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Background The mechanisms of early traumatic-induced coagulopathy are not well understood. Our aim was to examine the role of platelets and fibrinogen to early coagulopathy in the rat after hemorrhagic shock. Methods Adult Sprague-Dawley rats were anesthetized and randomly assigned to: 1) Baseline, 2) Hemorrhage or 3) Shock (n = 10 each). Controlled phlebotomy occurred over 20 min and animals were left in shock 60 min. Coagulation was assessed using PT, aPTT, ROTEM and ELISAs. Results PT and aPTT increased 5 to 7 times following hemorrhage and shock. Prolongation of EXTEM and INTEM clotting times, lower clot elasticity and increased EXTEM lysis index (LI) indicated a hypocoagulopathy. After 20 min hemorrhage, LI(30–60) in FIBTEM was ~ 100%, EXTEM 83–87% and APTEM 80–82% indicating a platelet contribution to the coagulopathy with no hyperfibrinolysis. After 60 min shock, the situation was reversed with fibrinogen loss being a contributor. This apparent switch from a platelet- to a fibrinogen-based coagulopathy, with fibrinolysis, was supported by ≥ 15% in maximum lysis (ML), a threefold increase in plasma PAI-1 after hemorrhage, and undetectable levels after shock. Curiously, the relative contribution of fibrinogen/platelet ratio to clot amplitude, determined from FIBTEM/EXTEM A10 ratio (and MCF), remained unchanged at ~ 1:5 for baseline, hemorrhage and shock despite a progressive hypocoagulopathy. Significant increases in P-selectin, acidosis and lactate indicated systemic endothelial damage and tissue hypoperfusion. Conclusions Hypocoagulopathy following severe hemorrhage and shock in the rat appeared to involve a two-step process of platelet dysfunction followed by fibrinogen impairment, possibly linked to progressive endothelial dysfunction. [ABSTRACT FROM AUTHOR]

Background: Insulin has been shown to exert positive inotropic effects in several in vivo ex vivo models and in human hearts. Resuscitation following hemorrhagic shock results in myocardial contractile dysfunction. However, the optimal timing for treatment with insulin for the cardioprotection effects is unclear. Objectives: The objective of this study was to test the hypothesis that treatment with insulin before resuscitation provides better cardioprotection than treatment with insulin after resuscitation. Materials and Methods: Rats were assigned to 3 experimental groups (n = 6 per group): (1) Hemorrhagic shock and resuscitation, (2) hemorrhagic shock resuscitated then treated with insulin and (3) hemorrhagic shock treated with insulin before resuscitation. Rats were hemorrhaged for 60 min to rach mean arterial blood pressure of 40 mmHg. Rats were resuscitated in vivo by reinfusion of the shedded blood to restore normotension and monitored for 60 min. Rats were treated or not with insulin 200 μU/g body weight intramuscularly either before or after resuscitation. The maximum of the left ventricular developed pressure (+dP/dt) was measured for 60 min in the isolated perfused hearts using the Langendorff method. Blood samples were obtained for measurements of tumor necrosis factor-alpha (TNF-α). Results: Treatment with insulin before resuscitation following hemorrhagic shock significantly elevated max dP/dt compared with insulin treatment after resuscitation and the untreated group. TNF-α levels were lower in the insulin treatment before resuscitation compared to the treatment after resuscitation and the untreated group. Conclusion: Insulin treatment before resuscitation following hemorrhagic shock provides better cardiac protection than treatment with insulin after resuscitation, as evidenced by the improved myocardial contractility, preservation of myocardial structure. The mechanism of cardiac protection involves decrease in the inflammatory response to shock by lowering the levels of TNF. [ABSTRACT FROM AUTHOR]

Background Bradykinin (BK) has many biological effects in inflammation, allergy, and septic shock. Studies have shown that low doses of BK can induce vascular relaxation and high doses can induce vascular contraction in many pathophysiological conditions, but the role and mechanisms that high doses of BK have on vascular contraction in hemorrhagic shock are not clear. Methods With hemorrhagic-shock rats and hypoxia-treated superior mesenteric artery (SMA), we investigated the role and mechanisms of high doses of BK-induced vascular contraction in hemorrhagic shock. Results High doses of BK (500-50,000 ng/kg in vivo or 10-10 to 10-5 mol/L in vitro) dose dependently induced vascular contraction of SMA and increased the vascular calcium sensitivity in normal and hemorrhagic-shock rats. Less than 10-10 mol/L of BK induced vascular dilation BK-induced increase of vascular contractile response and calcium sensitivity was reduced by denudation of the endothelium, 18α-glycyrrhetic acid (an inhibitor of myoendothelial gap junction) and connexin 43 antisense oligodeoxynucleotide. Further studies found that high concentrations of BK-induced vascular contraction in hemorrhagic shock was closely related to the activation of Rho A-Rho kinase pathway and Protein Kinase C (PKC) α and ε. Conclusions High doses of BK can induce vascular contraction in hemorrhagic shock condition, which is endothelium and myoendothelial gap junction dependent. Cx43-mediated activation of Rho A-Rho kinase and Protein Kinase C (PKC) pathway plays a very important role in this process. This finding provided a new angle of view to the biological role of BK in other pathophysiological conditions such as hemorrhagic shock or hypoxia. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to investigate the effect of volume-controlled hemorrhage and hypothermia on rats with blunt chest trauma, evaluating bacterial translocation (BT), lung tissue malondialdehyde (MDA), nitric oxide (NO) levels, and erythrocyte deformability (ED). Methods In our study, 10 animals each were included in 6 groups. Groups were as follows: a group with blunt chest trauma only (Group T), a group with hemorrhage only (Group H), a normothermic group with comorbidity of trauma and hemorrhage (Group NT), a mild hypothermic group with trauma and hemorrhage (Group MH), a moderate hypothermic group with trauma and hemorrhage (Group MoH), and a control group (Group C). Sodium pentobarbital (50 mg/kg, intraperitoneally) anesthesia was administered. Thoracic trauma was generated using kinetic energy at the middle of the chest (2.45 J). Stage 3 hemorrhagic shock was initiated. After 24 hours, the rats were killed and red blood cell deformability, BT development in the liver, spleen, and mesenteric lymph nodes, and NO and MDA levels in lung tissue, kept at –80°C, were measured. Results In Groups MH and MoH, there was no difference in ED values, though they were lower than those in Group NT (p < 0.05). BTwas more prevalent in Group NT than in the other groups. In Group NT, the growth of BT was greater than in other groups (p < 0.05). The level of NO in Group H was higher than in the control group (p < 0.05). In Group MoH, the level of MDA was lower than in Group MH (p < 0.05). Conclusion Hypothermia seems to demonstrate protective effects on ED and BT by reducing oxidative stress. The protective effects of therapeutic hypothermia on ED may be due to the effect of reducing NO and/or MDA. There was no difference in effect between mild and moderate hypothermia in terms of the formation of ED and BT. [ABSTRACT FROM AUTHOR]

Studies have shown that local application of platelet-derived growth factor (PDGF) can be used for the treatment of acute and chronic wounds. We investigated if systemic application of PDGF has a protective effect on acute hemorrhagic shock in rats in the present study. Using hemorrhagic shock rats and isolated superior mesenteric arteries, the effects of PDGF-BB on hemodynamics, animal survival, and vascular reactivity as well as the roles of the gap junction proteins connexin (Cx)40 and Cx43, PKC, and Rho kinase were observed. PDGF-BB (1-15 μg/kg iv) significantly improved the hemodynamics and blood perfusion to vital organs (liver and kidney) as well as vascular reactivity and improved the animal survival in hemorrhagic shock rats. PDGF recovering shock-induced vascular hyporeactivity depended on the integrity of the endothelium and myoendothelial gap junction. Cx43 antisense oligodeoxynucleotide abolished these improving effects of PDGF, whereas Cx40 oligodeoxynucleotide did not. Further study indicated that PDGF increased the activity of Rho kinase and PKC as well as vascular Ca2+ sensitivity, whereas it did not interfere with the intracellular Ca2+ concentration in hypoxiatreated vascular smooth muscle cells. In conclusion, systemic application of PDGF-BB may exert beneficial effects on hemorrhagic shock, which are closely related to the improvement of vascular reactivity and hemodynamics. The improvement of PDGF-BB in vascular reactivity is vascular endothelium and myoendothelial gap junction dependent. Cx43, Rho kinase, and PKC play very important role in this process. These findings suggest that PDGF may be a potential measure to treat acute clinical critical diseases such as severe trauma, shock, and sepsis. [ABSTRACT FROM AUTHOR]

Abstract: Haemorrhagic shock is a life threatening condition, and, as such, it is important to understand the mechanisms taking part in its reversal. In the 1990s, it was shown that activation of serotonin 1A receptors is responsible for the circulatory decompensation and development of the sympathoinhibitory phase. In previous reports, it was demonstrated that activation of serotonin 1A receptors induces resuscitative effects in haemorrhaged rats. However, the effectory mechanisms still require further investigation. The aim of the present study was to determine whether the sympathetic nervous system participates in the effects of serotonin through central serotonin 1A receptors in haemorrhagic shock in rats. In order to determine the role of the sympathetic nervous system alpha-1-, alpha-2-, and beta-adrenergic receptor agonists – prazosin, yohimbine and propranolol, respectively, were used. We found that stimulation of the central serotonin 1A receptors by the administration of a selective agonist – 8-hydroxy-2-(di-n-propylamino)tetralin, 1-(2,5-dimethoxy-4-iodophenyl)-aminopropane (8-OH-DPAT) into the lateral brain ventricle is connected with the activation of compensation mechanisms leading to the increase in the heart rate and blood pressure. The current results demonstrate that the stimulation of peripheral alpha-1-, alpha-2- and beta-adrenergic receptors plays an essential role in the resuscitative effect triggered by the stimulation of central serotonin 1A receptors. [Copyright &y& Elsevier]

Abstract: Background: Studies have shown that shock-induced vascular hyporeactivity is associated with the decrease in 20-kDa myosin light chain (MLC20) phosphorylation. Whether and how a non-MLC20 phosphorylation pathway participates in the regulation of vascular reactivity after shock is not known. Methods: With superior mesentery artery (SMA) obtained from rats in hemorrhagic shock and hypoxia-treated SMA, the regulatory effect of platelet-derived growth factor (PDGF) on vascular reactivity and the roles of caldesmon, 27-kDa heat shock protein (HSP27), extracellular signal–regulated protein kinase (Erk), and p38 mitogen–activated protein kinase (MAPK), the main molecules that are involved in the non-MLC20 phosphorylation pathway of the regulation of smooth-muscle contraction, were investigated. Results: PDGF (40–100 ng/mL) increased the vascular reactivity after shock in a dose-dependent manner, whereas it did not increase the MLC20 phosphorylation in a dose-dependent manner. PDGF with concentration more than 60 ng/mL did not further increase the MLC20 phosphorylation, whereas upregulated the phosphorylation of HSP27, Erk, and p38MAPK, and the activity of myosin adenosine triphosphatase in SMAs, and downregulated the phosphorylation of caldesmon. p38MAPK antagonist, SB203580, not only antagonized PDGF-induced increase in the phosphorylation of HSP27, but also antagonized PDGF-induced decrease in the phosphorylation of caldesmon, whereas Erk antagonist, PD98059, only antagonized PDGF-induced decrease in the phosphorylation of caldesmon. Conclusions: These findings suggested that a non-MLC20 phosphorylation pathway participated in the regulation of vascular reactivity after shock. Caldesmon- and HSP27-mediated change in myosin adenosine triphosphatase activity and Erk and p38MAPK played an important role in this process. These findings may provide some potential targets for the treatment of vascular hyporeactivity after shock. [Copyright &y& Elsevier]

Background: Myocardial contractile dysfunction plays a major role in the outcome of trauma patients. Nitric oxide (NO) has been shown to increase following haemorrhagic shock. Peroxynitrite which is produced by the reaction of NO with reactive oxygen species leads to nitrosative stress mediated organ injury and myocardial contractile dysfunction. Aminoguanidine is a selective inhibitor of inducible nitric oxide synthase (iNOS). Objectives: The aim of this study was to determine the protective effects of inhibiting the production of NO using aminoguanidine (AG) on myocardial contractility, following hemorrhagic shock and resuscitation in rats. Methods: Male Sprague-Dawley rats were assigned to 3 experimental groups (n = 6 per group):1) Normotensive rats (N), 2) Hemorrhagic shock rats (HS), and 3) Hemorrhagic shock rats treated with AG 60 mg/kg AG intra-arterially (HS-AG). Rats were hemorrhaged over 60 minutes to reach a mean arterial blood pressure of 40 mmHg. Rats were treated with 1 ml of 60 mg/Kg AG intra-arterially after 60 minutes haemorrhagic shock,. Resuscitation was performed in vivo by the reinfusion of the shed blood for 30 minutes to restore normo-tension. Hearts were harvested and ex vivo perfused in the Langendorff System and myocardial function was determined by measuring the left ventricular end diastolic pressure (LVEDP) and left ventricular systolic pressure (LVSP). Left ventricular generated pressure (LVGP) and + dP/dt max was calculated. Results: Hemorrhagic shock rats treated with AG exhibited a significant increase in left ventricular generated pressure LVGP (137.1±9.4 mmHg) and + dP/dtmax (589.6±110.7 mmHg/sec) compared with the untreated group (44.43±20.18 mmHg, 289.8±25.0 mmHg/sec). Conclusion: Treatment with AG protects the myocardium from post-resuscitation myocardial dysfunction. [ABSTRACT FROM AUTHOR]

The article presents a study which investigates the resuscitation with aged blood exacerbates liver injury in hemorrhagic anesthetized rat model. It states that the study was conducted at a research laboratory at the Hebrew University in Jerusalem, and used a prospective, controlled study and magnetic resonance imaging (MRI). Results show that stored blood showed reduction in the deformability of red blood cell (RBC).

Abstract: Background: In vivo or in vitro hypoxic preconditioning (HPC) can protect various tissues and cells against subsequent ischemia and/or reperfusion (hypoxia and/or reoxygenation) injury. Total HPC (THPC) in animal models is largely aimed at protecting single organs; however, scant data exist on whole body protection. The present study investigated whether THPC could protect anesthetized rats against the systemic injury induced by hemorrhagic shock and resuscitation (HS/R). Methods: The 4-cycle THPC protocol consisted of 5 min of inhalation hypoxia (fraction of inspired oxygen 10%, N2 90% plus oxygen 10%) followed by 10 min of inhalation air (oxygen 21%). An acute HS/R model of anesthetized rats was used. The experiment was divided into two parts of the Severe HS/R and Moderate HS/R, differentiated by a shed blood volume of 60% or 50% (HS/R60% or HS/R50%, respectively) of the total blood volume of rats, respectively. In the Severe HS/R part, the heart rate, respiration rate, and mean arterial pressure of the rats were measured, and the survival of the rats was observed. We examined the pathomorphologic changes in the vital organs of rats and measured the arterial blood gas, heart rate, respiration rate, and mean arterial pressure of the rats in the Moderate HS/R part. Results: THPC did not result in irreversible changes or death in the rats. The rats in the THPC + HS60%/R group had a significantly greater survival rate than those in the HS60%/R group (59% versus 33%, log-rank test, chi-square = 4.356, P = 0.037). The histopathologic lung score of the rats in the HS50%/R group (1.7 ± 0.5) was significantly greater than that in the THPC + HS50%/R (1.1 ± 0.6, P = 0.046). The arterial blood gas pH was lower in the HS50%/R group than in the THPC + HS50%/R group. THPC had a greater influence on the arterial partial pressure of oxygen and carbon dioxide than on bicarbonate radical and base excess. The respiration rate in the THPC + HS/R group was faster than that in the HS/R group. No significant differences in heart rate or mean arterial pressure were seen between the THPC + HS/R and HS/R groups. Conclusions: In anesthetized rats, THPC provided early protection against the subsequent systemic injury caused by hemorrhagic shock following resuscitation. THPC might exert systemic protection by improving the function of vital organs (e.g., lungs and, perhaps, the brain). [Copyright &y& Elsevier]

Abstract: Background: Severe hemorrhagic shock often results in cardiac arrest due to vital organ hypoperfusion, especially of the heart. Although fluid resuscitation is the mainstay of management in hemorrhagic shock, treatment of cardiac arrest in association with severe hemorrhagic shock is unclear. Objective: This study was designed to determine the effect of early infusion of norepinephrine on hemodynamics and survival in hemorrhagic shock. Methods: Twelve Sprague-Dawley rats were bled to about 35% of estimated blood volume for 30 min and randomized to one of two groups: the study group received norepinephrine (10 μg/kg/min) in 5% dextrose solution (n = 6); the control group received the same volume of 5% dextrose (n = 6) concurrently with Lactated Ringer''s solution. After 30 min of resuscitation, half of the shed blood was transfused in both groups. Time to cardiac arrest and mean arterial pressure (MAP) were compared between the two groups. Results: MAP during the resuscitation period was higher in the norepinephrine group than in the control group. Five of 6 rats in the norepinephrine group but none of the control group survived until the transfusion period (83.3% vs. 0.0%, respectively; p = 0.003). Median time to cardiac arrest was significantly longer in the norepinephrine group (67.0 min, interquartile range [IQR] 60.0–77.0) than in controls (41.0 min, IQR 40.0–47.0; p = 0.002). Conclusions: Early use of norepinephrine in a rat model of hemorrhagic shock increased mean arterial pressure during the resuscitation period and delayed the onset of cardiac arrest. [Copyright &y& Elsevier]

The article presents a study which examines the effect of billary tract external drainage on pathomorphism and cytokine expression of liver, lungs, and intestine in Sprague-Dawley rats with hemorrhagic shock. It reveals that billary tract external drainage has reduced the putrescence and exfoliation of intestinal vilii, denaturation and the infiltration of lung's inflammatory cells. It suggests that it decreases the messenger RNA expression of tumor necrosis factor and attenuate tissue injuries.

Although angiotensin II (Ang II) plays a key role in development of organ ischemia-reperfusion injury, it remains unclear whether it is involved in development of intestinal injury following trauma-hemorrhage (T-H). Studies have shown that 17β-estradiol (E2) administration following T-H improves small intestinal blood flow; however, it is unclear whether Ang II plays a role in this E2-mediated salutary effect. Male Sprague-Dawley rats underwent laparotomy and hemorrhagic shock (removal of 60% total blood volume, fluid resuscitation after 90 mm). At onset of resuscitation, rats were treated with vehicle, E2, or E2 and estrogen receptor antagonist ICI 182,780 (ICI). A separate group of rats was treated with Ang II subtype I receptor (ATIR) antagonist losartan. At 24 h after T-H, plasma Ang II, IL-6, TNF-α, intercellular adhesion molecule (ICAM)- 1, cytokine-induced neutrophil chemoattractant (CINC)-1 and CINC-3 levels, myeloper- oxidase (MPO) activity, and AT 1 R expression were determined. T-H significantly increased plasma and intestinal Ang II, IL-6, TNF-α levels, intestinal ICAM-!, CINC-!, CINC-3 levels, MPO activity, and AT1R protein compared with shams. E2 treatment following T-H attenuated increased intestinal MPO activity, Ang II level, and AT1R protein expression. ICI administration abolished the salutary effects of E2. In contrast, losartan administration attenuated increased MPO activity without affecting Ang II and AT1R levels. Thus Ang II plays a role in producing small intestine inflammation following T-H, and the salutary effects of E2 on intestinal inflammation are mediated in part by Ang II and AT1R downregulation. [ABSTRACT FROM AUTHOR]

Abstract: Background:: In volume- or pressure-controlled hemorrhagic shock (HS) a bolus intravenous infusion of hypertonic/hyperoncotic solution (HHS) proved beneficial compared to isotonic crystalloid solutions. During uncontrolled HS in animals, however, HHS by bolus increased blood pressure unpredictably, and increased blood loss and mortality. We hypothesized that a titrated i.v. infusion of HHS, compared to titrated lactated Ringer''s solution (LR), for hypotensive fluid resuscitation during uncontrolled HS reduces fluid requirement, does not increase blood loss, and improves survival. Methods:: We used our three-phased uncontrolled HS outcome model in rats. HS phase I began with blood withdrawal of 3ml/100g over 15min, followed by tail amputation. Then, hydroxyethyl starch 10% in NaCl 7.2% was given i.v. to the HHS group (n=10) and LR to the control group (n=10), both titrated to prevent mean arterial pressure (MAP) from falling below 40mmHg during HS time 20–90min. At HS 90min, resuscitation phase II of 180min began with hemostasis, return of all the blood initially shed, plus fluids i.v. as needed to maintain normotension (MAP≥70mmHg). Liver dysoxia was monitored as increase in liver surface pCO2 during phases I and II. Observation phase III was to 72h. Results:: During HS, preventing a decrease in MAP below 40mmHg required HHS 4.9±0.6ml/kg (all data mean±S.E.M.), compared to LR 62.2±16.6ml/kg (P<0.001), with no group difference in MAP. Uncontrolled blood loss during HS from the tail stump was 13.3±1.9ml/kg with HHS infusion, versus 12.6±2.5ml/kg with LR infusion (P=0.73). Serum sodium concentrations were moderately elevated at the end of HS in the HHS group (149±3mmol/l) versus the LR group (139±1mmol/l) (P=0.001), and remained elevated throughout. Liver pCO2 increased during HS in both groups equally (P<0.001 versus baseline), and tended to return to baseline levels at the end of HS. Blood gas and lactate values throughout did not differ between groups. During HS, 2 of 10 rats in the HHS group versus 0 of 10 in the LR group died (P=0.47). There was no difference between HHS and LR groups in survival rates to 72h (3 of 10 in the HHS group versus 2 of 10 in the LR group) (P=1.0). Survival times, by life table analysis, were not different (P=0.75). Conclusion:: In prolonged uncontrolled HS, a titrated i.v. infusion of HHS can maintain controlled hypotension with only one-tenth of the volume of LR required, without increasing blood loss. This titrated HHS strategy may not increase the chance of long-term survival. [Copyright &y& Elsevier]