Pentoxifylline in resuscitation of experimental hemorrhagic shock

BACKGROUND: Pentoxifylline improves survival in animal models of hemorrhagic shock. The purpose of this study was to determine the physiologic effects of pentoxifylline in hemorrhagic shock that may be responsible for improved survival. METHODS: Randomized, prospective, blinded trials in Sprague-Dawley rats subjected to hemorrhage and resuscitation, with or without pentoxifylline. RESULTS: Pentoxifylline had no effect on BP or cardiac output. However, tissue oxygenation and oxygen consumption were increased with pentoxifylline resuscitation. Pentoxifylline resuscitation also significantly decreased polymorphonuclear leukocyte adhesiveness. CONCLUSIONS: Pentoxifylline improves tissue oxygenation and oxygen consumption posthemorrhage and this effect is not due to increased cardiac output. Therefore, it must be due to improved microcirculatory blood flow. This effect may be due to decreased polymorphonuclear leukocyte adhesiveness induced by pentoxifylline resuscitation.     

Fluid resuscitation with hemoglobin vesicles in a rabbit model of acute hemorrhagic shock

Several hemoglobin (Hb)-based oxygen carriers are available for use in clinical situations, but their use risks inducing cardiovascular dysfunction as a result of Hb interacting with nitric oxide. Hb vesicles (HbV) are liposome-encapsulated purified human Hb with polyethylene glycol chains at the surface. This study evaluated the effects of HbV on hemodynamics, tissue and systemic oxygenation, and osmotic pressure after fluid resuscitation in an acute hemorrhagic shock model. Hemorrhagic shock was induced in 24 anesthetized mechanically ventilated male rabbits by withdrawing blood to a mean arterial blood pressure (MAP) of 30 to 35 mmHg over 15 min and maintaining this state for 30 min. The animals were resuscitated by replacing the blood with equal volumes of HbV in recombinant human albumin solution (HbV/rHSA), rHSA alone, or Ringer lactated solution (RL), or with three times the withdrawn volume of RL and observed for 2 h. Fluid resuscitation restored MAP, central venous pressure, and cardiac index values, but these fell again within 2 h in rabbits treated with RL. Fluid resuscitation using HbV/rHSA immediately increased MAP and cardiac index but not systemic vascular resistance, maintained a high level of oxygen consumption, and reduced the blood glucose level, which increased after hemorrhage. Fluid resuscitation using HbV/rHSA did not disturb microoxygenation in the brain, kidneys, liver, or muscle; allowed an immediate recovery of tissue oxygenation without decreasing cardiac output or increasing systemic vascular resistance, and increased the oxygen consumption. HbV solution offers the advantages of systemic oxygenation without impairing microcirculation in the treatment of hemorrhagic shock.     

Effects of arterial oxygen content on oxidative stress during resuscitation in a rat hemorrhagic shock model

Objective

To examine whether reactive oxygen species (ROS) production is affected by arterial oxygen content (CaO₂) in attempted resuscitation to restore blood pressure from hemorrhagic shock (HS) or not.

Methods

Under light anesthesia and spontaneous beating, 16 rats underwent HS for 80 min, during which 3.0 mL/100 g of blood was withdrawn, followed by resuscitation attempt for 70 min. At 80 min, rats were randomized into a high-CaO₂ group (Group 1, transfusion under fractional inspired oxygen (F_IO₂) of 1.0, n = 8) or a low-CaO₂ group (Group 2, fluid administration under F_IO₂ of 0.21, n = 8). In each group, either blood or lactate Ringer's (LR) solution was infused to maintain mean arterial pressure ≥75 mmHg under each F_IO₂ concentration. CaO₂, O₂ utilization coefficient (UC) and plasma %CoQ9 were compared between groups.

Results

Mean infused volume for attempted resuscitation was 7.6 ± 1.0 mL of blood in Group 1, and 31.4 ± 5.5 mL of LR solution in Group 2. At the end of resuscitation, CaO₂ was 18.5 ± 1.2 vol% in Group 1, almost double the 9.1 ± 0.8 vol% in Group 2 (P < 0.01). O₂ UC and %CoQ9 in all rats increased from baselines of 0.25 ± 0.12 and 7.6 ± 1.8% to 0.44 ± 0.13 and 9.7 ± 1.8% after resuscitation, respectively (P < 0.05 vs. baseline for each), but did not differ significantly between the groups.

Conclusion

In a rat HS model, attempted resuscitation to restore blood pressure increased O₂ UC as well as %CoQ9. However, the magnitude of %CoQ9 increase that represents ROS production is not affected by CaO₂ during resuscitation from HS.     

Polymerized bovine hemoglobin can improve small-volume resuscitation from hemorrhagic shock in hamsters

Systemic and microvascular hemodynamic responses to hemorrhagic shock volume resuscitation with hypertonic saline followed by infusion of polymerized bovine hemoglobin (PBH) at different concentrations were studied in the hamster window chamber model to determine the role of plasma oxygen-carrying capacity and vasoactivity during resuscitation. Moderate hemorrhagic shock was induced by arterial controlled bleeding of 50% of blood volume (BV), and a hypovolemic state was maintained for 1 h. Volume was restituted by infusion of hypertonic saline (7.5% NaCl), 3.5% of BV, followed by 10% of BV of PBH at 2 different concentrations. Resuscitation was followed for 90 min and was carried out using 13 gPBH/dL (PBH13), PBH diluted to 4 gPBH/dL in albumin solution at matching colloidal osmotic pressure (PBH4), and an albumin-only solution at matching colloidal osmotic pressure (PBH0). Systemic parameters, microvascular hemodynamics, and functional capillary density were determined during hemorrhage, hypovolemic shock, and resuscitation. The PBH13 caused higher arterial pressure without reverting vasoconstriction and hypoperfusion. The PBH4 and PBH0 had lower MAP and partially reverted vasoconstriction. Only treatment with PBH4 restored perfusion and functional capillary density when compared with PBH13 and PBH0. Blood gas parameters and acid-base balance recovered proportionally to microvascular perfusion. Tissue PO2 was significantly improved in the PBH4 group, showing that limited restoration of oxygen-carrying capacity is beneficial and compensates for the effects of vasoactivity, a characteristic of molecular hemoglobin solutions proposed as blood substitutes.     

Complement activation during hemorrhagic shock and resuscitation in swine

Activation of the complement (C) cascade is known to play a key role in the adverse immune consequences of hemorrhagic trauma with subsequent shock and resuscitation. However, it is not clear whether hypovolemia per se, without trauma and resuscitation, can also lead to C activation. To address this question, we studied the presence, kinetics, and cause of C activation in a porcine model of hemorrhagic shock and resuscitation in the absence of trauma. Pigs were bled to and kept at 35 mmHg for 90 min, followed by hypotensive resuscitation with different fluids and, finally, with shed blood. The animals developed severe lactic acidosis between 30 and 90 min, which was accompanied by a trend for initial rise and subsequent 40% drop of CH50/mL, indicating massive C activation even before resuscitation, i.e., before reperfusion damage could have occurred. Resuscitation with plasma expanders caused 20% additional C consumption, whereas whole blood raised CH50/mL. Plasma C5a decreased initially and then significantly increased at 60 and 180 min, whereas thromboxane B2 showed a 3-fold increase at 30 and 60 min. Plasma LPS was also increased above baseline at 90 and 180 min. In in vitro studies with pig blood, spontaneous C5a formation, as well as zymosan-induced C consumption, was significantly enhanced under the conditions of lactic acidosis. Our data suggest that lactic acidosis, endotoxemia, and possibly other ischemia-related tissue alterations act in a vicious cycle in inducing C activation and, hence, aggravation of shock. The biphasic course of CH50/mL and C5a changes may reflect yet unrecognized physiological responses to hemorrhage-related C activation.     

Enalaprilat improves systemic and mesenteric blood flow during resuscitation from hemorrhagic shock in dogs

We investigated the systemic and mesenteric cardiovascular effects of administering enalaprilat during resuscitation from hemorrhage. Dogs were hemorrhaged (mean arterial pressure [MAP] 40-45 mmHg for 30 min, then 30-35 mmHg for 30 min) and were then resuscitated with intermittent lactated Ringer's solution (200 mL/kg/h during first 40 min, and 60 mL/kg/h during the following 130 min, MAP 75-80 mmHg). A constant-rate infusion of saline with or without enalaprilat (0.02 mg/kg/h) was initiated after 40 min of resuscitation. Blood flows declined with hemorrhage, increased with resuscitation, and then declined during the initial 40 min of resuscitation. Enalaprilat administration resulted in blood flow increases not seen in the controls (ending values for cardiac index: 2.8 +/- 0.4 L/min/m2 vs. 1.6 +/- 0.3 L/min/m2; celiac arterial flow 314 +/- 66 L/min/m2 vs. 139 +/- 13 mL/min/m2; and portal venous flow 596 +/- 172 L/min/m2 vs. 414 +/- 81 mL/min/m2 for enalaprilat versus controls, respectively). The greater flows with enalaprilat appeared to be due to prevention of the increases in afterload noted in the controls (ending arterial elastance values 3.73 +/- 0.97 mmHg/m2/mL vs. 7.74 +/- 1.80 mmHg/m2/mL for enalaprilat versus controls, respectively). We conclude that administration of a constant-rate infusion of enalaprilat during resuscitation can be used to improve systemic and mesenteric blood flow.     

不同时间输注红细胞悬液对大鼠失血性休克复苏的影响

目的探讨红细胞悬液延迟输注30 min对大鼠失血性休克复苏的影响。方法 24只Wistar大鼠随机分为假手术(SHAM)、RBC 1和RBC 2组(n=8),RBC 1和RBC 2组制备重度失血性休克大鼠模型,先后采用晶胶复合液和红细胞悬液复苏,RBC 2组红细胞悬液延迟输注30 min;监测生理、血气等指标。结果与RBC1组相比,RBC 2组平均动脉压(MAP)和体温恢复延迟,RBC 1组复苏结束后2组MAP分别为(116.99±11.06)和(73.72±14.34)mm Hg(P0.01);RBC 1组复苏结束后30 min,2组MAP分别为(103.07±9.59)和(120.61±10.73)mmHg(P0.01)。RBC 1组复苏结束后120 min RBC 1组体温(37.28±0.80)℃明显低于RBC 2组(38.83±0.58)℃(P0.01)。与SHAM组相比,RBC 1和RBC 2组休克后pH、PCO2、BE和ctHb明显降低,PO2明显升高;复苏后PCO23 h,RBC 1和RBC 2组碱剩余(BE)值明显低于SHAM组。结论在失血性休克液体复苏的基础上,红细胞悬液延迟输注30 min对失血性休克大鼠模型的生理、血气等指标无明显影响。提示紧急救治中输血准备工作耗时可能不影响失血性休克的复苏效果。     

Fluid resuscitation with hemoglobin vesicles prevents Escherichia coli growth via complement activation in a hemorrhagic shock rat model

Hemoglobin vesicles (HbVs) could serve as a substitute for red blood cells (RBCs) in resuscitation from massive hemorrhage. A massive transfusion of RBCs can increase the risk of infection, which is not caused by contaminating micro-organisms in the transfused RBCs but by a breakdown of the host defense system. We previously found that complement activity was increased after resuscitation with HbVs at a putative dose in a rat model of hemorrhagic shock. It is known that complement system plays a key role in host defense in the embryonic stage. Therefore, the objective of this study was to address whether the suppression of bacterial infections in hemorrhagic shock rats was a result of increased complement activity after massive HbV transfusion. For this purpose, Escherichia coli were incubated with plasma samples obtained from a rat model of hemorrhagic shock resuscitated by HbVs or RBCs, and bacterial growth was determined under ex vivo conditions. As a result, E. coli growth was found to be suppressed by increased complement activity, mediated by the production of IgM from spleen. However, this antibacterial activity disappeared when the E. coli were treated with complement-inactivated plasma obtained from splenoctomized rats. In addition, the resuscitation of HbVs from hemorrhagic shock increased the survival rate and viable bacterial counts in blood in cecum ligation and puncture rats, a sepsis model. In conclusion, the resuscitation of HbVs in the rat model of hemorrhagic shock suppresses bacterial growth via complement activation induced by IgM.     

Esophageal capnometry during hemorrhagic shock and after resuscitation in rats

Background  

Splanchnic perfusion following hypovolemic shock is an important marker of adequate resuscitation. We tested whether the gap between esophageal partial carbon dioxide tension (PeCO ₂) and arterial partial carbon dioxide tension (PaCO ₂) is increased during graded hemorrhagic hypotension and reversed after blood reinfusion, using a fiberoptic carbon dioxide sensor.     

Resuscitation from hemorrhagic shock using polymerized hemoglobin compared to blood

The development of an alternative to blood transfusion to treat severe hemorrhage remains a challenge, especially in far forward scenarios when blood is not available. Hemoglobin level (Hb)–based oxygen (O₂) carriers (HBOCs) were developed to address this need. Hemopure (HBOC-201, bovine Hb glutamer-250; OPK Biotech, Cambridge, MA), one such HBOC, has been approved for clinical use in South Africa and Russia. At the time of its approval, however, few studies aimed to understand Hemopure's function, administration, and adverse effects compared to blood. We used intravital microscopy to study the microcirculation hemodynamics (arteriolar and venular diameters and blood flow and functional capillary density [FCD]) and oxygenation implications of Hemopure administration at different Hb concentrations—4, 8, and 12 gHb/dL—compared to fresh blood transfusion during resuscitation from hemorrhagic shock. Experiments were performed in unanesthetized hamsters instrumented with a skinfold window chamber, subjected to hemorrhage (50% of the blood volume), followed by 1-hour hypovolemic shock and fluid resuscitation (50% of the shed volume). Our results show that fluid resuscitation with Hemopure or blood restored systemic and microvascular parameters. Microcirculation O₂ delivery was directly correlated with Hemopure concentration, although increased vasoconstriction was as well. Functional capillary density reflected the balance between enhanced O₂ transport and reduced blood flow: 12 gHb/dL of Hemopure and blood decreased FCD compared to the lower concentrations of Hemopure (P < .05). The balance between O₂ transport and tissue perfusion can provide superior resuscitation from hemorrhagic shock compared to blood transfusion by using a low Hb concentration of HBOCs relative to blood.     

低血容量性休克大鼠全身氧动力学的变化研究

目的：研究低血容量性休克时全身氧动力学的变化特点。方法：按４ｍｌ／ｋｇ,每隔０．５分次从静脉放血,观察大鼠休克过程中全身氧供给（ＤＯ２）,氧消耗（ＶＯ２）和氧摄取率（ＥｘｔＯ２）的变化。结果：失血后１．５小时血红蛋白浓度开始显著降低,心率明显加快,失血２．０小时平均动脉压明显下降,此时ＤＯ２亦开始进行性下降,由于ＥｘｔＯ２出现代偿升高,ＶＯ２维持相对不变;     

Subcutaneous and liver tissue oxygen tension in hemorrhagic shock: an experimental study with whole blood and two colloids

Because it is difficult to verify the efficacy of hemorrhagic shock treatment, we compared subcutaneous O2 tension (PscO2) with liver oxygenation in efforts to correct shock in piglets with two different colloids, hydroxyethyl starch (HES-120) and dextran-70. Nineteen animals were bled to shock and the shed blood was retransfused in the control group. Liver oxygenation was measured directly by means of a silicone tube used as a tonometer, and indirectly by calculating liver O2 consumption (VO2). PscO2 was monitored with a needle electrode. The two colloid groups were compared by measuring plasma lactate, and the plasma colloid osmotic pressure (COPp). PscO2 followed closely the changes in liver tissue PO2 during the experiment; it seems to be a useful tool in estimating volume filling during the treatment of hemorrhagic shock. A wider variation was noted in calculated liver VO2 compared with hepatic venous PO2 or liver tissue PO2. Despite the fact that COPp increased to a higher level after the administration of dextran, HES proved to be at least as effective as dextran in restoring mean arterial pressure, cardiac output, liver oxygenation, PscO2, arterial pH, arterial plasma lactate, and liver lactate uptake.     

高原创伤失血性休克氧疗的实验研究

[目的 ]探讨高原创伤失血性休克氧疗效果 ,为临床用氧提供理论依据。 [方法 ]模拟高原环境 ,制作失血性休克兔模型 ,给予不同浓度氧疗加补液 (Ⅰ、Ⅱ、Ⅲ组 )、氧疗 (Ⅳ组 )和单纯补液组(V组 ) ,休克 1h后进行治疗 ,观察平均动脉压 (MAP)、中心静脉压 (CVP)、血气分析、存活时间 ;再设计理想浓度氧疗加补液 (T组 )和单纯补液对照 (C组 ) ,观察心功能指标。 [结果 ]Ⅰ组、Ⅱ组MAP回升与Ⅳ组有差异 (P <0 .0 5 ,P <0 .0 1) ;Ⅰ组CVP回升与Ⅳ组、Ⅴ组比较有差异 (P <0 .0 1) ;治疗 1hⅣ组HCO3 -下降与Ⅰ组比较 ,P <0 .0 5 ;I组成活时间最长 ;治疗后T组、C组左室收缩压 (LVSP)、左室舒张末压(LVEDP)、左室压力上升及下降的最大速率 (±dp/dtmax)的提高与休克 1h比较均有差异 (P <0 .0 1) ;C组mPAP升高较T组明显 (P <0 .0 5 )。 [结论 ]氧疗是高原失血性休克扩容救治条件下必不可少的护理措施 ,在安全范围内选择高浓度持续给氧 ,有利于改善心功能和有效循环血量 ,减轻酸中毒 ,延长存活时间。     

高压氧对失血性休克复苏后炎症反应的影响

目的观察高压氧对大白鼠失血性休克复苏后炎症反应的影响并探讨其作用机制。方法Wistar大鼠随机分为三组：高压氧治疗组、休克组和对照组。建立大鼠失血性休克模型,自体血和生理盐水复苏后应用2．0绝对大气压高压氧治疗,于休克前、休克后、复苏后和复苏后24h取血检测血红细胞SOD、血浆卧限a、血浆iNOS值,并进行统计学（one-way ANOVA plus SNK）分析。观察复苏后24h大鼠肝、肠、肺组织病理改变并进行病理损伤评分。结果复苏后24h高压氧治疗组血红细胞SOD值高于休克组,高压氧治疗组血浆iNOS值和TNFoa值低于休克组,差异具有统计学意义（P〈0．05）。病理损伤评分：高压氧治疗组病理损伤与休克组相比减轻,差异具有统计学意义（P〈0．05）。结论 高压氧可能通过增强机体清除活性氧和自由基、阻止炎症介质的产生,进而减轻大鼠失血性休克复苏后的炎症反应和组织脏器的病理损伤。     

Nitroglycerin attenuates vasoconstriction of HBOC-201 during hemorrhagic shock resuscitation

Background

Vasoconstriction, an inherent property of Hemoglobin Based Oxygen Carriers (HBOC) potentially due to nitric oxide (NO) scavenging, may increase cardiovascular complications in HBOC resuscitated trauma patients. The purpose of this study was to determine if co-administration of a weak NO donor, intravenous nitroglycerin (NTG), with HBOC-201 during resuscitation from hemorrhagic shock could safely attenuate HBOC-201 vasoconstriction.

Methods and results

Hemorrhagic shock was induced in 44 swine randomized to receive fluid resuscitation with HBOC, HBOC + NTG10 mcg/kg/min, HBOC + NTG20 mcg/kg/min, HBOC + NTG40 mcg/kg/min, Hetastarch (HES), HES + NTG20 mcg/kg/min, NTG20 mcg/kg/min and Lactated Ringers (LR). HBOC resuscitation from hemorrhagic shock increased mean arterial pressure (MAP = 94 ± 33 mmHg), mean pulmonary artery pressure (MPAP = 29 ± 11 mmHg) and systemic vascular resistance (SVR = 2684 ± 871 dyn s/cm⁵) in comparison to HES. Co-administration of NTG during HBOC resuscitation attenuated vasoconstriction with HBOC + 40 mcg/kg/min demonstrating the most robust reduction in vasoconstriction (MAP = 59 ± 23 mmHg, MPAP = 18 ± 7 mmHg, and SVR = 1827 ± 511 dyn s/cm⁵), although the effects were transient. Co-administration of NTG with HBOC did not alter base deficit, lactate, methemoglobin levels, nor cause profound hypotension during resuscitation.

Conclusion

Nitroglycerin attenuates vasoconstrictive properties of HBOC when co-administered during resuscitation in this swine model of hemorrhagic shock. Translational survival studies are required to determine if this strategy of attenuation of the vasoconstriction of HBOC-201 reduces cardiovascular complications and improves outcome with HBOC fluid resuscitation for hemorrhagic shock.