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Objective: ET-26 HCl is a promising sedative–hypnotic anesthetic with virtually no effect on adrenocortical steroid synthesis. However, whether or not ET-26 HCl also has a sufficiently wide safety margin and hemodynamic stability similar to that of etomidate and related compounds remains unknown. In this study, the effects of ET-26 HCl, etomidate and propofol on therapeutic index, heart rate (HR), mean arterial pressure (MAP), maximal rate for left ventricular pressure rise (Dmax/t), and maximal rate for left ventricular pressure decline (Dmin/t) were investigated in healthy rats and a rat model of uncontrolled hemorrhagic shock (UHS). Methods: 50% effective dose (ED50) and 50% lethal dose (LD50) were determined after single bolus doses of propofol, etomidate, or ET-26 HCl using the Bliss method and the up and down method, respectively. All rats were divided into either the normal group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group) or the UHS group and received either etomidate, ET-26 HCl or propofol, (n = 6 per group). In the normal group, after preparation for hemodynamic and heart-function monitoring, rats were administered a dose of one of the test agents twofold-higher than the established ED50, followed by hemodynamic and heart-function monitoring. Rats in the UHS group underwent experimentally induced UHS with a target arterial pressure of 40 mmHg for 1 hour, followed by administration of an ED50 dose of one of the experimental agents. Blood-gas analysis was conducted on samples obtained during equilibration with the experimental setup and at the end of the experiment. Results: In the normal group, no significant differences in HR, MAP, Dmax/t and Dmin/t (all P > 0.05) were observed at any time point between the etomidate and ET-26 HCl groups, whereas HR, MAP and Dmax/t decreased briefly and Dmin/t increased following propofol administration. In the UHS group, no significant differences in HR, MAP, Dmax/t and Dmin/t were observed before and after administration of etomidate or ET-26 HCl at ED50 doses (all P > 0.05). Administration of propofol resulted in brief, statistically significant reductions in HR and Dmax/t, with a brief increase in Dmin/t (P ˂ 0.05), while no significant differences in MAP were observed among the three groups. The blood-lactate concentrations of rats in the ET-26 HCl group were significantly lower than those in etomidate and propofol groups (P ˂ 0.05). Conclusions: ET-26 HCl provides a similar level of hemodynamic stability to that obtained with etomidate in both healthy rats, and rat models of UHS. ET-26 HCl has the potential to be a novel induction anesthetic for use in critically ill patients. [ABSTRACT FROM AUTHOR]

Background The plasmin/plasminogen inhibitor tranexamic acid (TXA) is mainly used in elective surgeries with a higher blood loss to avoid uncontrolled bleeding. Recently, TXA has also been shown to reduce mortality in trauma patients. It is assumed that its beneficial effects are principally caused by its antifibrinolytic properties. We hypothesize that TXA also improves survival in a modified Wigger's model of hemorrhagic shock by a mechanism other than antifibrinolysis. Materials and methods Male Wistar rats were intermittently bled until the mean arterial blood pressure was dropped to 25-30 mm Hg (severe shock). After shock induction, the animals received either 0.14-0.15 mL TXA (30 mg/kg) i.v. or the equivalent volume of 0.9% NaCl given as bolus. Adjacent to the shock period, the rats were resuscitated with Ringer's solution within 30 min and observed for another 150 min unless the animals died earlier. Results In the animals treated with TXA, survival was clearly prolonged and acid–base parameters showed some differences as compared to the animals receiving only NaCl. In the model used, coagulation slightly declined, but an increased fibrinolysis was not observed. Conclusions Since in the applied shock model fibrinolysis is negligible, we postulate that TXA is capable of providing protection against hemorrhagic shock independent from its antifibrinolytic properties. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that the hypothalamus participates in the decompensatory phase of hemorrhage by measuring Fos immunoreactivity and by inhibiting neuronal activity in selected hypothalamic nuclei with lidocaine or cobalt chloride. Previously, we reported that inactivation of the arcuate nucleus inhibited, but did not fully prevent, the fall in arterial pressure evoked by hypotensive hemorrhage. Here, we report that hemorrhage (2.2 ml/100 g body weight over 20 min) induced Fos expression in a high percentage of cells in the paraventricular, supraoptic and arcuate nuclei of the hypothalamus as shown previously. Lower densities of Fos immunoreactive cells were also found in the medial preoptic area (mPOA), anterior hypothalamus, lateral hypothalamus (LH), dorsomedial hypothalamus, ventromedial hypothalamus (VMH) and posterior hypothalamus. Bilateral injection of lidocaine (2%; 0.1 μl or 0.3 μl) or cobalt chloride (5 mM; 0.3 μl) into the tuberal portion of the LH immediately before hemorrhage was initiated reduced the magnitude of hemorrhagic hypotension and bradycardia significantly. Lidocaine injection into the VMH also attenuated the fall in arterial pressure and heart rate evoked by hemorrhage although inactivation of the mPOA or rostral LH was ineffective. These findings indicate that hemorrhage activates neurons throughout much of the hypothalamus and that a relatively broad area of the hypothalamus, extending from the arcuate nucleus laterally through the caudal VMH and tuberal LH, plays an important role in the decompensatory phase of hemorrhage. [ABSTRACT FROM AUTHOR]

Background Vascular hyporeactivity in severe hemorrhagic shock could induce refractory hypotension and is an important cause of death. The global acute inflammatory response induced in shock triggers the over-expression of reactive oxygen species, NO, ET1 and TNF-α, which play essential roles in the pathology of vascular hyporeactivity. This leads to a hypothesis that inhibition of the complement system, the mediator of the inflammatory cascade, might be a promising therapeutic exploration for vascular hyporeactivity. Methods We use cobra venom factor (CVF) and the soluble form of CR1 (sCR1) which deplete or inhibit complement C3 respectively to examine its role in vascular hyporeactivity in a conscious hemorrhagic shock rat model. Results We first confirmed the over-activation of C3 during shock and the down-regulation effects of CVF and sCR1 on C3. Then, both CVF and sCR1 could significantly mitigate the over-expression of serum NO, ET-1, TNF-α and reactive oxygen species. Finally, the vascular reactivity of superior mesenteric arteries (SMA) was examined in vitro, which confirmed the massive reduction of vascular reactivity in shock, which was significantly rescued by both CVF and sCR1. Conclusions Inhibition of C3 might improve the reactivity of SMA to norepinephrine during hemorrhagic shock possibly through the downregulation of NO, ET1, TNF-α and reactive oxygen radicals. [ABSTRACT FROM AUTHOR]

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]

Our study intended to determine the effects on oxygen uptake ( V ˙ O 2 ) of restoring a normal rate of O 2 delivery following blood transfusion (BT) after a severe hemorrhage (H). Spontaneously breathing urethane anesthetized rats were bled by removing 20 ml/kg of blood over 30 min. Rats were then infused with their own shed blood 15 min after the end of H. At mid-perfusion, half of the rats received a unique infusion of the decoupling agent 2,4-dinitrophenol (DNP, 6 mg/kg). V ˙ O 2 and arterial blood pressure (ABP) were continuously measured throughout the study, along with serial determination of blood lactate concentration [La]. Animals were euthanized 45 min after the end of reperfusion; liver and lungs were further analyzed for early expression of oxidative stress gene using RT-PCR. Our bleeding protocol induced a significant decrease in ABP and increase in [La], while V ˙ O 2 dropped by half. The O 2 deficit progressively accumulated during the period of bleeding reached −114 ± 53 ml/kg, just before blood transfusion. Despite the transfusion of blood, a significant O 2 deficit persisted (−82 ± 59 ml/kg) 45 min after reperfusion. This slow recovery of V ˙ O 2 was sped up by DNP injection, leading to a fast recovery of O 2 deficit after reperfusion, becoming positive (+460 ± 132 ml/kg) by the end of the protocol, supporting the view that O 2 supply is not the main controller of V ˙ O 2 dynamics after BT. Of note is that DNP also enhanced oxidative stress gene expression (up-regulation of NADPH oxidase 4 in the lung for instance). The mechanism of slow recovery of O 2 requirement/demand following BT and the resulting effects on tissues exposed to relatively high O 2 partial pressure are discussed. [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]

Nitric oxide (NO) participates in shock and poorer portal hypotensive effect to vasoconstrictors in portal hypertension with hemorrhage, the so-called splanchnic hyposensitivity. Relative adrenal insufficiency accompanies hemorrhagic shock and is found in liver disease, the ‘hepatoadrenal syndrome’, but the relevant interactions remain unsettled. Portal hypertensive rats were induced by partial portal vein ligation (PVL). Experiments were performed on the 14th day post PVL: (I) ACTH stimulation test for rats without or with hemorrhage; (II) Glypressin response (mean arterial pressure, MAP; portal pressure, PP) in rats (a) without hemorrhage or with hemorrhage, injected with (b) distilled water (DW), (c) dexamethasone 3 mg/kg; (III) To survey the dose-dependent effects of glucocorticoid without being confounded by endogenous adrenal hormone, glypressin response was surveyed in PVL rats with adrenalectomy: (a) without hemorrhage or with hemorrhage, injected with (b) DW; (c) dexamethasone 3 mg/kg; (d) dexamethasone 5 mg/kg. Plasma tumor necrosis factor-α (TNF-α) concentrations and abdominal aorta (AA), superior mesenteric artery (SMA) NO synthases (NOS) mRNA expressions were determined. The results showed that ACTH induced corticosterone release similarly in PVL rats with or without hemorrhage. In bleeding PVL rats, dexamethasone (1) down-regulated AA NOS and enhanced glypressin-induced MAP elevation; (2) did not influence glypressin-induced PP reduction; (3) reduced TNF-α. In bleeding PVL and adrenalectomized rats, high-dose dexamethasone (1) down-regulated AA/SMA NOS; (2) enhanced glypressin-induced MAP elevation and PP reduction; (3) reduced TNF-α. In conclusion, bleeding portal hypertensive rats failed to enhance corticosterone release, suggesting a relative adrenal insufficiency. High-dose dexamethasone reversed systemic hypotension and splanchnic hyporesponsiveness to glypressin in adrenalectomized PVL rats accompanied by TNF-α and NOS down-regulation, suggesting the importance of adequate adrenocorticoid supplement in portal hypertension with hemorrhage and adrenal dysfunction. [ABSTRACT FROM AUTHOR]

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]

Abstract: Aims: Hemorrhagic shock leads to a higher risk of mortality and morbidity in obese patients, however the mechanisms for these outcomes are unclear. We hypothesized that following severe hemorrhage, blood pressure control in conscious obese Zucker rats (OZ) is impaired. Main methods: Experiments were performed in conscious lean Zucker rats (LZ) and OZ. Blood pressure, heart rate, cardiac output, total peripheral resistance (TPR), plasma renin activity (PRA), plasma antidiuretic hormone (ADH), and blood gasses were measured before and after severe hemorrhage (35% of the total blood volume). Key findings: Basal blood pressure, cardiac output, TPR, PRA, and ADH levels were not different between LZ and OZ. Compared to LZ, OZ exhibited impaired baroreflex control of heart rate and showed higher levels of vascular adrenergic tone. One hour after the hemorrhage, LZ and OZ exhibited similar decreases in cardiac output. However, blood pressure, heart rate, TPR, PRA, and ADH levels were lower in OZ than in LZ. Significance: These results indicate that conscious OZ has impaired blood pressure compensation after hemorrhage due to a blunted increase in TPR. This is due at least in part to an impaired regulation of vasoconstrictor hormones. To our knowledge, the current study is the first to demonstrate that hemodynamic responses and associated hormone secretion are impaired in a conscious obese model. [Copyright &y& Elsevier]

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).

Introduction: Different vasoactive factors can modulate cardiovascular adaptation to hemorrhagic shock including Nitric Oxide (NO). In this study we investigated the effect of the NO synthase inhibitor for treatment of decompensated hemorrhagic shock in normotensive and hypertensive rats. Methods: Twenty-four male Wistar rats were divided into two groups: The normotensive and hypertensive groups. Hypertension was induced by the DOCA-Salt method for eight weeks. Then, the animals were given hemorrhagic shock by continuously withdrawing blood until the mean arterial pressure (MAP) reached to 40 mmHg. The animals were maintained in the shock state for 120 minutes. Subsequently, they were randomly assigned to L-NAME-treated and non-treated groups and monitored for 60 minutes. The survival time was recorded. Blood samples were taken before and after the shock and 60 minutes after L-NAME administration. Results: Infusion of L-NAME caused a significant increase in MAP in normotensive animals, however, slightly increased MAP in hypertensive animals. The heart rate did not significantly alter. Hemorrhage caused a marked increase in serum nitrite levels in both groups (P<0.05). L-NAME treatment significantly reduced the serum nitrite concentration in the normotensive group (P<0.05), without any change in the hypertensive group. All animals who received L-NAME treatment survived at the end of experiment. Fifty percent of the hypertensive animals died four hours after the experiment. The 72-hour survival rate was similar in the L-NAME treated groups. Conclusion: L-NAME infusion during decompensated hemorrhagic shock plays a protective role in the improvement of hemodynamic responses and short-term survival rate in normotensive animals. [ABSTRACT FROM AUTHOR]

Abstract: Background: We have previously demonstrated that treatment with histone deacetylase inhibitors (HDACI), such as valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), can improve survival after hemorrhagic shock in animal models. Hemorrhage results in hypoacetylation of proteins which is reversed by HDACI. These agents are known to acetylate insulin receptor substrate-I (IRS-I), which in turn activates the Akt survival pathway. This study investigated whether HDACI exert their beneficial effects through the Akt survival pathway. Methods: Wistar–Kyoto rats (N =21) underwent hemorrhage (60% blood loss) and were randomized into 3 groups; no resuscitation (NR), and treatment with VPA or SAHA. Kidneys were harvested at 1, 6, and 24h after HDACI treatment and analyzed for acetylated histone 3 at lysine 9 residue (Ac-H3K9), phosphorylated Akt (phospho-Akt), BAD and Bcl-2 proteins. Results: Hemorrhaged animals were in severe shock, with mean arterial pressures of 25–30mmHg and lactic acid 7–9mg/ml. Only animals treated with VPA and SAHA survived to the 6- and 24-h timepoints. Treatment with HDACI produced a biologic effect on rat kidney cells inducing acetylation of histone H3K9, which peaked after 1h of treatment, and was statistically significant in the VPA group (p =0.01) compared to NR. Phospho-Akt protein increased in the VPA group with a reciprocal decrease in the pro-apoptotic BAD protein in both groups which was statistically significant in the VPA group after 1h (p =0.007) and 24h (p =0.006) of treatment and in the SAHA group after 24h of treatment (p =0.028). Anti-apoptotic Bcl-2 protein markedly increased after 6 (p =0.04) and 24h (p =0.014) of VPA treatment. Bcl-2 also increased in the SAHA group, but failed to reach statistical significance. Conclusion: Treatment with HDACI increases phosphorylation of Akt with a subsequent decrease in the pro-apoptotic BAD protein. The above mechanism facilitates the action of anti-apoptotic protein Bcl-2. HDACI protect kidney cells subjected to hemorrhagic shock in rodents through the Akt survival pathway. [Copyright &y& Elsevier]

Introduction: The aim of this study is to evaluate whether hemorrhage and resuscitation affect liver, intestinal, and renal expressions of heat shock protein 70 (HSP70), inducible nitric oxide synthase (iNOS), and apoptosis indexes (TUNEL, caspase-3 activation) and whether the expression of these proteins can be modulated by pyrrolidine dithiocarbamate (PDTC) after a nonlethal hemorrhagic shock (HS) in rats. Methods: Forty rats were randomized into four groups: sham-operated, only HS, HS/resuscitation with blood plus normal saline (NS), and HS/resuscitation with blood/NS plus PDTC, 15 mg/kg body weight, intravenously. Rats were subjected to HS by blood removal to a mean arterial pressure of 35-40 mmHg through the femoral artery. After 1 hr of shock, the animals were resuscitated according to the experimental protocol. HSP70, iNOS, cleaved caspase-3 expression, and TUNEL were analyzed in liver, small intestine, and kidney 3 hr after resuscitation. Results: HS upregulated HSP70, iNOS, cleaved caspase-3 expression, and induced apoptosis (TUNEL) ( p < .05 to < .001). Resuscitation was not associated with further increase of their expressions. The administration of PDTC during resuscitation decreased liver, intestinal, and renal activation of iNOS and apoptosis indexes ( p < .05 to < .001), and was associated with further increase in HSP70 expression ( p < .05). Conclusions: Our results show that HS resuscitation with PDTC modulates several signaling pathways (HSP70, iNOS, TUNEL, and caspase-3) in a rat model. The results suggest that PDTC administration-by reducing apoptosis and iNOS expression-may have a potential role in minimizing organ damage after severe hemorrhage. [ABSTRACT FROM AUTHOR]

The article presents a study which identifies whether increasing levels of O-linked β-N-acetylglucosamine (O-GlcNAc) could ameliorate post trauma-hemorrhage and resuscitation (TH-R). The study which adapted the volume-controlled hemorrhagic shock model, used male adult Sprague-Dawley rats wherein their organ injuries and inflammatory responses were examined. The result shows that O-GlcNAc increasing levels could ameliorate the 24-hr survival after undergoing a trauma hemorrhage.

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]

Pentraxin 3 (PTX3) is an acute-phase protein, which can be produced by a variety of tissue cells at the site of infection or inflammation. It plays an important role in innate immunity in the lung and in mediating acute lung injury. The aim of this study was to determine the effect of mechanical ventilation on PTX3 expression in multiple lung injury models. Male Sprague-Dawley rats were challenged with intravenous injection of lipopoly-saccharide (LPS) or hemorrhage followed by resuscitation (HS). The animals were then subjected to either relatively higher (12 mI/kg) or lower (6 mI/kg, positive end-expiratory pressure of 5 cmH2O) volume ventilation for 4 h. High-volume ventilation significantly enhanced PTX3 expression in the lung, either alone or in combination with LPS or hemorrhage. A significant increase of PTX3 immunohistochemistry staining in the lung was seen in all injury groups. The PTX3 expression was highly correlated with the severity of lung injury determined by blood gas, lung elastance, and wet-to-dry ratio. To determine the effects of HS, LPS, or injurious ventilation (25 mI/kg) alone on PTX3 expression, another group of rats was studied. Injurious ventilation significantly damaged the lung and increased PTX3 expression. A local expression of PTX3 induced by high-volume ventilation, either alone or in combination with other pathological conditions, suggests that it may be an important mediator in ventilator-induced lung injury. [ABSTRACT FROM AUTHOR]

Previous studies showed that females in the proestrus stage of the reproductive cycle maintain organ functions after trauma-hemorrhage. However, it remains unknown whether the female reproductive cycle is an important variable in the regulation of lung injury after trauma-hemorrhage and, if so, whether the effect is mediated via upregulation of heme oxygenase (HO)-1. To examine this, female Sprague-Dawley rats during diestrus, proestrus, estrus, and metestrus phases of the reproductive cycle or 14 days after ovariectomy underwent soft tissue trauma and then hemorrhage (mean blood pressure 40 mmHg for 90 min followed by fluid resuscitation). At 2 h after trauma-hemorrhage or sham operation, lung myeloperoxidase (MPO) activity and intercellular adhesion molecule (ICAM)-1, cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-3, and HO-1 protein levels were measured. Plasma 17β-estradiol concentration was also determined. The results indicated that trauma-hemorrhage increased lung MPO activity and ICAM-1, CINC-1, and CINC-3 levels in ovariectomized females. These parameters were found to be similar to sham-operated animals in proestrus female rats subjected to trauma-hemorrhage. Lung HO-1 protein level in proestrus females was increased significantly compared with female rats subjected to trauma-hemorrhage during diestrus, estrus, and metestrus phases of the reproductive cycle and ovariectomized rats. Furthermore, plasma 17β-estradiol level was highest in proestrus females. Administration of the HO inhibitor chromium mesoporphyrin prevented the attenuation of shock-induced lung damage in proestrus females. Thus these findings suggest that the female reproductive cycle is an important variable in the regulation of lung injury following trauma-hemorrhage and that the protective effect in proestrus females is likely mediated via upregulation of HO-1. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Nitric oxide has been implicated in the cardiovascular adaptation to hemorrhagic shock. Our aim was to study the potential role of nitric oxide synthases (NOS) in the cardiovascular response in hemorrhagic hypotension produced experimentally in anesthetized rats. Methods: Groups of animals (n =14, per group): (a) normotensive; (b) hypovolemic (20% blood loss); (c) normotensive and pretreatment with N G-nitro-l-arginine methyl ester (l-NAME); (d) hypovolemic and pretreatment with l-NAME. Results: l-NAME restored the hypotension induced by hemorrhage. Blood loss decreased heart rate in the first stage increasing at 60 and 120 min. l-NAME blunted this effect. Right atria and left ventricle histochemical NOS activities increased at 60 and 120 min (atria 8% and 24%, respectively; ventricle 21% and 45%, respectively). This activity increased 17% in smooth muscle at 120 min. Heart endothelial NOS protein levels increased in heart at 60 min being attenuated at 120 min. Inducible NOS protein levels raised significantly in right atria, left ventricle and aorta at 120 min. Conclusion: Hemorrhagic shock induced a time-dependent and specific NOS activation modulating cardiovascular function. The inhibition of nitric oxide system appears to prevent the acceleration of heart rate during late phases after acute hypovolemic state induced by blood loss. [Copyright &y& Elsevier]

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]

Uncontrolled hemorrhage, resulting from traumatic injuries, continues to be the leading cause of death in civilian and military environments. Hemorrhagic deaths usually occur within the first 6 hours of admission to hospital; therefore, early prehospital identification of patients who are at risk for developing shock may improve survival. The aims of the current study were: 1. To establish and characterize a unique model of uncontrolled internal hemorrhage induced by massive renal injury (MRI), of different degrees (20-35% unilateral nephrectomy) in rats, 2. To identify early biomarkers those best predict the outcome of severe internal hemorrhage. For this purpose, male Sprague Dawley rats were anesthetized and cannulas were inserted into the trachea and carotid artery. After abdominal laparotomy, the lower pole of the kidney was excised. During 120 minutes, hematocrit, pO2, pCO2, base excess, potassium, lactate and glucose were measured from blood samples, and mean arterial pressure (MAP) was measured through arterial tracing. After 120 minutes, blood loss was determined. Statistical prediction models of mortality and amount of blood loss were performed. In this model, the lowest blood loss and mortality rate were observed in the group with 20% nephrectomy. Escalation of the extent of nephrectomy to 25% and 30% significantly increased blood loss and mortality rate. Two phases of hemodynamic and biochemical response to MRI were noticed: the primary phase, occurring during the first 15 minutes after injury, and the secondary phase, beginning 30 minutes after the induction of bleeding. A Significant correlation between early blood loss and mean arterial pressure (MAP) decrements and survival were noted. Our data also indicate that prediction of outcome was attainable in the very early stages of blood loss, over the first 15 minutes after the injury, and that blood loss and MAP were the strongest predictors of mortality. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Hemorrhage alone without concomitant trauma often results in a hypercoagulable state that makes it difficult to prevent clotting within the blood withdrawal catheters. Although systemic administration of heparin can ameliorate this problem, heparin use has many additional actions that may confound interpretation of the hemorrhage experiments. The problem can be resolved by the use of a dual lumen catheter that anticoagulates only the blood within the withdrawal circuit. We describe the design of such a catheter and evaluate its function in studies of hemorrhagic shock in rats. Materials and methods: Construction directions are provided for the dual lumen catheter along with a commercial source. The catheters were connected to computer controllable infusion syringes. Either citrate or heparin was used for regional extracorporeal anticoagulation. Rats were anesthetized and hemorrhaged to 40mmHg for more than 15min through the use of a computer program written in Labview. Ionized calcium measurements were obtained pre- and posthemorrhage. Results: The catheters remained patent throughout the experiments. There was no significant difference in the ionized calcium whether citrate or heparin was used for extracorporeal anticoagulation. Conclusion: The dual lumen catheters are suitable for the study of hemorrhagic shock in rats without the need for systemic anticoagulation. The catheters can be used with computer-controlled hemorrhage procedures. [Copyright &y& Elsevier]

Acute blood loss triggers heightened vasoconstriction which contributes to maintenance of the blood pressure. Hemorrhage also induces shock proteins, including heme oxygenase (HO)-1. HO metabolizes heme to form carbon monoxide (CO), which inhibits nitric oxide synthase to promote endothelial dysfunction. This study examines the hypothesis that hemorrhage induces HO-1, to enhance CO production and promote endothelial dysfunction which contributes to the restoration of blood pressure. Male Sprague-Dawley rats (300-350g) with chronic femoral arterial catheters were subjected to a 45% hemorrhage (shock). Hemorrhage produced vasodepression from 117±2 mmHg to 78±6 mmHg in 1 hour. At 36hrs, vascular HO-1 was induced (shock: 2.7±0.3 vs unbled: 1.1±0.2 ng/mg Pr), which was accompanied by a 25% increase in expired CO and restoration of arterial pressures to 106±2 mmHg. First order gracilis muscle arterioles, isolated from each group, were mounted in a microvessel chamber, superfused with oxygenated Krebs buffer and exposed to constant midpoint, but altered endpoint pressures to establish graded levels of luminal flow (0-50µL/min). Flow-induced dilation was abolished in shock arterioles (Δmax 0±0µm vs Δmax18±1µm, shock vs unbled; P<0.05). Acute pretreatment with an inhibitor of HO, chromium mesoporphyrin (15µmol/L) restored flow-induced dilation to control levels (Δmax 30±1µm). These data show that hemorrhagic shock can induce HO-1 to increase CO formation and promote endothelial dysfunction. Accordingly it suggests that shock induced increases in CO formation may contribute to the restoration of blood pressure via its well established ability to inhibit nitric oxide synthase. [ABSTRACT FROM AUTHOR]

WHPC extends the survival of mice exposed to lethal environmental hypoxia by preserving structural and functional integrity of key organs. We now examined whether WHPC would also prolong survival in response to hemorrhagic shock. Conscious male rats were subjected to bleeding of 60% of their estimated blood volume (∼37.2 ml/kg) over 30 min. We found that naïve rats died 76+9 min after the completion of bleeding (n=15) and this process was associated with progressively increasing metabolic acidosis and cell/organ injury. In contrast, more than 80% of rats treated with WHPC (6 cycles of 8% O2x10-min/21% O2x10-min) 2 h before bleeding survived >6 h without fluid resuscitation (n=14, p<0.001) and displayed significantly reduced acidosis and cell/organ injury. Although it decreased drastically following bleeding in all rats, Oz consumption in those treated with WHPC was significantly higher, suggesting better tissue perfusion in these animals. Furthermore, surviving animals appeared to be recovering from the initial impact of massive blood loss, with accelerated compensation and sustained maintenance of key variables above critical levels (mean arterial pressure >60 mmHg, blood base excess >-6 mmol/L, and plasma lactate <5 mmol/L). WHPC treatment 8 h before bleeding was associated with similar beneficial effects. We conclude that WHPC provides a robust protective mechanism against acute hemorrhagic shock. [ABSTRACT FROM AUTHOR]

Hemorrhagic shock reflects low tissue perfusion that is inadequate to maintain normal metabolic functions. Often associated with this condition are impairments in cellular oxygen utilization. Rats bred for high (HCR) vs low (LCR) aerobic running capacity have greater O2 uptake and improved cardiovascular function (Gonzalez et al., J Appl Physiol 101: 1288, 2006). Hence, it was hypothesized that HCR would be more tolerant to global ischemia than LCR. To address this hypothesis, survival time to a severe controlled hemorrhage was measured. Male rats (generation 12) were catheterized and, ∼ 24 hours later, 55% of the calculated blood volume was removed during a 26 min period from conscious unrestrained animals. Rats were observed for 6 hr or until death. Contrary to our hypothesis, survival time in HCR (173 ± 55 min; n=8) did not differ (P = 0.24) from that in LCR (254 ± 52 min; n=8). Similarly, there were no differences between strains in blood pH, lactate, and base deficit values pre or post-hemorrhage. Since oxygen uptake and cardiac function are different in these rat strains, these results suggest that other mechanisms must play a more dominant role in determining survival time to hemorrhage. [ABSTRACT FROM AUTHOR]