 17-month period. Data on base excess at presentation, vital signs, shock index (SI), injury severity score (ISS), and mortality at 24 hours and one week was collected and analysed., Results: Arterial and venous blood gas tests were performed on 260 and 134 patients, respectively. Patients were stratified into groups based on their SI and ISS for analysis. There was no statistical difference between mean venous blood gas and arterial blood gas levels at presentation when SI > 0.7, regardless of ISS (p > 0.05). The mortality rate was 4.57%. Both venous and arterial base excess was lower in nonsurvivors compared to survivors (p < 0.05). However, at 24 hours and one week, the difference in base excess values at presentation between survivors and nonsurvivors was greater when using venous base excess compared to arterial base excess (11.53 vs. 4.28 and 11.41 vs. 2.66, respectively)., Conclusion: In conclusion, venous base excess can replace arterial base excess in trauma patients as a means of identifying and prognosticating early shock., (Copyright © Singapore Medical Association.)

Background: The initiation of coagulation in trauma is thought to originate from exposed tissue factor (TF); recent data have led to the alternative hypothesis that damage-associated molecular patterns may contribute to postinjury coagulation. In acute traumatic coagulopathy, aberrant coagulation is mediated via the activated protein C (aPC) pathway; the upstream regulators of this process and its relation to TF remain uncharacterized. To examine the role of the TF pathway in mediating acute traumatic coagulopathy, we used specific antibody blockades in an established murine model of traumatic hemorrhagic shock, hypothesizing that both coagulation activation after injury and aPC-mediated coagulopathy are driven by TF via thrombin., Methods: Mice underwent an established model of trauma and hemorrhage and were subjected to either sham (vascular cannulation) or trauma-hemorrhage (cannulation, laparotomy, shock to mean arterial pressure of 35 mm Hg); they were monitored for 60 minutes before sacrifice. Mice in each group were pretreated with either targeted anti-TF antibody to block the TF pathway or hirudin for specific blockade of thrombin. Plasma was assayed for thrombin-antithrombin (TAT) and aPC by enzyme-linked immunosorbent assay., Results: Compared with controls, trauma-hemorrhage mice treated with anti-TF antibody had significantly reduced levels of TAT (2.3 ng/mL vs. 5.7 ng/mL, p = 0.016) and corresponding decreases in aPC (16.3 ng/mL vs. 31.6 ng/mL, p = 0.034), with reductions to levels seen in sham mice. Direct inhibition of thrombin yielded similar results, with reduction in aPC to levels below those seen in sham mice., Conclusion: In this study, blockade of the TF pathway led to the attenuation of both thrombin production and aPC activation observed in traumatic shock. Specific thrombin inhibition achieved similar results, indicating that aPC-related coagulopathy is mediated via thrombin activated by the TF pathway. The near-complete blockade of TAT and aPC observed in this model argues for a dominant role of the TF-thrombin pathway in both coagulation activation after injury and traumatic coagulopathy.

Background: Metabolic acidosis has been proposed as the gold standard to define shock in trauma patients. Other studies determine the presence of shock by use of serum lactate. However, not all medical centers have the ability to utilize point-of-care lactate at bedside., Objective: This study seeks to determine the relationship between serum lactate and metabolic acidemia in trauma patients, and if metabolic acidemia can be used to guide therapy. We hypothesized that acidemia would be strongly correlated with lactate levels and would be associated with activation of massive transfusion (MT) in the presence of shock in trauma., Methods: This was a prospective observational cohort study, level II evidence; this study aids in decision-making. Setting was a Level I academic, urban trauma center. The study took place from July 1, 2012 to March 1, 2013 and included patients who were ≥18 years old and required trauma team activation. Observations included baseline demographics (age, gender, type of injury), vital signs, point-of-care arterial blood gas, lactate, and need for MT., Results: One hundred patients were enrolled over the study period. The average age was 34 years, and 82% were male. Forty patients were acidemic (pH < 7.35), and there was a significant difference in lactate levels between the acidemic and non-acidemic groups (p < 0.002). We found a strong correlation between pH and lactate: rs = -0.38, t = -4.03, p < 0.001. In addition, using a logistic regression, we show that pH was associated with activation of MT (p = 0.002)., Conclusion: This is a prospective observational cohort study with level II evidence. This study demonstrates that acidemia was strongly correlated to serum lactate, lactate levels were higher in the acidemic group, and metabolic acidemia was associated with the activation of MT for trauma patients at our institution., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: There are two opposing possibilities for the main pathogenesis of trauma-induced coagulopathy: an acute coagulopathy of trauma shock and disseminated intravascular coagulation with the fibrinolytic phenotype., Objective: The objective of this study was to clarify the main pathogenesis of trauma-induced coagulopathy using a rat model of Noble-Collip drum trauma., Methods: Eighteen rats were divided into the control, trauma 0, and trauma 30 groups. The trauma 0 and 30 groups were exposed to Noble-Collip drum trauma. Blood samples were drawn without, immediately after, and 30 min after Noble-Collip drum trauma in the control, trauma 0, and trauma 30 groups, respectively. Coagulation and fibrinolysis markers were measured. Thrombin generation was assessed according to a calibrated automated thrombogram., Results: Spontaneous thrombin bursts resulting from circulating procoagulants were observed in the nonstimulated thrombin generation assay immediately after trauma. Soluble fibrin levels (a marker of thrombin generation in the systemic circulation) were 50-fold greater in the trauma groups than in the control group. The resultant coagulation activation consumed platelets, coagulation factors, and antithrombin. Endogenous thrombin potential and factor II ratio were significantly negatively correlated with antithrombin levels, suggesting insufficient control of thrombin generation by antithrombin. High levels of active tissue-type plasminogen activator induced hyperfibrin(ogen)olysis. Soluble thrombomodulin increased significantly. However, activated protein C levels did not change., Conclusions: The systemic thrombin generation accelerated by insufficient antithrombin control leads to the consumption of platelets and coagulation factors associated with hyperfibrin(ogen)olysis. These changes are collectively termed disseminated intravascular coagulation with the fibrinolytic phenotype.

Background: A wealth of evidence from animal experiments has indicated that hypertonic saline (HS) maybe a better choice for fluid resuscitation in traumatic hypovolemic shock in comparison with conventional isotonic saline. However, the results of several clinical trials raised controversies on the superiority of fluid resuscitation with HS. This meta-analysis was performed to better understand the efficacy of HS in patients with traumatic hypovolemic shock comparing with isotonic saline., Materials and Methods: According to the search strategy, we searched the PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials, which was completed on October 2013. After literature searching, two investigators independently performed the literature screening, assessment of quality of the included trials, and data extraction. Disagreements were resolved by consensus or by a third investigator if needed. The outcomes included mortality, blood pressure, fluid requirement, and serum sodium., Results: Six randomized controlled trials were included in the meta-analysis. The pooled risk ratio for mortality at discharge was 0.96 (95% confidence interval [CI], 0.82-1.14), whereas the pooled mean difference for the change in systolic blood pressure from baseline and the level of serum sodium after infusion was 6.47 (95% CI, 1.31-11.63) and 7.94 (95% CI, 7.38-8.51), respectively. Current data were insufficient to evaluate the effect of HS on the fluid requirement for the resuscitation., Conclusions: The present meta-analysis was unable to demonstrate a clinically important improvement in mortality after the HS administration. Moreover, we observed HS administration maybe accompanied with significant increase in blood pressure and serum sodium., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Trauma-induced coagulopathy (TIC) is present soon after injury and is associated with increased transfusion requirements and worse outcomes. The pathophysiological mechanisms, which result in the widespread derangements of hemostasis following major trauma hemorrhage, are as yet not fully defined. Profound activation of fibrinolytic pathways and fibrinogen depletion appear to be fundamental processes in the development of TIC and offer potential therapeutic targets. Collaborative and multi-disciplinary scientific study is thus a research priority in order to characterize the primary drivers of TIC and develop targeted and efficacious treatment strategies.

Introduction: We tested two hypotheses that disseminated intravascular coagulation (DIC) and acute coagulopathy of trauma-shock (ACOTS) in the early phase of trauma are similar disease entities and that the DIC score on admission can be used to predict the prognosis of patients with coagulopathy of trauma., Methods: We conducted a retrospective study of 562 trauma patients, including 338 patients whose data were obtained immediately after admission to the emergency department. We collected serial data for the platelet counts, global markers of coagulation and fibrinolysis, and antithrombin levels. DIC was diagnosed according to the Japanese Association for Acute Medicine (JAAM) DIC scoring system, and ACOTS was defined as a prothrombin-time ratio of >1.2., Results: The higher levels of fibrin/fibrinogen degradation products (FDP) and D-dimer and greater FDP/D-dimer ratios in the DIC patients suggested DIC with the fibrinolytic phenotype. The DIC patients with the fibrinolytic phenotype exhibited persistently lower platelet counts and fibrinogen levels, increased prothrombin time ratios, higher FDP and D-dimer levels, and lower antithrombin levels compared with the non-DIC patients on arrival to the emergency department and during the early stage of trauma. Almost all ACOTS patients met the criteria for a diagnosis of DIC; therefore, the same changes were observed in the platelet counts, global markers of coagulation and fibrinolysis, and antithrombin levels as noted in the DIC patients. The JAAM DIC score obtained immediately after arrival to the emergency department was an independent predictor of massive transfusion and death due to trauma and correlated with the amount of blood transfused., Conclusions: Patients who develop DIC with the fibrinolytic phenotype during the early stage of trauma exhibit consumption coagulopathy associated with increased fibrin(ogen)olysis and lower levels of antithrombin. The same is true in patients with ACOTS. The JAAM DIC score can be used to predict the prognosis of patients with coagulopathy of trauma.

Objective: To investigate the effects of necrostatin-1( Nec-1) on the liver of rats with trauma induced hemorrhagic shock., Methods: Trauma induced hemorrhagic shock model was produced by adopting the left femur, tibia fracture and soft tissue injury, bleeding and reperfusion in male Sprague-Dawley (SD) rats. A total of 22 rats were divided into model group and Nec-1 group with 11 rats in each group by randomized digital number method and the 72-hour mortality was observed. In addition, 72 rats were randomly divided into sham group, model group, Nec-1 group with 24 rats in each group. Rats in sham group were only received anesthesia, separating a nd ligating blood vessels, without trauma induced hemorrhagic and reperfusion, and the rats in Nec-1 group were received 1 mg/kg Nec-1 through femoral vein 5 minutes before reperfusion, and the rats in Nec-1 group were received the same amount of solvent. The serum and liver tissues of each group were collected at 2, 4, 8 hours after reperfusion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by automatic biochemistry analyzer. The pathology changes in liver were observed by hematoxylin-eosin (HE) staining. The mRNA expressions of tumor necrosis factor-α (TNF-α) and interleukin -1β (IL-1β) in the liver were determined by reverse transcription-polymerase chain reaction (RT-PCR). The protein expressions of receptor interaction of protease 1/3( RIP1/RIP3) were also assessed by Western blot analysis., Results: Compared to the model group, Nec-1 significantly reduced the 72 hour mortality [18.18% (2/11) vs. 63.64% (7/11), P = 0.040]. Two hours after trauma induced hemorrhagic shock and reperfusion, the expressions of ALT and AST in model group were significantly increased compared with those in sham group. [ ALT (U/L): 110.21 ± 22.32 vs. 80.98 ± 19.94, AST (U/L): 364.29 ± 64.83 vs. 279.76 ± 70.64, both P<0.05], and reached the peak at 8 hours [ALT (U/L): 387.41± 47.11 vs. 82.76 ±22.44, AST ( U/L): 973.35 ±77.51 vs.261.49 ± 52.03, both P <0.01]. Levels of serum ALT and AST in NEc-1 group were significantly decreased compared with model group [ALT (U/L) 4 hours: 144.64 ± 33.79 vs. 213.96 ± 36.21, 8 hours: 159.48 ± 43.57 vs. 387.41>11; AST (U/L): 4 hours: 398.78 ± 59.48 vs. 630.61 ± 59.93, 8 hours: 427.38 ± 80.75 vs. 973.35 ± 77.51, all P < 0.01] Under light microscopy, it was noted that the hepatic sinus expansion, liver cells degeneration, necrosis, as well as infiltration of abundant inflammatory cells were observed. But the pathology changes in hepatic tissues were significantly mitigated in Nec-1 group. Along with the time extension, the mRNA expressions of TNF-α and IL-β and the protein expressions of RIP1 and RIP3 were markedly up-regulated. Compared with model group, difference in the mRNA expressions of TNF-α and IL-β in hepatic tissues in Nec-1 group were statistically significant, and the most obvious difference was at 8 hours [TNF-α mRNA: 1.457 ± 0.081 vs. 2.317 ± 0.062, IL-β mRNA: 0.690 ± 0.087 vs. 1.812 ± 0.112, both P<0.01]. But there was no statistically significant difference in RIP1 and RIP3 between Nec-1 group and model group [RIP1 protein 8 hours: 0.561 ± 0.033 vs. 0.587 ± 0.036, RIP3 protein 8 hours: 0.976 ± 0.040 vs. 1.044 ± 0.115, both P > 0.05]., Conclusion: Nec-1 may be remarkable protect effect on the liver of rats with trauma induced hemorrhage shock and reperfusion, and the intrinsic mechanisms need further investigation.

Background: We tested the hypotheses that an increase in systemic thrombin activity occurs in both disseminated intravascular coagulation (DIC) with the fibrinolytic phenotype and in acute coagulopathy of trauma shock (ACoTS), and that the patients diagnosed as having ACoTS overlap or are identical with those diagnosed as having DIC., Methods: We made a prospective study of 57 trauma patients, including 30 patients with DIC and 27 patients without DIC. Patients with ACoTS, defined as a prothrombin time ratio >1.2, were also investigated. We included 12 healthy volunteers as controls. The levels of soluble fibrin, antithrombin, prothrombinase activity, soluble thrombomodulin, and markers of fibrin(ogen)olysis were measured on days 1 and 3 after the trauma. The systemic inflammatory response syndrome and the Sequential Organ Failure Assessment were scored to evaluate the extent of inflammation and organ dysfunction., Results: Patients with DIC showed more systemic inflammation and greater Sequential Organ Failure Assessment scores and were transfused with more blood products than the patients without DIC. On day 1, normal prothrombinase activity, increased soluble fibrin, lesser levels of antithrombin, and increased soluble thrombomodulin were observed in patients with DIC in comparison with controls and non-DIC patients. These changes were more prominent in patients with DIC who met the overt criteria for DIC established by the International Society on Thrombosis and Haemostasis. Multiple regression analysis showed that antithrombin is an independent predictor of high soluble fibrin in DIC patients. Greater levels of fibrin and fibrinogen degradation products, D-dimer, and the fibrin and fibrinogen degradation products/D-dimer ratio indicated increased fibrin(ogen)olysis in DIC patients. Almost all ACoTS patients overlapped with the DIC patients. The changes in the measured variables in ACoTS patients coincided with those in DIC patients., Conclusion: Normal prothrombinase activity and insufficient control of coagulation give rise to systemic increase in thrombin generation and its activity in patients with DIC with the fibrinolytic phenotype at an early phase of trauma. The same is true in patients with ACoTS, and shutoff of thrombin generation was not observed., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Haemorrhagic shock remains a leading cause of death in trauma patients. The concept of haematologic damage control is gradually taking place in the management of traumatic haemorrhagic shock. It is based primarily on the early implementation of a quality blood transfusion involving erythrocytes, plasmas and platelets transfusion. Red blood cell transfusion is mainly supported by the oxygen carrier properties of erythrocytes. However, it appears that erythrocytes ability to modulate the bioavailability of nitric oxide (NO) plays a major role in capillary opening and perfusion. Erythrocytes are also actively involved in the processes of hemostasis and coagulation. In this context, it seems difficult to define a threshold of hemoglobin concentration to determine the implementation of a blood transfusion in traumatic haemorrhagic shock., (Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.)

Background: Trauma centers are increasingly advocating the replacement of arterial blood gas measurements with venous blood gas measurements for simplification of base deficit (BD) determination. These values have never been demonstrated to agree in important trauma populations, such as for patients in occult shock (OS) or the elderly. The goal of this study was to investigate the level of agreement between venous and arterial BDs from blood gases in critically ill or injured patients, specifically in OS and the elderly., Methods: This is a retrospective, consecutive, cohort study using matched pairs of venous and arterial blood gases from patients admitted to the Trauma and Neurosurgery Intensive Care Unit in a Level I trauma center in Toronto, Ontario, Canada. Agreement between near simultaneous arterial and venous BD was calculated using the Bland-Altman method. McNemar's test was used for differences in BDs in the presence or absence of OS and in elderly patients., Results: BDs for 466 arterial and venous samples from 72 patients were compared pairwise. There was no significant difference between samples (p = 0.88). Ninety-eight percent of samples were within 3.0 mmol/L of each other. No significant differences were detected between venous and arterial BD in the presence of OS or in the elderly (p = 0.72 and p = 0.25, respectively)., Conclusion: Arterial and venous BDs agree, including in the presence of OS and in the elderly. Consideration may be given to venous sampling both in the intensive care unit or in other areas of care, such as the trauma bay., Level of Evidence: Diagnostic study, level III.

Background: Normally, end-tidal CO(2) is within 2 mm Hg of arterial PO(2) (PaCO(2)). However, if dead space in the lungs increases owing to shock with poor lung perfusion, the arterial-end tidal PCO(2) difference [P(a-ET)CO(2)] increases. We have found that in severely injured patients, P(a-ET)CO(2) of less than 10 mm Hg is associated with survival and P(a-ET)CO(2) of greater than 16 mm Hg is usually fatal. Our initial studies suggested that intravenously administered bicarbonate increases P(a-ET)CO(2)., Methods: This retrospective therapeutic study evaluated the effects of intravenously administered bicarbonate in a cohort of 225 severely acidotic (arterial pH ≤ 7.10) trauma patients who underwent emergency surgery from 1989 through 2011. Patients were divided into groups: early deaths (<48 hours), deaths in the operating room, deaths within 48 hours, and survivors. Winter's formula was defined as PaCO(2) = (HCO(3)) (1.5) + 8 ± 4., Results: Of the 225 patients, the mean (SD) initial arterial pH was 6.92 (0.16) with HCO(3) of 11.0 (3.5) mEq/L. According to the Winter's formula, PaCO(2) should have been 24 (4) mm Hg but actually was 50 (14) mm Hg. In 73 patients, the effect of an average of two to eight vials of bicarbonate increased HCO(3) from 10.5 (3.1) mEq/L to 16.8 (4.0) mEq/L. In addition, PaCO(2) increased from 44 (9) mm Hg to 51 (11) mm Hg and end-tidal CO(2) stayed relatively constant (26 [6] to 25 [5]). This resulted in a increase in P(a-ET)CO(2) from 17 (9) mm Hg to 24 (13) mm Hg, affecting survival. In the final values after resuscitation, the P(a-ET)CO(2) in the 75 patients who survived was 10 (6) mm Hg, while the 103 patients who died in the operating room or within 48 hours of surgery had a P(a-ET)CO(2) of 23 (10) mm Hg (p < 0.001)., Conclusion: In severely acidotic, critically injured patients, reducing the PaCO(2) to less than 40 mm Hg and decreasing the P(a-ET)CO(2) to 10 (6) mm Hg should be attempted, using as little HCO(3) therapy as possible. Bicarbonate should be given only if severe acidosis persists despite resuscitation and if PaCO(2) levels near those which are appropriate can be obtained., Level of Evidence: Therapeutic study, level IV.

Background: Bone marrow dysfunction is common in severely injured trauma patients, with release of hematopoietic progenitor cells (HPC) into the peripheral blood. Granulocyte colony stimulating factor (G-CSF) is a potent stimulator of HPC mobilization. We hypothesized that plasma G-CSF levels are elevated after trauma and correlate with postinjury anemia and infection., Study Design: Blood from 83 severely injured patients was collected at several time points for determination of G-CSF levels and HPC mobilization and compared with that from healthy volunteers. Data were categorized by age, sex, Injury Severity Score (ISS), and whether the patient was in shock. Hemoglobin and transfusion requirements and hospital-acquired infection data were recorded. Data are expressed as mean ± SEM., Results: After trauma, there is a 50-fold increase in plasma levels of G-CSF in trauma patients compared with controls (1,640.4 ± 304.3 pg/mL vs 33.0 ± 6.8 pg/mL, p < 0.001). Patients who presented in shock had 5-times higher G-CSF levels than nonshock trauma patients and a 75-fold increase compared with controls (2,528.7 ± 536.4 pg/mL vs 728.0 ± 191.0 pg/mL vs 33.0 ± 6.8 pg/mL, p < 0.001). Age, sex, and ISS had no effect on G-CSF levels. Mobilization of HPC was sustained for up to 10 days after injury and involved multiple cells types. Higher G-CSF levels were also associated with lower hemoglobin levels and greater transfusion requirements 3 weeks after injury and a higher incidence of hospital-acquired pneumonia and bacteremia., Conclusions: Plasma G-CSF is markedly elevated after injury and is greater in patients who present in shock. The rise in G-CSF was also associated with prolonged mobilization of HPC. Elevation of G-CSF in humans after severe trauma may play a significant role in the development of post-traumatic bone marrow dysfunction, anemia, and infection., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The level of soluble vascular endothelial growth factor receptor 1 (sVEGFR1) is increased in sepsis and strongly associated with disease severity and mortality. Endothelial activation and damage contribute to both sepsis and trauma pathology. Therefore, this study measured sVEGFR1 levels in trauma patients upon hospital admission hypothesizing that sVEGFR1 would increase with higher injury severity and predict a poor outcome., Methods: Prospective observational study of 80 trauma patients admitted to a Level I Trauma Centre. Data on demography, biochemistry, Injury Severity Score (ISS), transfusions and 30-day mortality were recorded and plasma/serum (sampled a median of 68 min (IQR 48-88) post-injury) was analyzed for sVEGFR1 and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue injury (histone-complexed DNA fragments, hcDNA), endothelial activation and damage (von Willebrand Factor Antigen, Angiopoietin-2, soluble endothelial protein C receptor, syndecan-1, soluble thrombomodulin (sTM)), coagulation activation/inhibition and fibrinolysis (prothrombinfragment 1 + 2, protein C, activated Protein C, tissue-type plasminogen activator, plasminogen activator inhibitor-1, D-dimer) and inflammation (interleukin-6). Spearman correlations and regression analyses to identify variables associated with sVEGFR1 and its predictive value., Results: Circulating sVEGFR1 correlated with injury severity (ISS, rho = 0.46), shock (SBE, rho = -0.38; adrenaline, rho = 0.47), tissue injury (hcDNA, rho = 0.44) and inflammation (IL-6, rho = 0.54) (all p < 0.01) but by multivariate linear regression analysis only lower SBE and higher adrenaline and IL-6 were independent predictors of higher sVEGFR1. sVEGFR1 also correlated with biomarkers indicative of endothelial glycocalyx degradation (syndecan-1, rho = 0.67), endothelial cell damage (sTM, rho = 0.66) and activation (Ang-2, rho = 0.31) and hyperfibrinolysis (tPA, rho = 0.39; D-dimer, rho = 0.58) and with activated protein C (rho = 0.31) (all p < 0.01). High circulating sVEGFR1 correlated with high early and late transfusion requirements (number of packed red blood cells (RBC) at 1 h (rho = 0.27, p = 0.016), 6 h (rho = 0.27, p = 0.017) and 24 h (rho = 0.31, p = 0.004) but was not associated with mortality., Conclusions: sVEGFR1 increased with increasing injury severity, shock and inflammation early after trauma but only sympathoadrenal activation, hypoperfusion, and inflammation were independent predictors of sVEGFR1 levels. sVEGFR1 correlated strongly with other biomarkers of endothelial activation and damage and with RBC transfusion requirements. Sympathoadrenal activation, shock and inflammation may be critical drivers of endothelial activation and damage early after trauma.

Background: After severe trauma and hemorrhage, it is generally assumed that the rate of fluid shift from the interstitial space into the vasculature is relatively slow and that initial hematocrit (Hct) does not reflect estimated blood loss. This study challenges that idea and tests the hypothesis that initial Hct correlates with signs of shock and hemorrhage in trauma patients., Methods: Data were retrospectively reviewed from 198 trauma patients requiring emergency surgery at a Level I center from July 2009 to April 2010. Patients were divided into quartiles based on the initial Hct measured within 10 minutes of arrival. Categorical data were compared using χ(2) test or Fisher's exact test, as appropriate. Normally distributed data were compared using Student's t test or analysis of variance. Nonparametric data were compared with a Mann-Whitney U test or Kruskal-Wallis test. Post hoc analysis was conducted using the Bonferroni correction or paired Mann-Whitney U tests., Results: The study population was 83% male, aged 35 ± 1 years (mean ± SE), with 71% penetrating injuries. Lower initial Hct correlated with hypotension (p < 0.001), acidosis (p = 0.003), altered mental status (p < 0.001), Injury Severity Score (p < 0.001), Revised Trauma Score (p < 0.001), estimated blood loss (p < 0.001), and usage of packed red blood cells (p < 0.001), fresh frozen plasma (p = 0.003), crystalloid (p = 0.021), and vasopressors (p < 0.001)., Conclusion: Admission Hct correlates with signs of shock and hemorrhage in trauma patients requiring emergency surgery because fluid shifts rapidly from the interstitial space into the vasculature. This finding of a rapid Hct change contradicts the current teaching in most trauma textbooks.

Background: Arterial base deficit (ABD) measurement is a standard test for assessment of the trauma patient's metabolic response to shock. Venous blood is readily available earlier during the trauma resuscitation. The aim of this study is to analyze the difference (correlation, agreement, clinical significance) between the first peripheral venous base deficit (pVBD) and the first ABD during trauma resuscitation., Methods: Consecutive trauma patients >18 years presenting to John Hunter Hospital (JHH), Newcastle, Australia, from January 2007 until July 2007 requiring arterial blood gas sampling had a peripheral venous blood gas performed simultaneously. A survey of JHH trauma clinicians and members of the American Association for the Surgery of Trauma was performed to determine a clinically relevant difference between two serial base deficit measurements. Pearson correlation and Bland-Altman tests were performed., Results: During the 7-month period, 127 patients (79% men, mean age, 46.3 [±18.4 years] and median injury severity score of 15 [interquartile range, 8-23; range, 1-75]) were included into the study. The average peripheral ABD (pABD) and pVBD were -2.2 mmol/L±3.8 mmol/L and -1.3 mmol/L±3.8 mmol/L, respectively. The average difference between measurements was 0.9 (range, -1.7 to +3.5; 95% confidence interval, 0.7-1.0) with pVBD>pABD. The Pearson test showed highly significant correlation (r=0.97, p<0.0001). The survey of 11 JHH and 56 American Association for the Surgery of Trauma clinicians determined 2 mmol/L as clinically relevant difference between two base deficit measurements. All individual paired sample's difference sat within the clinically relevant limits and>95% (121 of 127) of samples sat within the 1.96 standard deviation acceptable by the Bland-Altman plot., Conclusion: There is near perfect correlation and clinically acceptable agreement between pABD and pVBD values on simultaneous testing. pVBD is an acceptable test to assess trauma patients' initial metabolic status when occult blood loss suspected.

A significant proportion of severely injured patients develop early coagulopathy, characterized by abnormal clot formation, which impairs resuscitation and increases mortality. We have previously demonstrated an isolated decrease in clot strength by thrombelastography in a swine model of nonresuscitated traumatic shock. In order to more closely examine platelet-fibrin interactions in this setting, we define the observed decrease in clot strength in terms of platelet-induced clot contraction and clot elastic modulus using the Hemostasis Analysis System (HAS) (Hemodyne Inc., Richmond, Virginia, USA). Whole blood was sampled for HAS measurements, metabolic measurements, cell counts, and fibrinogen concentration at baseline prior to injury and again at a predetermined level of traumatic shock defined by oxygen debt. Male swine (N=17) received femur fracture and controlled arterial hemorrhage to achieve an oxygen debt of 80 ml/kg. Platelet counts were unchanged, but fibrinogen concentration was reduced significantly during shock (167.6 vs. 66.7 mg/dl, P=0.0007). Platelet contractile force generated during clot formation did not change during shock (11.7 vs. 10.4 kdynes, P=0.41), but clot elastic modulus was dynamically altered, resulting in a lower final value (22.9 vs. 17.3 kdynes/cm, P<0.0001). In this model of traumatic shock, platelet function was preserved, whereas terminal clot elastic modulus was reduced during shock in a manner most consistent with early changes in the mechanical properties of the developing fibrin fiber network.

Background: Logistics complicate fluid resuscitation of traumatic shock on the battlefield. Traumatic shock can result in oxygen debt (O(2)D) accumulation that is fatal. However, the ability of fluid strategies to repay O(2)D are not commonly reported. This pilot study examined various resuscitation fluids, including a combination of PEGylated bovine hemoglobin and hypertonic saline (AfterShock™) on their ability to repay O(2)D in traumatic shock., Methods: 41 anesthetized swine underwent hemorrhage to an O(2)D of 80 mL/kg. Animals received one of the following: 500 mL whole blood, 500 mL AfterShock™, 500 mL hypertonic (7.2%) saline, 250 mL hypertonic (7.2%) saline, 500 mL Hetastarch (6%), or 500 mL lactated Ringer's. Oxygen transport variables (O(2)D, oxygen consumption, oxygen delivery, central venous hemoglobin oxygen saturation, oxygen extraction ratios), lactate clearance, and survival were monitored for 3h after treatment. Data were analyzed using mixed-model ANOVA and comparisons were made to the performance of whole blood., Results: Only animals receiving AfterShock™, 500 mL hypertonic saline, and 500 mL Hetastarch survived to 180 min. While not statistically significant AfterShock™ demonstrated trends in improving the repayment of O(2)D and in improving oxygen transport variables despite having lower levels of global oxygen delivery compared to whole blood, Hetastarch and 500 mL hypertonic saline groups., Conclusion: Use of 500 mL AfterShock™, 500 mL of 7.2% saline or 500 mL of Hetastarch resulted in improved short-term survival. While not statistically significant, AfterShock™ demonstrated trends in improving O(2)D. These findings may have implications for designing resuscitation fluids for combat casualty care., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The strategy for correction of metabolic acidosis and coagulation profile disorders in severe traumatic shock was adduced. There was established, that severe traumatic shock is characterized by prominent metabolic acidosis, the bases deficiency reduction, the lactate content in arterial blood enhancement, as well as ionized calcium in the blood serum, significant enhancement of the partially activated thromboplastin time and protrombin time, what witnesses the prominent coagulation disorders presence on the metabolic acidosis background. The "Soda-buffer" (manufactured by "Yuriya Pharm", Ukraine) preparation application in a complex of infusion-transfusion therapy permits in early terms to correct effectively the metabolic acidosis and coagulopathy signs in the injured persons, suffering severe trauma. Effective correction of metabolic acidosis and disorders of coagulation profile permits to lower trustworthily the erythrocytic mass volume transfused as well as fresh-frozen plasm while the infusion-transfusion therapy conduction.

Introduction: It is debated whether early trauma-induced coagulopathy (TIC) in severely injured patients reflects disseminated intravascular coagulation (DIC) with a fibrinolytic phenotype, acute coagulopathy of trauma shock (ACoTS) or yet other entities. This study investigated the prevalence of overt DIC and ACoTS in trauma patients and characterized these conditions based on their biomarker profiles., Methods: An observational study was carried out at a single Level I Trauma Center. Eighty adult trauma patients (≥18 years) who met criteria for full trauma team activation and had an arterial cannula inserted were included. Blood was sampled a median of 68 minutes (IQR 48 to 88) post-injury. Data on demography, biochemistry, injury severity score (ISS) and mortality were recorded. Plasma/serum was analyzed for biomarkers reflecting tissue/endothelial cell/glycocalyx damage (histone-complexed DNA fragments, Annexin V, thrombomodulin, syndecan-1), coagulation activation/inhibition (prothrombinfragment 1+2, thrombin/antithrombin-complexes, antithrombin, protein C, activated protein C, endothelial protein C receptor, protein S, tissue factor pathway inhibitor, vWF), factor consumption (fibrinogen, FXIII), fibrinolysis (D-dimer, tissue-type plasminogen activator, plasminogen activator inhibitor-1) and inflammation (interleukin (IL)-6, terminal complement complex (sC5b-9)). Comparison of patients stratified according to the presence or absence of overt DIC (International Society of Thrombosis and Hemostasis (ISTH) criteria) or ACoTS (activated partial thromboplastin time (APTT) and/or international normalized ratio (INR) above normal reference)., Results: No patients had overt DIC whereas 15% had ACoTS. ACoTS patients had higher ISS, transfusion requirements and mortality (all P < 0.01) and a biomarker profile suggestive of enhanced tissue, endothelial cell and glycocalyx damage and consumption coagulopathy with low protein C, antithrombin, fibrinogen and FXIII levels, hyperfibrinolysis and inflammation (all P < 0.05). Importantly, in non-ACoTS patients, apart from APTT/INR, higher ISS correlated with biomarkers of enhanced tissue, endothelial cell and glycocalyx damage, protein C activation, coagulation factor consumption, hyperfibrinolysis and inflammation, that is, resembling that observed in patients with ACoTS., Conclusions: ACoTS and non-ACoTS may represent a continuum of coagulopathy reflecting a progressive early evolutionarily adapted hemostatic response to the trauma hit and both are parts of TIC whereas DIC does not appear to be part of this early response.

Background: Clot strength by Thrombelastography (TEG) is associated with mortality during trauma and has been linked to severity of tissue hypoperfusion. However, the optimal method for monitoring this important relationship remains undefined. We hypothesize that oxygen transport measurements will be associated with clot strength during traumatic shock, and test this hypothesis using a swine model of controlled traumatic shock., Methods: N = 33 swine were subjected to femur fracture and hemorrhagic shock by controlled arterial bleeding to a predetermined level of oxygen debt measured by continuous indirect calorimetry. Hemodynamics, oxygen consumption, systemic central venous oxygenation (ScvO₂), base excess, lactate, and clot maximal amplitude by TEG (TEG-MA) as clot strength were measured at baseline and again when oxygen debt = 80 ml/kg during shock. Oxygen transport and metabolic markers of tissue perfusion were then evaluated for significant associations with TEG-MA. Forward stepwise selection was then used to create regression models identifying the strongest associations between oxygen transport and TEG-MA independent of other known determinants of clot strength., Results: Multiple markers of tissue perfusion, oxygen transport, and TEG-MA were all significantly altered during shock compared to baseline measurements (p < 0.05). However, only ScvO₂ demonstrated a strong bivariate association with TEG-MA measured during shock (R = 0.7, p < 0.001). ScvO₂ measured during shock was also selected by forward stepwise selection as an important covariate in linear regression models of TEG-MA after adjusting for the covariates fibrinogen, pH, platelet count, and hematocrit (Whole model R² = 0.99, p ≤ 0.032)., Conclusions: Among multiple measurements of oxygen transport, only ScvO₂ was found to retain a significant association with TEG-MA during shock after adjusting for multiple covariates. ScvO₂ should be further studied for its utility as a clinical marker of both tissue hypoxia and clot formation during traumatic shock.

Clinically relevant animal models capable of simulating traumatic hemorrhagic shock are needed. We developed a hemorrhagic shock model with male New Zealand rabbits (2200-2800 g, 60-70 days old) that simulates the pre-hospital and acute care of a penetrating trauma victim in an urban scenario using current resuscitation strategies. A laparotomy was performed to reproduce tissue trauma and an aortic injury was created using a standardized single puncture to the left side of the infrarenal aorta to induce hemorrhagic shock similar to a penetrating mechanism. A 15-min interval was used to simulate the arrival of pre-hospital care. Fluid resuscitation was then applied using two regimens: normotensive resuscitation to achieve baseline mean arterial blood pressure (MAP, 10 animals) and hypotensive resuscitation at 60% of baseline MAP (10 animals). Another 10 animals were sham operated. The total time of the experiment was 85 min, reproducing scene, transport and emergency room times. Intra-abdominal blood loss was significantly greater in animals that underwent normotensive resuscitation compared to hypotensive resuscitation (17.1 ± 2.0 vs 8.0 ± 1.5 mL/kg). Antithrombin levels decreased significantly in normotensive resuscitated animals compared to baseline (102 ± 2.0 vs 59 ± 4.1%), sham (95 ± 2.8 vs 59 ± 4.1%), and hypotensive resuscitated animals (98 ± 7.8 vs 59 ± 4.1%). Evidence of re-bleeding was also noted in the normotensive resuscitation group. A hypotensive resuscitation regimen resulted in decreased blood loss in a clinically relevant small animal model capable of reproducing hemorrhagic shock caused by a penetrating mechanism.

Background: Decreased red blood cell (RBC) deformability and activation of neutrophils (polymorphonuclear leukocytes [PMN]) after trauma-hemorrhagic shock (T/HS) have been implicated in the development of multiple organ dysfunction. Experimentally, female animals seemed to be protected from the effects of T/HS, at least in part, because of elevated estrogen levels. Thus, we examined the relative role of estrogen receptor (ER)-alpha and -beta in this protective response., Methods: To accomplish this goal, RBC deformability and neutrophil respiratory burst activity were measured in several groups of hormonally intact or ovariectomized (OVX) female rats subjected to T/HS (laparotomy plus hemorrhage to an MAP of 30 mm Hg to 35 mm Hg for 90 minutes) or trauma-sham shock (T/SS) and 3 hours of reperfusion. These groups included rats receiving vehicle, estradiol, or either an ER-alpha agonist or an ER-beta agonist administered at the end of the shock period just before volume resuscitation., Results: RBC deformability and neutrophil activation were similar among all the T/SS groups and were not different from that observed in the non-OVX female rats subjected to T/HS. In contrast, RBC deformability was reduced and neutrophil activation was increased in the OVX, T/HS female rats as compared with the T/SS groups or the non-OVX, T/HS rats. The administration of estrogen to the T/HS, OVX rats returned RBC and neutrophil function to normal. Both the ER-alpha and -beta agonist partially, but not completely, protected the OVX rats from T/HS-induced loss of RBC deformability, whereas only the ER-beta agonist prevented the increase in neutrophil activation., Conclusions: The protective effects of estrogen on T/HS-induced RBC deformability are mediated, at least in part, via activation of both ER-alpha and -beta, whereas ER-beta activation is involved in limiting T/HS-induced neutrophil activation.

There were examined 40 patients with traumatic shock and 10 healthy blood-donor (1-st group). The patients were divided into two groups: patients with traumatic shock based on standard program of intensive therapy and patients with traumatic shock based on standard program of intensive therapy plus Plaferone LB. The blood test was made on 1st and 5th day of stationary treatment. TNF-alpha was examined in blood plasma by immunophermetic method and NO, FeS-NO by electro-paramagnetic resonance method. It was revealed, that Plapherone LB has no affect on TNF-alpha concentration, but it modulates NO concentration.

The results of the study lead to the conclusion that the development of burn disease in children is accompanied by significant lymphocytic structural metabolic changes that determine the functional capabilities of cells and the immune system as a whole. There is an evident activation of the glutathione antioxidant system, a drastic activation of enzymes that ensure Krebs cycle reactions, as well as activation of anaerobic processes. The above changes are mainly caused by the activated sympathoadrenal system that is characteristic of stresses. The knowledge about the metabolic mechanisms responsible for the development of cellular reactions to burn shock and burn disease permits specification of the elements of the pathogenesis of these severe conditions and substantiation of the possibility of using metabolic correction in the complex treatment of children with the above pathology.

The time course of changes in oxygen and acid-base homeostatic parameters was studied in children with grades 1, 2, 3, and 4 traumatic shock. The directionality of changes was ascertained in oxygen and acid-base balance and the influence of hemodynamic, hemocoagulation, hemorheological, and energy-generating functions in the destabilization of oxygen and acid-base homeostatic parameters were established. A package of medical measures that promote improved oxygen and acid-base balance in children with traumatic shock is stated.

Objective: To investigate the effect of Soluvit on stress reaction and leucocyte function in serious burn patients in shock stage., Methods: Eighty-seven serious burn patients, who did not undergo operation, were divided into Soluvit treatment group and control group randomly. Patients in Soluvit treatment group were treated with two bottles of Soluvit everyday from postburn 1 st to 14 th day. Patients in control group were given 500 ml normal saline infusion instead. Blood samples were collected for determination of cortisol and malondialdehyde every 4 hours on postburn 1 st day. Leucocyte were isolated for testing chemotaxis distance and phagocytic power on postburn 7 th and 14 th day respectively., Results: The serum cortisol contents in serious burn patients were significantly elevated at 2-4 hours after treatment in Soluvit treatment and control groups. Serum cortisol and malondialdehyde levels were higher than normal values in all serious burn patients in shock stage at 10-12 hours after treatment. But the changes of serum cortisol and malondialdehyde in Soluvit treatment group were all lower than those in control group at 10-48 and 14-48 hours after treatment, respectively (all P<0.05). Leucocyte chemotaxis distance in Soluvit treatment group was longer than that in control group on both postburn 7 th and 14 th day (P<0.05 and P<0.01). In contrast, there were no significant differences in phagocytic power between two groups (both P>0.05)., Conclusion: Above results suggest that Soluvit can mitigate stress reaction and lipid peroxidation action, but enhance leucocyte chemotaxis function in severe burn patients.

We have recently shown that during the acute phase, postburn female pediatric burn patients had significantly increased levels of anabolic hormones with an associated decreased hypermetabolism leading to a significant shorter intensive care unit stay compared with male patients. The aim of the present study was to determine possible differences between girls and boys in body composition, hypermetabolism, and hormone pattern in the long term. Sixty-two children (1-16 years old) who sustained a severe thermal injury (>or=40% total body surface area) were included into the study. Patients were further divided into girls (n = 22) and boys (n = 40). Patient demographics, nutritional support, and mortality were noted. Resting energy expenditure (REE) was measured by indirect calorimetry, body composition by dual-energy x-ray absorptiometry (Hologic Inc, Waltham, Mass) at discharge, 3, 6, 9, 12, 18, and 24 months after burn. In addition, blood was drawn at the same time points, and serum hormones were measured. There were no significant differences between girls and boys for demographics, nutritional intake, or concomitant injuries. Predicted REE was significantly decreased in girls at discharge, 6, 12, and 18 months postburn (P < 0.05). Dual-energy x-ray absorptiometry scan showed that girls had improved change in bone mineral content and percent fat compared with boys (P < 0.05). There were no differences in changes in height, body weight, lean body mass, and total fat between groups. Girls had significantly higher levels of insulinlike growth factor 1, insulinlike growth factor binding protein 3, free thyroxine index, T4, and insulin when compared with boys (P < 0.05). No differences were found for T3 uptake, osteocalcin, cortisol, growth hormone, and parathyroid hormone (PTH) between groups. Data indicate that girls have a reduced REE associated with changes in bone content and endogenous anabolic hormones.

Our previous studies confirmed the phenomenon of burn depth progression despite adequate Parkland formula resuscitation [Kim et al. J Burn Care Rehabil 2001;22960:406-6]. Repetitive ischemia-reperfusion injury (I-R) is a plausible explanation and is suggested by the concomitant swings we have observed in serum base deficit (BD) during resuscitation from burn shock. We chose to explore whether laser Doppler imaging (LDI) evidence of burn depth progression mirrored cycles of I-R (episodic swings in continuously measured BD). Positive findings would support the hypothesis that repetitive episodes of I-R is a factor in burn depth progression despite apparently adequate resuscitation. A total of 14 patients with severe life-threatening burns (median 51% TBSA) underwent continuous BD monitoring using a Paratrend 7 (Malvern PA) during 48 hours of resuscitation. Fluid needs were estimated using the Parkland formula, then were titrated to urine output. The slopes of BD changes were then analyzed. Worsening of BD greater than 0.2 mmol/l/min was noted, and a proportion derived relative to pooled data on 5-minute intervals. In four of the patients, LDI scans were performed on six representative areas sequentially every 4 hours. The analysis of median flux in these LDI images provided real-time determination of burn depth progression. Eight patients eventually died. Only four patients achieved a normal BD within 12 hours of monitoring despite exceeding the Parkland formula estimate and meeting urinary output parameters. Our analysis also showed cyclical peaks and valleys in the BD curve (P < .001), suggesting repetitive I-R insults. All increases in BD preceded changes that could be detected in vital signs or urine output. Finally, LDI confirmed that the burn depths continued to progress despite apparently adequate resuscitation, and also showed that there are similar peaks and valleys in the perfusion of the wounds (P < .0001), which mimic the changes in the BD curve. Responses to fluid resuscitation do not follow a linear pattern in the case of massive burns. These results in repetitive periods of tissue hypoperfusion evidenced by BD alterations and may contribute to progressive deepening of the burn wound.

Unlabelled: Trauma results in activation of the hypothalamic-pituitary-adrenal axis to mediate a cascade of neurohormonal changes as a defensive mechanism. Its prolongation, however, leads to a hypermetabolic, hypoperfused, and immunosuppressed state, setting the stage for subsequent sepsis and organ failure. Androstenetriol (5-androstene-3beta, 7beta, 17betatriol - AET), a metabolite of dehydroepiandrosterone, up-regulates the host immune response markedly, prevents immune suppression and controls inflammation, leading to improved survival after lethal infections by several diverse pathogens and lethal radiation. Such actions may be useful in improving survival from traumatic shock., Hypothesis: The neurosteroid AET will increase survival following traumatic shock., Methods: A combat relevant model of traumatic shock was used. Male Sprague-Dawley rats were anesthetized, catheterized and subjected to soft tissue injury (laparotomy). Animals were allowed to regain consciousness over the next 0.5 h and then bled 40% of their blood volume over 15 min. Forty-five minutes after the onset of hemorrhage animals were randomized to receive either a single subcutaneous dose of AET (40 mg/kg, sc) or vehicle (methylcellulose). Volume resuscitation consisted of l-lactated Ringer's (three times the shed blood volume), followed by packed red blood cells (one-third shed red cell volume). Animals were observed for three days., Results: A total of 24 animals were studied. Of the 12 animals randomized to receive AET, all (100%) survived compared to 9 of 12 animals (75%) randomized to receive the vehicle (p < 0.05)., Conclusion: AET significantly improved survival when administered subcutaneously in a single dose in this rodent model of traumatic shock. Further survival and mechanism studies are warranted.

Objective: To investigate the influence of the changes in the levels of calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY) on cardiac function of severe burn patients during shock stage., Methods: Sixty severe burn patients with total burn surface area larger than 30% were enrolled as experiment group (E group) , and they received fluid resuscitation and debridement during shock stage. Sixty healthy volunteers were enrolled as control group (C group). The changes in the plasma level of CGRP, NPY and cTnT in E and C groups were observed at 1, 3, 6, 12, 24, 48 post-burn hours (PBH). The correlation among the CGRP, NPY and cTnT in the C group were analyzed., Results: At 3 PBH, the plasma level of CGRP in E group (28 +/- 6) ng/L was lower than that in C group (55 +/- 7) ng/L , and it reached the lowest level at 12 PBH (15 +/- 4)ng/L . It was still lower than that in C group at 48 PBH (P < 0.05). The levels of NPY and cTnT in E group were significantly increased at 1PBH [(136 +/- 20) ng/L, (0.41 +/- 0.08) microg/L] compared with that in C group[ (86 +/- 13) ng/L, (0.16 +/- 0.06) microg/L], peaking at 12PBH [(189 +/- 31) ng/L, (1.78 +/- 0. 47) microg/L], and remaining higher than those in C group at 48PBH. There exhibited obvious negative correlation between the changes in the level of CGRP and cTnT ( r = -0.76, P < 0.01), while obvious positive correlation was found between the changes in level of NPY and cTnT ( r = 0.79, P < 0.01)., Conclusion: The decrease in CGRP level and the increase in NPY level might play important roles in myocardial injury during shock stage of severe burn patients.

Objective: To observe the effect of methylene blue (MB) on the changes in plasma nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and visceral pathologic changes in rabbits with traumatic shock., Methods: Eighteen rabbits were randomly assigned into 3 groups (n=6): sham operation group, traumatic shock with normal saline (NS) resuscitation group (NS group), and traumatic shock with MB resuscitation group (MB group). In NS group and MB group, hemodynamics was monitored, and plasma contents of NO, TNF-alpha and IL-6 were determined before shock, after shock, after resuscitation, and 0.5, 2 and 4 hours after resuscitation. In sham operation control group, hemodynamics monitoring and plasma contents of NO, TNF-alpha and IL-6 were also determined. Tissue samples of the liver and intestine were obtained after experiments for microscopic examination., Results: Compared with NS group, hemodynamics was stable in MB group. The levels of plasma NO in rabbits after traumatic shock were much higher than those of before shock. In NS group, the levels of plasma NO were progressively increased after resuscitation, reaching peak level at 0.5 hour after resuscitation, then decreased thereafter but still remaining higher than those of before shock. But in MB group, the levels of plasma NO after resuscitation were obviously decreased. In sham operation group, the levels of plasma NO showed no significant changes during the whole course. The levels of plasma TNF-alpha and IL-6 in rabbits after traumatic shock were much higher than those of before shock. But after intravenous administration of MB, the levels of plasma TNF-alpha and IL-6 after resuscitation showed no significant difference compared with the baseline levels. In sham operation group, the levels of plasma TNF-alpha and IL-6 showed no significant changes during the entire course. In NS group, the organs showed prominent pathologic changes. But in MB group, less pathologic changes in the organs were milder, and in sham operation group, there was no obvious pathologic changes in the organs., Conclusion: NO, TNF-alpha and IL-6 play important roles in the pathologic process of traumatic shock and the administration of MB after resuscitation can decrease the levels of plasma NO, TNF-alpha and IL-6, improve hemodynamics in traumatic shock, and protect the important organs.

Objective: To investigate the influence on the concentration of plasma endotoxin by inhibition of complement activation in traumatic hemorrhagic shock rats., Methods: Eighty male SD rats were randomly divided into two groups: control and cobra venom factor (CVF) treatment groups. The hemorrhagic shock induced by trauma was replicated in both groups. The animals were killed preshock and at 1, 6, and 24 hours postresuscitation. Twenty-four hours before hemorrhage, rats were given a mainline dose of either 50 microg/kg CVF or an equal volume of saline solution. The plasma and serum samples were collected at each time point to determine the concentration of endotoxin, the activity of CH50 and diamine oxidase (DAO), and the level of tumor necrosis factor (TNF-alpha) at various time points in two groups., Results: Compared with preshock in control group, serum CH50 levels were decreased promptly at 1 hour postresuscitation. Markedly elevation of the levels of endotoxin and TNF-alpha in blood were found at early time after resuscitation, and they were come rapidly back to the basic level at 6 and 24 hours phase. The activity of DAO in blood was increased significantly at 1 and 6 hours after resuscitation and declined promptly at 24 hours. Compared with the control group, significantly decline of the levels of endotoxin, TNF-alpha and DAO at the various time points after resuscitation were also found in the CVF group. The levels of CH50 in CVF group were always less than 5% during the experiment., Conclusion: In traumatic hemorrhagic shock rats CVF pretreatment could decline plasma endotoxin levels by preventing the injury of intestine and gut barrier function, decrease endotoxin translocation and reduce plasma endotoxin levels.

Clinicians now realize the limitations of the physical examination in detecting compensated shock states, the severity of uncompensated states, and in determining the adequacy of resuscitation in order to prevent subsequent post-traumatic multisystem organ failure and death. A renewed interest has developed in interrogating the state of oxygen transport at the end-organ level in the trauma patient. Although used as a research tool and now clinically to monitor cerebral oxygenation during complex cardiovascular and neurosurgery, near infrared absorption spectroscopy (NIRS) is being more aggressively investigated and now marketed clinically as a noninvasive means to assess tissue oxygenation in the trauma patient at the end organ level. This paper will describe the principles of NIRS and the basis for its proposed use in the trauma patient to assess tissue oxygenation. This includes its known limitations, current controversies, and what will be needed in the future to make this technology a part of the initial and ongoing assessment of the trauma patient. The ultimate goal of such techniques is to prevent misassessment of patients and inadequate resuscitation, which are believed to be major initiators in the development of multisystem organ failure and death.

Objective: The aim of the present study was the analysis of the specific hemorheological disorders during the middle stages of experimental traumatic and hemorrhagic shock., Methods: The following hemorheological properties were investigated: Red Blood Cell (RBC) aggregability, their deformability, and systemic hematocrit. The RBC aggregability was assessed by using the "Georgian technique". The RBC deformability was determined with the nuclepore membrane filter method of Reid. The hematocrit was measured by blood centrifugation. The results obtained were treated statistically by using the "Two sample T-test"., Results: We found that in the animals with traumatic shock the erythrocyte aggregability index increased by mean 181%, while in the hemorrhagic group this index on contrary decreased by mean 68% as compared to control group; The RBC deformability underwent a significant decrease during both traumatic and hemorrhagic shock: by a mean of 52% during the first and 62% during the second one. The systemic hematocrit decreased by a mean of 45% during the traumatic shock and by a mean of 50% during the hemorrhagic shock., Conclusion: The data obtained provide evidence that the hemorheological disorders are among the most significant microcirculatory disturbances in the pathogenesis of both the traumatic and the hemorrhagic shock.

Evidence is increasing that oxygen debt and its metabolic correlates are important quantifiers of the severity of hemorrhagic and post-traumatic shock and and may serve as useful guides in the treatment of these conditions. The aim of this review is to demonstrate the similarity between experimental oxygen debt in animals and human hemorrhage/post-traumatic conditions, and to examine metabolic oxygen debt correlates, namely base deficit and lactate, as indices of shock severity and adequacy of volume resuscitation. Relevant studies in the medical literature were identified using Medline and Cochrane Library searches. Findings in both experimental animals (dog/pig) and humans suggest that oxygen debt or its metabolic correlates may be more useful quantifiers of hemorrhagic shock than estimates of blood loss, volume replacement, blood pressure, or heart rate. This is evidenced by the oxygen debt/probability of death curves for the animals, and by the consistency of lethal dose (LD)25,50 points for base deficit across all three species. Quantifying human post-traumatic shock based on base deficit and adjusting for Glasgow Coma Scale score, prothrombin time, Injury Severity Score and age is demonstrated to be superior to anatomic injury severity alone or in combination with Trauma and Injury Severity Score. The data examined in this review indicate that estimates of oxygen debt and its metabolic correlates should be included in studies of experimental shock and in the management of patients suffering from hemorrhagic shock.