Traumatic Hemorrhagic Shock Research Articles

Modulation of Brain Transcriptome by Valproic Acid and Fresh Frozen Plasma Treatments after Traumatic Brain Injury and Hemorrhagic Shock

Modulation of Brain Transcriptome by Valproic Acid and Fresh Frozen Plasma Treatments after Traumatic Brain Injury and Hemorrhagic Shock

Endovascular Resuscitation with Aortic Balloon Occlusion in pediatric trauma

Background
 The use of Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) in resuscitation and trauma management in adults is increasing. However, there is limited data published concerning its use in pediatric patients.
 Methods
 We describe a case using REBOA for traumatic hemorrhagic shock in a pediatric patient according to the concept of EndoVascular resuscitation and Trauma Management (EVTM) at Örebro University Hospital in April 2019. Informed consent has been received.
 Results
 An 11-year-old boy arrived to the emergency room (ER) after a motor vehicle accident. Due to total hemodynamic collapse, cardiopulmonary resuscitation was initiated with return of spontaneous circulation. Zone 1 total REBOA was successfully performed for 7 minutes while damage control surgery was performed and massive transfusion was initiated to stabilize the patient. The patient survived and returned to almost normal daily activity.
 Conclusion
 REBOA for endovascular resuscitation and trauma management may be an additional method for temporary hemodynamic stabilization in pediatric patients and, in this specific patient, was used instead of resuscitative thoracotomy.
 
 Keywords: REBOA; Hemorrhage; Hemorrhagic Shock; Endovascular Resuscitation, Pediatric Trauma

Low-Dose Vasopressin in Patients with Traumatic Hemorrhagic Shock

Current dogma for treating trauma patients in shock favors volume repletion over vasopressors. To test whether low-dose arginine vasopressin (AVP)

Protective effects of plasma products on the endothelial-glycocalyx barrier following trauma-hemorrhagic shock: Is sphingosine-1 phosphate responsible?

Plasma is an important component of resuscitation after trauma and hemorrhagic shock (T/HS). The specific plasma proteins and the impact of storage conditions are uncertain. Utilizing a microfluidic device system, we studied the effect of various types of plasma on the endothelial barrier function following T/HS. Human umbilical vein endothelial cells (HUVEC) were cultured in microfluidic plates. The microfluidic plates were subjected to control or shock conditions (hypoxia/reoxygenation + epinephrine, 10 μM). Fresh plasma, 1 day thawed plasma, 5-day thawed plasma and lyophilized plasma were then added. Supplementation of sphingosine-1 phosphate (S-1P) was done in a subset of experiments. Effect on the endothelial glycocalyx was indexed by shedding of syndecan-1 and hyaluronic acid. Endothelial injury/activation was indexed by soluble thrombomodulin, tissue plasminogen activator, plasminogen activator inhibitor-1. Vascular permeability determined by the ratio of angiopoietin-2 to angiopoietin-1. Concentration of S-1P and adiponectin in the different plasma groups was measured. Human umbilical vein endothelial cells exposed to shock conditions increased shedding of syndecan-1 and hyaluronic acid. Administration of the various types of plasma decreased shedding, except for 5-day thawed plasma. Shocked HUVEC cells demonstrated a profibrinolytic phenotype, this normalized with all plasma types except for 5-day thawed plasma. The concentration of S-1P was significantly less in the 5-day thawed plasma compared with the other plasma types. Addition of S-1P to 5-day thawed plasma returned the benefits lost with storage. A biomimetic model of the microcirculation following T/HS demonstrated endothelial glycocalyx and endothelial cellular injury/activation as well as a profibrinolytic phenotype. These effects were abrogated by all plasma products except the 5-day thawed plasma. Plasma thawed longer than 5 days had diminished S1-P concentrations. Our data suggest that S1-P protein is critical to the protective effect of plasma products on the endothelial-glycocalyx barrier following T/HS.

Glycocalyx Degradation Is Independent of Vascular Barrier Permeability Increase in Nontraumatic Hemorrhagic Shock in Rats.

Glycocalyx shedding after traumatic hemorrhagic or septic shock, as well as different resuscitation fluids, has been causally linked to increased vascular barrier permeability (VBP) resulting in tissue edema. In nontraumatic hemorrhagic shock (NTHS), it remains questionable whether glycocalyx degradation in itself results in an alteration of VBP. The composition of fluids can also have a modulatory effect on glycocalyx shedding and VBP. We hypothesized that the shedding of the glycocalyx during NTHS has little effect on VBP and that the composition of fluids can modulate these effects. Fully instrumented Wistar-albino rats were subjected to a pressure-controlled NTHS (mean arterial pressure of 30 mm Hg) for 60 minutes. Animals were fluid resuscitated with Ringer's acetate, balanced hydroxyethyl starch (HES) solution, or 0.9% normal saline to a mean arterial pressure of 80 mm Hg and compared with shams or nonresuscitated NTHS. Glycocalyx shed products were determined at baseline and 60 minutes after fluid resuscitation. Skeletal muscle microcirculation was visualized using handheld vital microscopy. VBP changes were assessed using plasma decay of 3 fluorescent dyes (40- and 500-kDa dextran and 70-kDa albumin), Evans blue dye exclusion, intravital fluorescence microscopy, and determination of tissue edema (wet/dry weight ratio). All glycocalyx shedding products were upgraded as a result of NTHS. Syndecan-1 significantly increased in NTHS (mean difference, -1668; 95% confidence interval [CI], -2336 to -1001; P < .0001), balanced crystalloid (mean difference, -964.2; 95% CI, -1492 to -436.4; P = .0001), and HES (mean difference, -1030; 95% CI, -1594 to -465.8; P = .0001) groups at the end of the experiment compared to baseline. Hyaluronan levels were higher at the end of the experiment in nonresuscitated NTHS (-923.1; 95% CI, -1216 to -630; P = .0001) and balanced crystalloid (-1039; 95% CI, -1332 to -745.5; P = .0001) or HES (-394.2; 95% CI, -670.1 to -118.3; P = .0027) groups compared to controls. Glycocalyx shedding resulted in microcirculation alterations as observed by handheld video microscopy. Total vessel density was altered in the normal saline (mean difference, 4.092; 95% CI, 0.6195-7.564; P = .016) and hemorrhagic shock (mean difference, 5.022; 95% CI, 1.55-8.495; P = .0024) groups compared to the control group, as well as the perfused vessel density and mean flow index. Despite degradation of endothelial glycocalyx, VBP as determined by 4 independent assays remained intact and continued to be so following fluid resuscitation. NTHS induced glycocalyx shedding and microcirculation alterations, without altering VBP. Fluid resuscitation partially restored the microcirculation without altering VBP. These results challenge the concept that the glycocalyx barrier is a significant contributor to VBP.

Arginine vasopressin improves cerebral perfusion following controlled haemorrhage in adult ewes.

Traumatic haemorrhagic shock carries significant morbidity and mortality related to the severity and duration of tissue hypoperfusion, much of which occurs in the pre-hospital environment where therapy must be easy to use and would augment, not replace, local haemorrhage control measures. Vasopressor therapy use in haemorrhagic shock remains controversial. Potential benefits from improved blood pressure and tissue perfusion need to be weighed against possible harm from increased blood loss if haemorrhage is uncontrolled. We demonstrate that 20 IU I.M. vasopressin produces a progressive, sustained and clinically significant increase in blood pressure and carotid blood flow compared to 1mg I.M. adrenaline or placebo in an animal model of controlled haemorrhagic shock. I.M. vasopressin may play a role in the early management of haemorrhagic shock by improving cerebral perfusion and haemodynamic stability; however, further studies are required to establish the potential benefit against the risk of exacerbating haemorrhage, if it is uncontrolled. Haemorrhagic shock causes significant morbidity and mortality. Novel pre-hospital therapy to improve haemodynamic stability and cerebral perfusion may improve outcomes but remains controversial. In an ovine model of controlled haemorrhagic shock, the effects of early intramuscular arginine vasopressin (AVP), adrenaline or placebo on haemodynamic stability and cerebral perfusion were compared. Carotid pressure and flow catheters were placed in healthy, anaesthetized adult ewes. Frontal cortex cerebral oxygenation was measured using near infrared spectroscopy. Controlled, rapid, haemorrhage (∼30% estimated blood volume) was induced. Five minutes post-bleed a 1ml intramuscular dose of 0.9% saline, adrenaline 1mg or AVP 20IU was administered. Carotid blood pressure and flow improved significantly in the AVP group over the first 30min post-intervention. To emulate standard trauma care, 1L of 0.9% saline was infused 30min post-bleed followed by re-transfusion of the sheep's own blood at 60min post-bleed. Carotid blood pressure and flow in the AVP group remained significantly higher post-crystalloid infusion, but this difference was lost post-blood transfusion. Data were analysed by two-way ANOVA with time, group as the main factors. When compared to saline or adrenaline, a single dose of intramuscular AVP resulted in a progressive and sustained increase in carotid artery blood pressure and flow with commensurate increase in cerebral oxygenation. Intramuscular AVP has potential as an emergency pre-hospital therapy following exsanguinating haemorrhage; however, further studies are required to investigate whether the benefit of improved perfusion pressure outweighs the risks of exacerbating ongoing bleeding.

Timely completion of multiple life-saving interventions for traumatic haemorrhagic shock: a retrospective cohort study

BackgroundEarly control of haemorrhage and optimisation of physiology are guiding principles of resuscitation after injury. Improved outcomes have been previously associated with single, timely interventions. The aim of this study was to assess the association between multiple timely life-saving interventions (LSIs) and outcomes of traumatic haemorrhagic shock patients.MethodsA retrospective cohort study was undertaken of injured patients with haemorrhagic shock who presented to Alfered Emergency & Trauma Centre between July 01, 2010 and July 31, 2014. LSIs studied included chest decompression, control of external haemorrhage, pelvic binder application, transfusion of red cells and coagulation products and surgical control of bleeding through angio-embolisation or operative intervention. The primary exposure variable was timely initiation of ≥ 50% of the indicated interventions. The association between the primary exposure variable and outcome of death at hospital discharge was adjusted for potential confounders using multivariable logistic regression analysis. The association between total pre-hospital times and pre-hospital care times (time from ambulance at scene to trauma centre), in-hospital mortality and timely initiation of ≥ 50% of the indicated interventions were assessed.ResultsOf the 168 patients, 54 (32.1%) patients had ≥ 50% of indicated LSI completed within the specified time period. Timely delivery of LSI was independently associated with improved survival to hospital discharge (adjusted odds ratio (OR) for in-hospital death 0.17; 95% confidence interval (CI) 0.03–0.83; p = 0.028). This association was independent of patient age, pre-hospital care time, injury severity score, initial serum lactate levels and coagulopathy. Among patients with pre-hospital time of ≥ 2 h, 2 (3.6%) received timely LSIs. Pre-hospital care times of ≥ 2 h were associated with delayed LSIs and with in-hospital death (unadjusted OR 4.3; 95% CI 1.4–13.0).ConclusionsTimely completion of LSI when indicated was completed in a small proportion of patients and reflects previous research demonstrating delayed processes and errors even in advanced trauma systems. Timely delivery of a high proportion of LSIs was associated with improved outcomes among patients presenting with haemorrhagic shock after injury. Provision of LSIs in the pre-hospital phase of trauma care has the potential to improve outcomes.

Does the conventional landmark help to place the tip of REBOA catheter in the optimal position? A non-controlled comparison study

BackgroundResuscitative endovascular balloon occlusion of the aorta (REBOA) for patients with traumatic torso hemorrhagic shock is available to keep a minimum level of circulatory status as a bridge to definitive therapy. However, the trajectory for placement of REBOA in the aorta has not yet been clearly defined.MethodsWe conducted a retrospective observational cohort study in the two tertiary critical care and emergency center from December 2014 to October 2018. A total of 28 patients who underwent focused assessment with sonography for trauma (FAST) were studied via contrast computed tomography (CT), and 27 were analyzed.ResultsWe divided patients into two groups based on our CT findings. The REBOA deflate group included 16 patients, and the inflate group included 11 patients. The median trace value (interquartile range) of the blood vessel center line from the common femoral artery to the tip of REBOA (blood vessel length) and the length of REBOA itself from the common femoral artery to the tip of REBOA (REBOA insertion length) were 56.2 cm (54.5–57.2) and 55.2 cm (54.2–55.6), respectively (p < 0.0001) for the deflated group, and 51.4 cm (42.1–56.6) and 50.3 cm (42.3–55.0) (p = 0.594), respectively, for the inflated group.ConclusionsIf REBOA was deflated, it was placed 1.0 cm longer than the insertion length of REBOA catheter itself, but that was not the case when inflating REBOA. The individual difference was large to the extent that the balloon inflated and the extent to which the balloon was pushed back toward the caudal depending on the degree of blood pressure. Further studies would be needed to validate the study findings.

Mesenchymal stromal cells to protect kidney after traumatic hemorrhagic shock

Background & Aim Haemorrhagic shock (HS) refers to the inadequate perfusion of tissues due to the imbalance between systemic oxygen delivery and consumption. Blunt or penetrating trauma is the most common cause of HS. The development of multiorgan failure after severe trauma is one of the leading causes of morbidity and late mortality. Among critical organs, the Acute Kidney Injury (AKI) affects up to 50% of the patients and no etiologic treatment is available. Mesenchymal Stromal Cells (MSC) are multipotent cells found in a large number of adult tissues and used in clinical practice as a therapeutic agent for immunomodulation and tissue repair. Many studies have highlighted their immunomodulatory, anti-apoptotic/anti-oxidative stress, pro-angiogenic effect, stimulation of endogenous regenerative process or anti-fibrotic effect by direct contact or by secreting bioactive molecules. Our objective was to evaluate and optimize an early MSC therapy after traumatic hemorrhagic shock (THS) inducing an AKI. Methods, Results & Conclusion We have developed in vivo THS model and validated functional assays on cultures of immune and renal human cells. In vivo, rats were subjected to 1h of HS at a Mean Arterial Pressure of 30mmHg, associated with administration of 1ml plasma from THS animals. Biological and histological analyses are currently performed on D2, D7 and D21. In vitro, a cellular model of renal injury was developed by adding a "shock cocktail" (SC) containing inflammatory cytokines, HMGB1, histones and H2O2. Several criteria have been studied: Membrane polarization of the mitochondria by the JC1 dye, MitoSOX and CellROX probes to evaluate the mitochondrial and cytoplasmic oxidation state. Aggression of renal cells induced a decrease in the mitochondrial membrane polarization. The CellROX probe also showed an increase in cytoplasmic oxidative stress. We also developed a model of inflammation using THP1 cell line treated with SC. The SC induced an increase in TNFα secretion by THP1. Our main preliminary results indicated that MSCs improved the viability of renal cells, partially restored their mitochondrial membrane potential and decreased their cytoplasmic oxidative stress. In addition, they can exert an anti-inflammatory effect by inhibited the secretion of TNFα by THP1 and increased their secretion of the anti-inflammatory cytokine IL1RA. Finally, the pre-clinical model mimicking a polytrauma could be a formidable tool to evaluate the benefit of MSC therapy, away from shock. Haemorrhagic shock (HS) refers to the inadequate perfusion of tissues due to the imbalance between systemic oxygen delivery and consumption. Blunt or penetrating trauma is the most common cause of HS. The development of multiorgan failure after severe trauma is one of the leading causes of morbidity and late mortality. Among critical organs, the Acute Kidney Injury (AKI) affects up to 50% of the patients and no etiologic treatment is available. Mesenchymal Stromal Cells (MSC) are multipotent cells found in a large number of adult tissues and used in clinical practice as a therapeutic agent for immunomodulation and tissue repair. Many studies have highlighted their immunomodulatory, anti-apoptotic/anti-oxidative stress, pro-angiogenic effect, stimulation of endogenous regenerative process or anti-fibrotic effect by direct contact or by secreting bioactive molecules. Our objective was to evaluate and optimize an early MSC therapy after traumatic hemorrhagic shock (THS) inducing an AKI. We have developed in vivo THS model and validated functional assays on cultures of immune and renal human cells. In vivo, rats were subjected to 1h of HS at a Mean Arterial Pressure of 30mmHg, associated with administration of 1ml plasma from THS animals. Biological and histological analyses are currently performed on D2, D7 and D21. In vitro, a cellular model of renal injury was developed by adding a "shock cocktail" (SC) containing inflammatory cytokines, HMGB1, histones and H2O2. Several criteria have been studied: Membrane polarization of the mitochondria by the JC1 dye, MitoSOX and CellROX probes to evaluate the mitochondrial and cytoplasmic oxidation state. Aggression of renal cells induced a decrease in the mitochondrial membrane polarization. The CellROX probe also showed an increase in cytoplasmic oxidative stress. We also developed a model of inflammation using THP1 cell line treated with SC. The SC induced an increase in TNFα secretion by THP1. Our main preliminary results indicated that MSCs improved the viability of renal cells, partially restored their mitochondrial membrane potential and decreased their cytoplasmic oxidative stress. In addition, they can exert an anti-inflammatory effect by inhibited the secretion of TNFα by THP1 and increased their secretion of the anti-inflammatory cytokine IL1RA. Finally, the pre-clinical model mimicking a polytrauma could be a formidable tool to evaluate the benefit of MSC therapy, away from shock.

Effects of different target blood pressure resuscitation on peripheral blood inflammatory factors and hemodynamics in patients with traumatic hemorrhagic shock

To investigate the target blood pressure level of restrictive fluid resuscitation in patients with traumatic hemorrhagic shock. Sixty patients with traumatic hemorrhagic shock admitted to the First Affiliated Hospital of Bengbu Medical College from January 2016 to December 2018 were enrolled. All patients were resuscitated with sodium acetate ringer solution after admission. According to the difference of mean arterial pressure (MAP) target, the patients were divided into low MAP (60 mmHg ≤ MAP < 65 mmHg, 1 mmHg = 0.133 kPa), middle MAP (65 mmHg ≤ MAP < 70 mmHg) and high MAP (70 mmHg ≤ MAP < 75 mmHg) groups by random number table using the admission order with 20 patients in each group. Those who failed to reach the target MAP after 30-minute resuscitation were excluded and supplementary cases were deferred. The restrictive fluid resuscitation phase was divided into three phases: before fluid resuscitation, liquid resuscitation for 30 minutes and 60 minutes. The most suitable resuscitation blood pressure level was further speculated by monitoring the inflammatory markers and hemodynamics in different periods in each group of patients. Pearson correlation analysis was used to detect the correlation of variables. Before fluid resuscitation, there was no significant difference in hemodynamics or expressions of serum cytokines among the three groups. Three groups of patients were resuscitated for 30 minutes to achieve the target blood pressure level and maintain 30 minutes. With the prolongation of fluid resuscitation time, the central venous pressure (CVP), cardiac output (CO) and cardiac index (CI) were increased slowly in the three groups, and reached a steady state at about 30 minutes after resuscitation, especially in the high MAP group and the middle MAP group. The expressions of serum inflammatory factors in the three groups were gradually increased with the prolongation of fluid resuscitation time. Compared with the low MAP group and the high MAP group, after 30 minutes of resuscitation the middle MAP group was superior to the other two groups in inhibiting the expressions of pro-inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and promoting anti-inflammatory factors IL-10 [TNF-α mRNA (2-ΔΔCt): 0.21±0.13 vs. 0.69±0.34, 0.57±0.35; IL-6 mRNA (2-ΔΔCt): 0.35±0.31 vs. 0.72±0.39, 0.59±0.42; IL-10 mRNA (2-ΔΔCt): 1.25±0.81 vs. 0.61±0.46, 0.82±0.53; all P < 0.05], but there was no significant difference in promoting the expression of IL-4 mRNA among three groups. At 60 minutes of resuscitation, compared with the low MAP group and the high MAP group, the middle MAP group could significantly inhibit the expressions of TNF-α, IL-6 and promote IL-10 [TNF-α mRNA (2-ΔΔCt): 0.72±0.35 vs. 1.05±0.54, 1.03±0.49; IL-6 mRNA (2-ΔΔCt): 0.57±0.50 vs. 1.27±0.72, 1.01±0.64; IL-10 mRNA (2-ΔΔCt): 1.41±0.90 vs. 0.81±0.48, 0.94±0.61; all P < 0.05]. Compared with the high MAP group, the middle MAP group had significant differences in promoting the expression of IL-4 mRNA (2-ΔΔCt: 1.32±0.62 vs. 0.91±0.60, P < 0.05). There was no significant difference in serum cytokine expressions at different time points of resuscitation between the low MAP group and the high MAP group (all P > 0.05). Correlation analysis showed that there was a strong linear correlation between MAP and mRNA expressions of TNF-α, IL-6, IL-10 in the middle MAP group (r value was 0.766, 0.719, 0.692, respectively, all P < 0.01), but had no correlation with IL-4 (r = 0.361, P = 0.059). Fitting linear regression analysis showed an increase in 1 mmHg per MAP, the expression of TNF-α mRNA increased by 0.027 [95% confidence interval (95%CI) = 0.023-0.031, P < 0.001], IL-6 mRNA increased by 0.021 (95%CI = 0.017-0.024, P < 0.001), and IL-10 mRNA increased by 0.049 (95%CI = 0.041-0.058, P < 0.001). When patients with traumatic hemorrhagic shock received restrict fluid resuscitation at MAP of 65-70 mmHg, the effect of reducing systemic inflammatory response and improving hemodynamics is better than the target MAP at 60-65 mmHg or 70-75 mmHg. It is suggested that 65-70 mmHg may be an ideal target MAP level for restrictive fluid resuscitation.

Supplementation of multi‐vitamins, not glutamine alleviate erythrocyte oxidative status in rats with trauma‐hemorrhagic shock and resuscitation

Resuscitation fluid replacement is the major life saving strategy for patients with hemorrhagic shock; however, resuscitation‐induced oxidative stress may lead to systemic inflammation, multiple organ failure (MOF), and even death. Studies showed that reduction of oxidative stress and preservation of ATP production may improve MOF in animals with trauma‐hemorrhagic shock and resuscitation (THR). In addition, glutamine has been considered as a cellular fuel and is the source of glutathione and multi‐vitamins possess antioxidant activity and play important roles in energy metabolism. Therefore, we investigated the effects of single or simultaneous administration of multi‐vitamins and glutamine on antioxidant defense systems, including enzymatic and non‐enzymatic, in the plasma and erythrocytes of THR. Male SD rats were suffered with THR, including a 5 cm midline laparotomy and mean arterial pressure 30 to 35 mmHg for 60 min followed by resuscitation lactate Ringer's (LR) solution with or without L‐alanyl‐L‐glutamine and/or multi‐vitamins. The sham‐operated, parenterally fed rats were included. After infused with continuous, slow rate of LR solutions for 42 hours, the THR rats had significantly decreased red blood cells and hematocrit and increased erythrocyte glutathione (one‐way ANOVA, p&lt;0.05). Intravenous glutamine significantly increased erythrocyte total and protein‐bound thiol groups and plasma TBARS; intravenous multi‐vitamins significantly decreased erythrocyte TBARS; and combination of glutamine and multi‐vitamins significantly decreased erythrocyte TBARS and the ratio of plasma reduced to oxidized glutathione and increased plasma TBARS. In addition, multi‐vitamins was the main factor to decrease plasma total and protein‐bound thiol groups and plasma and erythrocyte TBARS and to increase the ratio of plasma reduced to oxidized glutathione (two‐way ANOVA, p &lt; 0.05). In conclusion, multi‐vitamins, not glutamine, may alleviate erythrocyte oxidative status in trauma‐hemorrhagic shock and resuscitation.Support or Funding InformationNSC 102‐2320‐B‐030‐005‐MY3This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Outcomes of traumatic hemorrhagic shock and the epidemiology of preventable death from injury.

The majority of potentially preventable deaths after trauma are related to hemorrhage and occur early after injury, with the largest number of deaths occurring before hospital arrival. Approximately one-fourth of trauma deaths may be potentially preventable through early medical and surgical interventions. Interventions dedicated to bleeding control and hemostatic resuscitation have demonstrated merit in decreasing hemorrhagic injury mortality. Advancing these novel strategies to the casualty in the prehospital phase of care, particularly in tactical or austere environments, may prove beneficial for hemorrhage mitigation to temporize the window of survival to definitive care. Future studies of resuscitation and survival after traumatic injury must include analysis of prehospital deaths to fully understand the outcomes of early interventions.

The Effects of Genetic 3-Mercaptopyruvate Sulfurtransferase Deficiency in Murine Traumatic-Hemorrhagic Shock.

Hemorrhagic shock is a major cause of death after trauma. An additional blunt chest trauma independently contributes to mortality upon the development of an acute lung injury (ALI) by aggravating pathophysiological consequences of hemorrhagic shock. The maintenance of hydrogen sulfide availability is known to play an important role during hemorrhage and ALI. We therefore tested the impact of a genetic 3-mercaptopyruvate sulfurtransferase mutation (Δ3-MST) in a resuscitated murine model of traumatic-hemorrhagic shock. Anesthetized wild-type (WT) and Δ3-MST mice underwent hemorrhagic shock with/without blunt chest trauma. Hemorrhagic shock was implemented for 1 h followed by retransfusion of shed blood and intensive care therapy for 4 h, including lung-protective mechanical ventilation, fluid resuscitation, and noradrenaline titrated to maintain a mean arterial pressure at least 50 mmHg. Systemic hemodynamics, metabolism, and acid-base status were assessed together with lung mechanics and gas exchange. Postmortem tissue samples were analyzed for immunohistological protein expression and mitochondrial oxygen consumption. 3-MST-deficient mice showed similar results in parameters of hemodynamics, gas exchange, metabolism, acid base status, and survival compared with the respective WT controls. Renal albumin extravasation was increased in Δ3-MST mice during hemorrhagic shock, together with a decrease of LEAK respiration in heart tissue. In contrast, mitochondrial oxygen consumption in the uncoupled state was increased in kidney and liver tissue of Δ3-MST mice subjected to the combined trauma. In summary, in a resuscitated murine model of traumatic-hemorrhagic shock, 3-MST deficiency had no physiologically relevant impact on hemodynamics and metabolism, which ultimately lead to unchanged mortality regardless of an additional blunt chest trauma.

Impact of plasma viscosity on microcirculatory flow after traumatic haemorrhagic shock: A prospective observational study.

Preclinical studies report that higher plasma viscosity improves microcirculatory flow after haemorrhagic shock and resuscitation, but no clinical study has tested this hypothesis. We investigated the relationship between plasma viscosity and sublingual microcirculatory flow in patients during resuscitation for traumatic haemorrhagic shock (THS). Sublingual video-microscopy was performed for 20 trauma patients with THS as soon as feasible in hospital, and then at 24 h and 48 h. Values were obtained for total vessel density, perfused vessel density, proportion of perfused vessels, microcirculatory flow index (MFI), microcirculatory heterogeneity index (MHI), and Point of Care Microcirculation (POEM) scores. Plasma viscosity was measured using a Wells-Brookfield cone and plate micro-viscometer. Logistic regression analyses examined relationships between microcirculatory parameters and plasma viscosity, adjusting for covariates (systolic blood pressure, heart rate, haematocrit, rate and volume of fluids, and rate of noradrenaline). Higher plasma viscosity was not associated with improved microcirculatory parameters. Instead, there were weakly significant associations between higher plasma viscosity and lower (poorer) MFI (p = 0.040), higher (worse) MHI (p = 0.033), and lower (worse) POEM scores (p = 0.039). The current study did not confirm the hypothesis that higher plasma viscosity improves microcirculatory flow dynamics in patients with THS. Further clinical investigations are warranted to determine whether viscosity is a physical parameter of importance during resuscitation of these patients.

Isoform 6-selective histone deacetylase inhibition reduces lesion size and brain swelling following traumatic brain injury and hemorrhagic shock.

Nonselective histone deacetylase (pan-HDAC) inhibitors, such as valproic acid (VPA), have demonstrated neuroprotective properties in trauma models. However, isoform-specific HDAC inhibitors may provide opportunity for more effective drug administration with fewer adverse effects. We investigated HDAC6 inhibition with ACY-1083 in an in vitro and an in vivo large animal model of injury. Mouse hippocampal cells were subjected to oxygen-glucose deprivation (0% O2, glucose-free and serum-free medium, 18 hours) and reoxygenation (21% O2, normal culture media, 4 hours) with/without VPA (4 mmol/L) or ACY-1083 (30 nmol/L, 300 nmol/L). Cell viability was measured by methylthiazolyl tetrazolium assay. Expression of hypoxia-inducible factor-1α, heat shock protein 70, and effectors in the phosphoinositide-3 kinase/mammalian target of rapamycin pathway were measured by Western blot analysis. Additionally, swine were subjected to combined traumatic brain injury and hemorrhagic shock and randomized to three treatment groups (n = 5/group): (i) normal saline (NS; 3× hemorrhage volume); (ii) NS + VPA (NS; 3× hemorrhage volume, VPA; 150 mg/kg), and (iii) NS + ACY-1083 (NS; 3× hemorrhage volume, ACY-1083; 30 mg/kg). After 6 hours, brain tissue was harvested to assess lesion size and brain swelling. Significant improvement in cell viability was seen with both HDAC inhibitors in the in vitro study. ACY-1083 suppressed hypoxia-inducible factor-1α expression and up-regulated phosphorylated mammalian target of rapamycin and heat shock protein 70 in a dose-dependent manner. Lesion size and brain swelling in animals treated with pharmacologic agents (VPA and ACY-1083) were both smaller than in the NS group. No differences were observed between the VPA and ACY-1083 treatment groups. In conclusion, selective inhibition of HDAC6 is as neuroprotective as nonselective HDAC inhibition in large animal models of traumatic brain injury and hemorrhagic shock.

Treatment of Traumatic - Hemorrhagic Shock

Shock represents a condition of inadequate tissue perfusion due to circulatory insufficiency. Hemorrhage is the most common cause of shock in injured patients. Traumatic hemorrhagic shock presents a life-threatening condition due to the development of multifunctional organ dysfunction syndrome, which can be diagnosed due to symptomatology and changes in vital parameters. This study aims to analyse the epidemiological characteristics of traumatic - hemorrhagic shock and to demonstrate the efficacy of therapy in hemodynamic stabilization in patients with shock during the first 12 hours of intensive treatment at University Clinical Center of Kosovo.

Valproic Acid and Neural Apoptosis, Inflammation, and Degeneration 30 Days after Traumatic Brain Injury, Hemorrhagic Shock, and Polytrauma in a Swine Model

A single-dose (150 mg/kg) of valproic acid (VPA) has been shown to decrease brain lesion size and improve neurologic recovery in preclinical models of traumatic brain injury (TBI). However, the longer-term (30 days) impact of single-dose VPA treatment after TBI has not been well evaluated. Yorkshire swine were subjected to TBI (cortical impact), hemorrhagic shock, and polytrauma. Animals remained in hypovolemic shock for 2 hours before resuscitation with normal saline (NS; volume= 3× hemorrhaged volume) or NS+ VPA (150 mg/kg) (n= 5/cohort). Brain samples were harvested 30 days after injuries. The cerebral cortex adjacent to the site of cortical impact was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemistry, and Western blot analysis. Neural apoptosis, inflammation, degeneration, plasticity, and signaling pathways were evaluated. For apoptosis, VPA treatment significantly decreased (p < 0.05) the number of TUNEL (+) cells and expression of cleaved-caspase 3. For inflammation and degeneration, expression of ionized calcium binding adaptor molecule-1, glial fibrillary acid protein, amyloid-β, and phosphorylated-Tau protein were significantly attenuated (p < 0.05) in the VPA-treated animals compared with the NS group. For, plasticity, VPA treatment also increased expression of brain-derived neurotrophic factor significantly (p < 0.05) compared with the NS group. For signaling pathways, nuclear factor-κB was decreased significantly (p < 0.05) and cytosolic IκBα expression was increased significantly (p < 0.05) in the VPA-treated animals compared with the NS group. Administration of a single dose of VPA (150 mg/kg) can decrease neural apoptosis, inflammation, and degenerative changes, and promote neural plasticity at 30 days after TBI. In addition, VPA acts, in part, via regulation of nuclear factor-κB and IκBα pathways.

Metabolomics analysis of gut barrier dysfunction in a trauma-hemorrhagic shock rat model

Intestinal barrier dysfunction has been implicated in the development of multiorgan dysfunction syndrome caused by the trauma-hemorrhagic shock (THS). However, the mechanisms underlying THS-induced gut barrier injury are still poorly understood. In the present study, we used the metabolomics analysis to test the hypothesis that altered metabolites might be related to the development of THS-induced barrier dysfunction in the large intestine. Under the induction of THS, gut barrier failure was characterized by injury of permeability and mucus layer, which were companied by the decreased expression of zonula occludens-1 in the colon and increased levels of inflammatory factors including tumor necrosis factor-α, interferon-γ, interleukin (IL)-6, and IL-1β in the serum. A total of 16 differential metabolites were identified in colonic tissues from THS-treated rats compared with control rats. These altered metabolites included dihydroxy acetone phosphate, ribose-5-phosphate, fructose, glyceric acid, succinic acid, and adenosine, which are critical intermediates or end products that are involved in pentose phosphate pathway, glycolysis, and tricarboxylic acid cycle as well as mitochondrial adenosine triphosphate biosynthesis. These findings may offer important insight into the metabolic alterations in THS-treated gut injury, which will be helpful for developing effective metabolites-based strategies to prevent THS-induced gut barrier dysfunction.

Chemokine (C-X-C motif) receptor 4 regulates lung endothelial barrier permeability during resuscitation from hemorrhagic shock

Chemokine (C-X-C motif) receptor 4 (CXCR4) agonists have been shown to protect lung endothelial barrier function in vitro. In vivo effects of CXCR4 modulation on lung endothelial permeability are unknown. Here we tested the effects of the CXCR4 agonist ubiquitin and the antagonist AMD3100 on lung vascular permeability and cytokine concentrations in a rat hemorrhage model. Animals were hemorrhaged (mean arterial blood pressure 30 mmHg for 30 min), treated with vehicle, ubiquitin (0.7 and 3.5 µmol/kg) or AMD3100 (3.5 µmol/kg), and resuscitated with crystalloids. Evans blue extravasation was employed to quantify lung vascular permeability. Ubiquitin dose-dependently reduced Evans blue extravasation into the lung. AMD3100 increased Evans blue extravasation. With AMD3100, TNFalpha levels in lung homogenates were increased; while TNFalpha levels were lower with ubiquitin, these differences did not reach statistical significance. Our findings suggest that CXCR4 regulates lung vascular permeability and further point towards CXCR4 as a drug target to confer lung protection during resuscitation from traumatic-hemorrhagic shock.

In-Depth Characterization of the Effects of Cigarette Smoke Exposure on the Acute Trauma Response and Hemorrhage in Mice.

Hemorrhagic shock accounts for a large amount of trauma-related mortality. The severity of trauma can be further aggravated by an additional blunt chest trauma (TxT), which independently contributes to mortality upon the development of an acute lung injury (ALI). Besides, cigarette smoke (CS) exposure before TxT enhanced posttraumatic inflammation, thereby aggravating ALI. We therefore aimed to characterize the impact of an acute and/or chronic lung injury on organ dysfunction in a murine model of traumatic hemorrhagic shock (HS). After 3 weeks of CS exposure, anesthetized mice underwent HS with/without TxT. Hemorrhagic shock was implemented for 1 h followed by retransfusion of shed blood and intensive care therapy for 4 h including lung-protective mechanical ventilation, fluid resuscitation, and noradrenaline titrated to maintain mean arterial pressure ≥50 mmHg. Lung mechanics and gas exchange were assessed together with systemic hemodynamics, metabolism, and acid-base status. Postmortem blood and tissue samples were analyzed for cytokine and chemokine levels, protein expression, mitochondrial respiration, and histological changes. CS exposure and HS alone coincided with increased inflammation, decreased whole blood sulfide concentrations, and decreased diaphragmatic mitochondrial respiration. CS-exposed mice, which were subjected to TxT and subsequent HS, showed hemodynamic instability, acute kidney injury, and high mortality. Chronic CS exposure per se had the strongest impact on inflammatory responses. The degree of inflammation was similar upon an additional TxT, however, mice presented with organ dysfunction and increased mortality rates. Hence, in mice the degree of inflammation may be dissociated from the severity of organ dysfunction or injury.