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Background: Uncontrolled hemorrhage (UH) remains the most common cause of death on the battlefield. This study examined the pathophysiological characteristics of UH in rats acutely exposed to high altitude., Material and Methods: Rats raised at sea level were randomly divided into two groups. Rats in the high-altitude group were exposed to hypobaric hypoxia in a hypobaric chamber (simulating 4000 m above sea level) for 2 d and then were performed a hemorrhagic shock protocol in the hypobaric chamber. Rats that underwent the same hemorrhage procedure at sea level were used as control. Anesthetized rats were bled to maintain their mean arterial pressure at 45 mmHg for 1 h. The distal quarter of the tail was amputated to allow free blood loss. After 1 h, the tail cut was ligated to induce hemostasis. mean arterial pressure, acid-base balance, blood loss, and survival were recorded. Rats were killed, and tissues were obtained for histological analysis., Results: Rats in the high-altitude group suffered less uncontrolled blood loss, more severe acidosis (lower pH and base excess), and inferior tissue oxygen supply (lower oxygen saturation and higher arterial lactate concentration) during the hemorrhage periods compared with the control group. Survival rates were significantly lower in the high-altitude group than those in the control group (P < 0.05), which was consistent with the results of pathological tissue injury., Conclusions: In this rat model of hemorrhagic shock, acute high-altitude exposure resulted in decreased UH but more serious hemorrhagic shock injuries than that at sea level., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Oxidative stress induced by hemorrhagic shock (HS) is known to initiate a systemic inflammatory response, which leads to subsequent acute lung injury. This study is aimed to assess the efficacy of exendin-4 (Ex-4) in attenuating lung injury in a rat model of HS and resuscitation (HS/R)., Methods: HS was induced in sodium pentobarbital-anesthetized adult male Wistar rats by withdrawing blood to maintain a mean arterial pressure of 30-35 mm Hg for 50 min. Then, the animals received Ex-4 (5 μg/kg) or vehicle (saline) intravenously and were resuscitated with a volume of normal saline 1.5 times that of the shed blood volume. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, and lung injury were evaluated at 2 h after resuscitation., Results: Ex-4 infusion reduced the methemoglobin content, the malondialdehyde content, the myeloperoxidase activity, and the expression of tumor necrosis factor-α and interleukin-6 in the lungs. The histologic injury was also markedly decreased in the Ex-4 group compared with the vehicle group., Conclusions: Ex-4 ameliorates the oxidative stress, inflammatory response, and subsequent acute lung injury occurring after HS/R. Although future studies are required to elucidate the underlying mechanism, our results indicate that Ex-4 infusion may be a promising strategy for improving lung injury in the treatment of HS., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Several kinds of crystalloid solutions have been used in the treatment of hemorrhagic shock (HS). Clinicians are faced with how to select the resuscitation fluids. The aim of the present study is to compare the effects of 3 crystalloid solutions, such as normal saline (NS), lactated Ringer's (LR), and Plasma-lyte A (PA), on acid-base status and intestine injury in rats subjected to HS., Methods: Thirty Wistar rats were divided into 4 groups. The sham group had no blood withdrawal. The other groups were subjected to severe HS and then injected with NS, LR, or PA. All treatments were followed with an infusion of red blood cell suspension. The mean arterial pressure was monitored throughout the experiment. The arterial blood gas, malonaldehyde, and myeloperoxidase levels in the small intestine were assayed 120 minutes after resuscitation., Results: Plasma-lyte A treatment could restore the pH, base excess (BE), HCO 3 - , Pao 2 , and Paco 2 . Comparing with sham group, NS failed to correct the decreased pH, BE, and HCO 3 - (P < .05), whereas LR treatment showed the decreased BE and HCO 3 - (P < .05) and increased Pao 2 (P < .05). There were no significant differences in malonaldehyde among the 4 groups (P > .05). Both PA and LR were more effective than NS in decreasing the myeloperoxidase level in the small intestine (P < .01)., Conclusions: Although the 3 crystalloid solutions play different roles, PA is better at correcting the acid-base balance and improving intestine injury during HS than NS and LR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Oxidative stress induced by hemorrhagic shock (HS) initiates a systemic inflammatory response, which leads to subsequent kidney injury. This study assessed the efficacy of c-type natriuretic peptide (CNP) in attenuating kidney injury in a rat model of hemorrhagic shock and resuscitation (HS/R). Sodium pentobarbital-anesthetized adult male Wistar rats underwent HS induced by the withdrawal of blood to a mean arterial pressure of 30-35 mmHg for 50 min. Then, the animals received CNP (25 μg/kg) or vehicle (saline) intravenously, followed byresuscitation with 1.5 times the shed blood volume in the form of normal saline. Mean arterial pressure was measured throughout the experiment, and acid-base status, oxidative stress, inflammation, tissue injury and kidney function were evaluated after resuscitation. CNP infusion reduced the malondialdehyde content, lowered the myeloperoxidase activity and decreased the expression of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β in the kidney. The histologic injury score and the plasma creatinine concentration were also significantly decreased after CNP treatment compared to the vehicle group. CNP treatment ameliorates oxidative stress, the inflammatory response, and consequently acute kidney injury after HS/R. Thus, CNP may represent a promising strategy to improve resuscitation for the treatment of HS and deserves further investigation.

Hemorrhagic shock/resuscitation involves overwhelming reactive oxygen species (ROS) that cause oxidative stress, inflammation, and subsequent tissue injury. We investigated the effects of the potent antioxidant carboxyfullerene (C 3 ) on acute liver injury during hemorrhage shock/resuscitation. C 3 infusion reduced the alanine aminotransferase (ALT) activity, methemoglobin content, malondialdehyde content, myeloperoxidase activity and expression levels of tumor necrosis factor -α and interleukin-6; it increased superoxide dismutase activity in the liver. The histologic injury score and apoptotic index were also markedly decreased after C 3 treatment compared with the vehicle group. Additionally, C 3 -treated rats showed a significant decrease in nuclear factor-κB DNA binding capacity, which was preceded by reduced phosphorylation of the nuclear factor κB (NF-κB) p65 subunit in the liver. C 3 nanoparticles ameliorate oxidative stress, the inflammatory response, and subsequent acute liver injury after hemorrhagic shock/resuscitation. These protective effects appear to be mediated through the inhibition of the nuclear factor-κB pathway. C 3 treatment may be a promising strategy to improve tissue injury in hemorrhagic shock/resuscitation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Gradually increased oxygen administration (GIOA) seems promising in hemorrhagic shock. However, the effects of GIOA on survival remain unclear, and details of GIOA are to be identified. After the induction of hemorrhagic shock, the rats were randomized into five groups (n = 9): normoxic group (Normo), hyperoxic group (Hypero), normoxic to hyperoxic group (GIOA1), long-time hypoxemic to hyperoxic group (GIOA2), and short-time hypoxemic to hyperoxic group (GIOA3). Survival was recorded for 96 h, plasma alanine transaminase, oxidative stress, hemodynamics, and blood gas were measured. The mean survival time of the GIOA3 was significantly longer than that of the Normo, Hypero, and GIOA2. Plasma alanine transaminase levels were significantly lower in the Normo, GIOA1, and GIOA3 compared to the Hypero and GIOA2 at 2 h post-resuscitation (PR). Plasma 3-nitrotyrosine levels at 2 h PR were significantly lower in the GIOA2 and GIOA3 compared to the Normo and Hypero. Central venous oxygen saturation at 2 h PR in the GIOA3 was significantly higher than the Normo; however, no significant difference was observed between GIOA1 and Normo. Besides, at 2 h PR, mean arterial pressure in the GIOA3 was significantly higher than the GIOA2; however, no significant difference was observed between GIOA1 and GIOA2. (1) GIOA could significantly prolong survival time compared to normoxemic resuscitation and hyperoxic resuscitation; (2) early moments of GIOA are critical to the benefits; and (3) hypoxemia at onset of resuscitation may be imperative, more works are needed to determine the optimal initial oxygen concentration of GIOA., (© 2016 by the Society for Experimental Biology and Medicine.)

Background: The optimal oxygen administration strategy during resuscitation from hemorrhagic shock (HS) is still controversial. Improving oxygenation and mitigating oxidative stress simultaneously seem to be contradictory goals. To maximize oxygen delivery while minimizing oxidative damage, the authors proposed the notion of gradually increased oxygen administration (GIOA), which entails making the arterial blood hypoxemic early in resuscitation and subsequently gradually increasing to hyperoxic, and compared its effects with normoxic resuscitation, hyperoxic resuscitation, and hypoxemic resuscitation in severe HS., Methods: Rats were subjected to HS, and on resuscitation, the rats were randomly assigned to four groups (n = 8): the normoxic, the hyperoxic, the hypoxemic, and the GIOA groups. Rats were observed for an additional 1 h. Hemodynamics, acid-base status, oxygenation, and oxidative injury were observed and evaluated., Results: Central venous oxygen saturation promptly recovered only in the hyperoxic and the GIOA groups, and the liver tissue partial pressure of oxygen was highest in the GIOA group after resuscitation. Oxidative stress in GIOA group was significantly reduced compared with the hyperoxic group as indicated by the reduced malondialdehyde content, increased catalase activity, and the lower histologic injury scores in the liver. In addition, the tumor necrosis factor-α and interleukin-6 expressions in the liver were markedly decreased in the GIOA group than in the hyperoxic and normoxic groups as shown by the immunohistochemical staining., Conclusions: GIOA improved systemic/tissue oxygenation and mitigated oxidative stress simultaneously after resuscitation from severe HS. GIOA may be a promising strategy to improve resuscitation from HS and deserves further investigation.

Objective: The goal of this study was to investigate the effect of hypertonic saline with 6% Dextran-70 (HSD) resuscitation on organ damage and the resuscitation efficiency of the combination of HSD and lactated ringers (LR) in a model of hemorrhage shock in dogs., Methods: Beagles were bled to hold their mean arterial pressure (MAP) at 50 ± 5 mmHg for 1 h. After hemorrhage, beagles were divided into three groups (n = 7) to receive pre-hospital resuscitation for 1 h (R1): HSD (4 ml/kg), LR (40 ml/kg), and HSD+LR (a combination of 4 ml/kg HSD and 40 ml/kg LR). Next, LR was transfused into all groups as in-hospital resuscitation (R2). After two hours of observation (R3), autologous blood was transfused. Hemodynamic responses and systemic oxygenation were measured at predetermined phases. Three days after resuscitation, the animals were sacrificed and tissues including kidney, lung, liver and intestinal were obtained for pathological analysis., Results: Although the initial resuscitation with HSD was shown to be faster than LR with regard to an ascending MAP, the HSD group showed a similar hemodynamic performance compared to the LR group throughout the experiment. Compared with the LR group, the systemic oxygenation performance in the HSD group was similar but showed a lower venous-to-arterial CO2 gradient (Pv-aCO2) at R3 (p < 0.05). Additionally, the histology score of the kidneys, lungs and liver were significantly lower in the HSD group than in the LR group (p < 0.05). The HSD+LR group showed a superior hemodynamic response but higher extravascular lung water (EVLW) and lower arterial oxygen tension (PaO2) than the other groups (p < 0.05). The HSD+LR group showed a marginally improved systemic oxygenation performance and lower histology score than other groups., Conclusions: Resuscitation after hemorrhagic shock with a bolus of HSD showed a similar hemodynamic response compared with LR at ten times the volume of HSD, but HSD showed superior efficacy in organ protection. Our findings suggest that resuscitation with the combination of HSD and LR in the pre-hospital setting is an effective treatment.

Background: Plasma expanders are commonly used in the management of critically ill patients, which may exhibit altered hemorheology. We evaluated the effects of various synthetic colloids and Lactated Ringer's (LR) solution on hemorheological parameters in vitro and in a rodent hemorrhagic shock model., Methods: For the in vitro experiments, rat blood was incubated with hydroxyethyl starch (HES) 130/0.4, HES 200/0.5, succinylated gelatine (GEL), or LR at various ratios. The control consisted of blood without dilution. The hemorheological parameters were measured after a 15-min incubation. For the in vivo study, rats were subjected to a severe volume-controlled hemorrhage and were resuscitated using a colloid solution (HES 130/0.4, HES 200/0.5, or GEL) or LR. The hemorheological parameters were measured 2 h after resuscitation., Results: The GEL significantly elevated the plasma viscosity compared to the other groups. In the in vitro study, GEL and LR accelerated the erythrocyte aggregation. There was no significant difference between HES 130/0.4, HES 200/0.5, and control groups regarding the aggregation amplitude and index. In the in vivo study, the aggregation amplitude increased significantly in the GEL group compared to the HES 130/0.4, HES 200/0.5, LR, and sham groups. There was no significant difference between the groups with respect to the elongation index in vivo., Conclusions: Hydroxyethyl starch did not change the erythrocyte aggregation compared to the control. GEL significantly accelerates the erythrocyte aggregation and elevates the plasma viscosity compared to hydroxyethyl starch. The in vitro hemorheological measurements most likely provide hints for the in vivo study.

Introduction: This study compared the effects of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin on oxidative stress and the inflammatory response in a rodent hemorrhagic shock model., Methods: Sodium pentobarbital-anesthetized adult male Wistar rats (200 g to 220 g) were subjected to a severe volume-controlled hemorrhage using arterial blood withdrawal (30 mL/kg to 33 mL/kg) and resuscitated with a colloid solution at the same volume as blood withdrawal (hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, or succinylated gelatin). Arterial blood gas parameters were monitored. Malondialdehyde (MDA) content and myeloperoxidase (MPO) activity in the liver, lungs, intestine, and brain were measured two hours after resuscitation. The levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 in the intestine were also measured., Results: Infusions of hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, significantly reduced MDA levels and MPO activity in the liver, intestine, lungs and brain, and it also inhibited the production of TNF-α in the intestine two hours after resuscitation. However, no significant difference between hydroxyethyl starch 200/0.5 and succinylated gelatin was observed., Conclusions: Hydroxyethyl starch 130/0.4, but not hydroxyethyl starch 200/0.5 or succinylated gelatin, treatment after hemorrhagic shock ameliorated oxidative stress and the inflammatory response in this rat model. No significant differences were observed after hydroxyethyl starch 200/0.5 or succinylated gelatin administration at doses of approximately 33 mL/kg.

Background: Hypothermia is common during hemorrhagic shock. To warm the victims or not has been controversial. This study aims to investigate the effect of warming during the initial time of hemorrhage on body temperature, blood pressure, and survival in rat hemorrhagic shock models., Methods: Forty anesthetized rats were divided into control group (n = 20) and warming group (n = 20). The rats of control group were placed on a wooden pad without heating, and the rats of warming group were placed on a heating pad maintained at 37°C ± 0.1°C. Blood withdrawal reached 40% of the total blood volume within 60 minutes. Numbers of survival rats, rectal temperature, and mean arterial pressure (MAP) were recorded when blood loss reached 0 (T0), 20% (T20), 30% (T30), and 40% (T40) of the total blood volume, respectively., Results: Rectal temperature and MAP decrease gradually in both groups during hemorrhage. Warming continuously makes the rectal temperature of the warming group (36.68°C ± 0.63°C) slightly higher than that of the control group (36.17°C ± 0.69°C) at T0. The rectal temperature and MAP of the warming group are higher than that of the control group at T20, T30, and T40 (p < 0.05). Survival rates of the warming group are higher than that of the control group (p < 0.01)., Conclusions: Warming during hemorrhage may prevent exacerbation of hypothermia and hypotension and therefore improve survival.

Nitric oxide (NO), an endothelial-derived relaxing factor, plays important roles in a variety of pathophysiological conditions such as hemorrhagic shock (HS). So far, the impact of NO administration in HS treatment has been controversial. Through literature review, we summarize here the biphasic effects of NO in early and late phases of HS. Evidence suggests that NO administration is beneficial in the early stage while detrimental in the late stage of HS. We further propose inhalation of NO as a novel therapeutic strategy for the treatment of HS in the early stage., (Copyright © 2011. Published by Elsevier Ltd.)