Alterations in tissue oxygen consumption and extraction after trauma and hemorrhagic shock

OBJECTIVES: Although trauma and hemorrhage are associated with tissue hypoperfusion and hypoxemia, changes in oxygen delivery (DO2), oxygen consumption VO2), and oxygen extraction at the organ level in a small animal (such as the rat) model of trauma and hemorrhage have not been examined. Therefore, the objectives of this study were to determine whether blood flow, DO2, VO2, and oxygen extraction ratio in various organs are differentially altered after trauma-hemorrhagic shock and acute resuscitation in the rat. DESIGN: Prospective, randomized animal study. SETTING: A university research laboratory. SUBJECTS: Male Sprague-Dawley rats (n = 6-7 animals/group) weighing 275-325 g. INTERVENTIONS: Male rats underwent laparotomy (i.e., soft tissue trauma) and were bled to and maintained at a blood pressure of 40 mm Hg until 40% of shed blood volume was returned in the form of lactated Ringer's solution. They were then resuscitated with four times the volume of shed blood with lactated Ringer's solution for 60 mins. At 1.5 hrs postresuscitation, cardiac output and blood flow were determined by using strontium-85 microspheres. Blood samples (0.15 mL each) were collected from the femoral artery and vein and the hepatic, portal, and renal veins to determine total hemoglobin and oxygen content. Systemic and regional DO2, VO2, and oxygen extraction ratio were then calculated. MEASUREMENTS AND MAIN RESULTS: Both the systemic hemoglobin and systemic arterial oxygen content in hemorrhaged animals at 1.5 hrs postresuscitation were >50% lower as compared with sham-operated controls. Cardiac output and blood flow in the liver, small intestine, and kidneys decreased significantly, but blood flow in the brain and heart remained unaltered after hemorrhage and resuscitation. Systemic DO2 and VO2 were 73% and 54% lower, respectively, than controls at 1.5 hrs after resuscitation. Similarly, regional DO2 and VO2 in the liver, small intestine, and kidneys decreased significantly under such conditions. In addition, the liver had the most severe reduction in VO2 (76%) among the tested organs. However, the oxygen extraction ratio in the liver of sham animals was the highest (72%) and remained unchanged after hemorrhage and resuscitation. CONCLUSION: Because the liver experienced the most severe reduction in VO2 associated with an unchanged oxygen extraction capacity, this organ appears to be more vulnerable to hypoxic insult after hemorrhagic shock.     

Relationship between hepatic blood flow and tissue lipid peroxidation in the early postburn period.

OBJECTIVES: To determine the effect of a body burn on effective or nutrient liver blood flow and the relationship between blood flow and oxidant-induced lipid peroxidation. DESIGN: Anesthetized sheep were given a 40% of total body surface, third-degree burn, after which animals were fluid resuscitated to return ventricular filling pressures and cardiac output to baseline values. Animals, for the 6-hr study period, were resuscitated with lactated Ringer's solution alone or lactated Ringer's solution plus 1500 mL of 5% hydroxyethyl starch or lactated Ringer's solution plus hydroxyethyl starch on which was complexed the iron chelator deferoxamine to prevent oxidant release. Effective liver blood flow was measured using the galactose infusion technique. Liver tissue lipid peroxidation was monitored using malondialdehyde content. RESULTS: We found that effective liver blood flow was decreased by 50% in the 4- to 5-hr postburn period, even when animals were resuscitated to baseline cardiac output values with lactated Ringer's solution. Tissue malondialdehyde content increased in the group treated with lactated Ringer's solution from a control value of 110 +/- 7 to 202 +/- 59 nmol/g of tissue. Resuscitation with hydroxyethyl starch restored postburn effective liver blood flow to control values, but malondialdehyde content was still increased two-fold. Resuscitation with hydroxyethyl starch and deferoxamine resulted in an increase in effective liver blood flow postburn to a value 80% above controls. In addition, lipid peroxidation was prevented. CONCLUSIONS: Effective liver blood flow is markedly decreased after burn injury, even with apparently adequate volume resuscitation, when using lactated Ringer's solution. Liver lipid peroxidation persists even when effective liver blood flow is maintained, indicating that the oxidant process is not solely related to blood flow. Infusion of the antioxidant deferoxamine during resuscitation not only prevents the lipid peroxidation, most likely by a nonblood-flow-related process, but also results in an increase in blood flow above normal rates, suggesting that postburn liver oxygen needs exceed normal values.     

Effect of experimental hemorrhagic shock on hepatic drug elimination.

OBJECTIVE: Exogenous substrates were used to measure hepatic function for the purposes of determining organ dysfunction and to evaluate the effect of experimental hemorrhagic shock with resuscitation on hepatic drug elimination. DESIGN: Prospective, controlled, non-randomized crossover trial. INTERVENTIONS: Eleven chronically instrumented immature swine were studied using a fixed-volume hemorrhage model (45 mL/kg blood removal over 15 mins) followed by resuscitation with lactated Ringer's solution at three times the volume of shed blood. One week before and immediately after hemorrhage and resuscitation, hepatic function markers (indocyanine green and antipyrine) were simultaneously administered intravenously. MEASUREMENTS: Physiologic data and blood samples were collected over 12 hrs after drug administration. Drug clearances, volumes of distribution, and half-lives were determined. MAIN RESULTS: For indocyanine green, there was no substantial change in pharmacokinetics from preshock to postshock, suggesting minimal change in hepatic blood flow. For antipyrine, clearance was decreased by 30% after shock and resuscitation (p = .05), suggesting that oxidative metabolism was acutely impaired. CONCLUSIONS: The information indicates that hepatic oxidative drug metabolism may be impaired early after hemorrhagic shock and that dosages of drugs in this class should be carefully examined when administered to patients who have sustained injury with hemorrhagic shock.     

Progesterone administration after trauma and hemorrhagic shock improves cardiovascular responses

OBJECTIVE: Studies have shown that female rats during the proestrus stage have significantly improved cell and organ functions after trauma-hemorrhage compared with male and ovariectomized females. This study investigated the hypothesis that progesterone can improve the depressed cardiovascular function in sex steroid-deficient female rats (i.e., ovariectomized females) after trauma-hemorrhage and resuscitation. DESIGN: Prospective study. SETTING: University laboratory. SUBJECTS: Ovariectomized female Sprague-Dawley rats (weight, 250-300 g). INTERVENTIONS: Rats underwent a 5-cm midline laparotomy (i.e., soft-tissue trauma), were bled to a mean arterial pressure of 35 mm Hg for approximately 90 mins, and were then resuscitated using Ringer's lactate. A single dose of progesterone (25 mg/kg of body weight) or vehicle was administered subcutaneously during resuscitation. MEASUREMENTS: At 20 hrs after trauma-hemorrhage or sham operation, cardiac output and heart performance and the circulating blood volume were assessed using the indocyanine green dilution technique and a left ventricular catheter. Furthermore, the binding activity of progesterone receptors in nuclear extracts of left ventricular tissue was determined. RESULTS: Cardiac output, heart performance, and circulating blood volume were significantly decreased in vehicle-treated animals after trauma-hemorrhage. Administration of progesterone significantly improved cardiac output and heart performance and increased the circulating blood volume. This was associated with an increased progesterone receptor activity in the left ventricular nuclear extracts. CONCLUSION: Because administration of progesterone after trauma-hemorrhage in sex steroid-deficient females improved cardiovascular responses, this hormone seems to be a useful adjunct for the treatment of cardiovascular depression in postmenopausal and ovariectomized female trauma patients.     

Resuscitation with hydroxyethyl starch solution prevents nuclear factor kappaB activation and oxidative stress after hemorrhagic shock and resuscitation in rats

Fluid resuscitation is vital for treating traumatic hemorrhagic shock (HS), but reperfusion is believed to have the adverse consequences of generating reactive oxygen species and inflammatory cytokines, both of which cause multiple organ dysfunctions. We investigated the effects of various resuscitation fluids on the changes of redox-sensitive molecules after HS and fluid resuscitation (HS/R). We induced HS by bleeding male Sprague-Dawley rats to a blood pressure of 30 to 40 mmHg for 60 minutes. Thirty minutes later, the rats were killed (HS group) or immediately resuscitated with shed blood (HS + BL group), L-isomer lactated Ringer's solution (HS + LR group), or hydroxyethyl starch (HS + HES group). After HS, we found a significant increase in nuclear factor kappaB DNA binding activity, which was effectively inhibited using HES solution or blood resuscitation. Moreover, resuscitation with blood or LR solution, but not HES solution, induced significant oxidative stress, manifested by a high ratio of oxidized glutathione to reduced glutathione in the lungs, liver, and spleen. HS alone, however, did not increase the ratio of the oxidized glutathione to reduced glutathione in all organs. Although the protein expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax varied in different organs, we found that resuscitation using HES solution prevented the HS-induced reduction of the Bcl-2/Bax ratio in the heart. HES solution was an appropriate resuscitation fluid in reversing nuclear factor kappaB activation, maintaining the Bcl-2/Bax ratio, and preventing oxidative stress after acute HS.     

L-arginine supplementation in hyperdynamic endotoxemic pigs: effect on nitric oxide synthesis by the different organs

OBJECTIVES: Under septic conditions, the protective role of nitric oxide in the organs may become compromised at a time of increased demand as a result of decreased availability of L-arginine. It remains unknown whether supplementation with L-arginine, as a substrate, can modulate organ nitric oxide production. DESIGN: Controlled study with laboratory animals. SETTING: University research laboratory. SUBJECTS: Female crossbred pigs. INTERVENTION: Pigs were challenged with Escherichia coli endotoxin (intravenously) and received intravenous fluid resuscitation for 24 hrs to reproduce a model of long-lasting hyperdynamic endotoxemia. Pigs were infused with either L-arginine or L-alanine intravenously during endotoxin and via the intragastric route after cessation of endotoxin infusion. The effects of L-arginine supplementation on nitric oxide synthesis and the relationships with arginine metabolism were determined with a stable isotope infusion protocol. Also, organ nitrite plus nitrate fluxes were measured. Implantation of multiple catheters enabled in vivo measurements across the hindquarter muscle, the portal-drained viscera, the liver, and the kidneys. MEASUREMENTS AND RESULTS: The isotope conversion method showed that L-arginine intervention significantly increased nitric oxide production by the portal-drained viscera, liver, and kidneys, resulting in elevated whole-body nitric oxide synthesis under endotoxemic and postendotoxemic conditions. Organ nitrite plus nitrate fluxes only tended to increase because of high variance among data. CONCLUSIONS: In this endotoxemia model, supplemental use of L-arginine favored nitric oxide synthesis in various organs.     

Bovine hemoglobin-based oxygen carrier (HBOC-201) for resuscitation of uncontrolled, exsanguinating liver injury in swine. Carolina Resuscitation Research Group

In the setting of rapidly exsanguinating hemorrhage, resuscitation with intravenous (i.v.) crystalloid solution may not sustain survival before availability of allogenic blood transfusion and surgery. This study tested the hypothesis that bovine hemoglobin-based oxygen carrier, HBOC-201, would improve resuscitation and extend early survival from exsanguinating hemorrhage. This study simulated the prehospital scenario of rapidly exsanguinating hemorrhage with prolonged prehospital time and lack of blood availability. Severe hemorrhagic shock was induced in swine by using multiple liver lacerations. At 9 min after the onset of bleeding, swine were randomized to receive approximately 10 mL/kg/min of i.v. lactated Ringer's solution (n = 10) or HBOC-201 (n = 7) to achieve a mean aortic pressure (MAP) of 60 mmHg. Thereafter, infusion rate was adjusted to maintain MAP at 60 mmHg for up to 2 h. All animals were initially successfully resuscitated. The results showed 2-h survival was 1 of 10 with lactated Ringer's and 7 of 7 with HBOC-201 (P = 0.0004). Nine lactated Ringer's swine had cardiovascular collapse at 36 +/- 10 min. Lactate at 30 min was 18 +/- 3 mmol/L with lactated Ringer's and 12 +/- 2 mmol/L with HBOC-201 (P < 0.05). Hematocrit was <1% in 9 of 10 lactated Ringer's and 6 of 7 HBOC-201 animals. These data indicate that HBOC-201 improved early survival and stabilized hemodynamic and metabolic parameters vs. lactated Ringer's in this swine model of liver injury with uncontrolled, lethal hemorrhage that simulates the prehospital care environment where allogenic blood is unavailable.     

Oxyradical-mediated hepatocellular Ca2+ alterations during hemorrhagic shock and resuscitation

Both altered Ca2+ homeostasis and injury by oxygen-free radicals (OFR) are pivotal mechanisms of cellular dysfunction. The purpose of this study was to evaluate the role of OFR and xanthine oxidase in hepatocellular Ca2+ dysregulation following hemorrhagic shock and resuscitation. Anesthetized rats were bled to a mean arterial blood pressure of 40 mm Hg for 60 min and then resuscitated with 60% of shed blood and 3-fold the shed blood volume as lactated Ringer's for another 60 min. Total Ca2+ uptake (Ca2+(up)), rate of Ca2+ influx (Ca2+(in)), and membrane Ca2+(flux) (Ca2+(flux)) were determined in isolated hepatocytes using 45Ca2+ incubation techniques. Hepatocyte oxidant injury was fluorometrically determined by thiobarbituric acid-reactive substances, oxidized, and reduced glutathione. Hemorrhage/resuscitation significantly increased Ca2+(up), Ca2+(in), and Ca2+(flux) compared with sham-operated rats. Continuous administration of superoxide dismutase or catalase (60,000 IU/kg body weight) during resuscitation substantially decreased Ca2+(up), Ca2+(in), Ca2+(flux), and oxidant injury. Pretreatment with allopurinol (50 mg/kg/day for 2 days) significantly inhibited enhanced plasma xanthine oxidase activity and hepatocyte glutathione oxidation, however, it did not prevent hepatocellular Ca2+ dysregulation. These data suggested a significant role of oxyradicals in ischemia/reperfusion-induced Ca2+ overload, however, xanthine oxidase activation seemed not to be a main source of these radicals.     

Depletion of liver glutathione potentiates the oxidative stress and decreases nitric oxide synthesis in a rat endotoxin shock model

OBJECTIVE: To verify the effects of liver glutathione depletion on redox status and nitric oxide system in a rat endotoxic shock model. DESIGN: Prospective, randomized, controlled study on rats. SETTING: A cardiocirculatory research laboratory. SUBJECTS: A total of 28 Sprague-Dawley male rats (200-250 g body weight) were divided into four experimental groups. INTERVENTIONS: Arterial blood, liver, and lung samples were taken from each animal under sodium pentobarbital (40 mg/kg i.p.) anesthesia 4 hrs after lipopolysaccharide (LPS group: 5 mg/kg i.p.; n = 7) or vehicle (control group: isotonic NaCl sterile solution i.p.; n = 7) treatments. Phorone (250 mg/kg i.p.) was injected to deplete glutathione in another two experimental groups of rats 30 mins before LPS (phorone+LPS group; n = 7) or vehicle (phorone group; n = 7) treatments, and 4 hrs later the same samples as in LPS and control groups were taken under anesthesia. MEASUREMENTS AND MAIN RESULTS: Compared with the control group, the LPS group presented higher plasma concentration of end products of nitric oxide metabolism nitrites/nitrates, higher lung activity of inducible nitric oxide synthase, and oxidative stress defined by increased plasma concentration of the lipid peroxides malonaldehyde and 4-hydroxynonenal, and decreased plasma total antioxidant capacity. Treatment with phorone depleted liver glutathione (80% to 90%). In the liver glutathione-depleted animals, the oxidative stress induced by LPS was potentiated and blunted the increases in inducible nitric oxide synthase and plasma nitrites/nitrates. CONCLUSION: These results show that depletion of the liver glutathione increases the oxidative stress and decreases nitric oxide synthesis of LPS-induced shock in rats.     

Regulation of Liver and Kidney Glucose-6-phosphatase Gene Expression in Hemorrhage and Resuscitation

The authors have recently demonstrated that increased gene expression of glucose-6-phosphatase (Glu-6-Pase) in hemorrhagic hypotension (HH) and following lactated Ringer's resuscitation (LR) is associated with a decrease in insulin and an increase in corticosterone concentrations. OBJECTIVE: To evaluate the in-vivo role of hormones the authors used insulin (IN), phentolamine and propranolol (PP) as an adrenergic blocker, and cyclic somatostatin (CS) as a glucagon blocker to prevent the induction of Glu-6-Pase gene expression in liver and kidney following HH and LR. METHODS: Hemorrhage was induced in fasted anesthetized rats, and the reduction of blood pressure to 40 mm Hg for a duration of 30 minutes was accomplished by withdrawal or infusion of shed blood. The resuscitated group underwent hemorrhage followed by fluid resuscitation with lactated Ringer's solution. RESULTS: Neither PP nor CS treatment could block the induction of Glu-6-Pase messenger ribonucleic acid (mRNA) following either HH or LR. However, the administration of IN significantly prevented the increase of Glu-6-Pase mRNA level and activity in both liver and kidney following HH and LR. This was associated with a normalization of plasma glucose, corticosterone, and glucagon levels and glucose-6-phosphate concentrations in liver and kidney toward prehemorrhage levels. CONCLUSIONS: These results indicate that in-vivo treatment with insulin during hemorrhagic hypotension and resuscitation is capable of preventing the increase in Glu-6-Pase gene expression in liver and kidney responsible for the observed hyperglycemia.     

腹部血管损伤非控制性休克分阶段早期液体复苏

目的 非控制性失血性休克(UHS)怎样进行液体复苏,目前尚无一致意见.本实验制作了腹部血管损伤UHS模型,并根据战创伤实际将模型分为四个阶段,探索早期液体复苏方案.方法 SD大鼠40只,左股动、静脉及左心室插管.开腹,于腹主动脉中下段用25G针头穿刺造成活动性出血.模拟战创伤实际,将动物分为受伤早期、早期救助期、后期救治期及观察期四个阶段.分组:①无复苏组:不进行液体复苏.②早期不复苏组:早期不复苏,后期救治期给予3倍腹腔出血量的林格氏液在15 min快速输入.③早期快速复苏组:于早期救助期在15 min快速输入45ml/kg的林格氏液,后期救治期输液同前.④假手术组.监测血压(MAP)、中心静脉压(CVP)及血乳酸及红细胞比容(Hct)等,统计腹腔出血量及存活时间.结果 血管损伤后15 min动物血压由94.3 mmHg下降到25.8 mmHg(P＜0.01),早期快速复苏组血压快速升高,但也很快下降.CVP变化与MAP相似.血乳酸在伤后均显著升高,4 h可达原来的3～4倍(P＜0.01).早期快速复苏及后期液体复苏后均导致Hct显著下降,并可以使血液乳酸水平的升高明显延缓.早期快速复苏动物腹腔出血量显著增加(由22.8 ml/kg增加到27.7 ml/kg,P＜0.05).无复苏组、早期不复苏组及院前快速复苏组动物平均存活时间为分别为50 min、120 min及93 min,三组动物分别在24 h、48 h及72 h内全部死亡.各组之间死亡率差异无统计学意义(P＞0.05).结论 腹部血管伤非控制性失血性休克早期快速输液不能有效减少乳酸含量、稳定增加全身循环血量以及保持正常血压,反而导致腹腔出血量增加、红细胞比容下降,最终不能延长存活时间、增加生存率.     

Influence of heme-based solutions on stress protein expression and organ failure after hemorrhagic shock

OBJECTIVE: Hemoglobin-based oxygen carriers (e.g., diaspirin-cross-linked hemoglobin [DCLHb] and hemoglobin glutamer-200 [HbG]) may have potential in the treatment of hemorrhagic shock. The nitric oxide scavenging and direct vasoconstrictive side effects of free hemoglobin of currently available preparations may increase organ injury after shock in contrast to non-oxygen-carrying heme solutions (e.g., hemin arginate [HAR]). However, both classes of substances might induce the protective enzyme heme oxygenase (HO)-1, particularly in the liver. The aim of the study was to assess the role of pretreatment with DCLHb, HbG, or HAR on HO-1 expression and organ injury after hemorrhagic shock. DESIGN: Prospective controlled laboratory study. SETTING: Animal research laboratory at a university hospital. SUBJECTS: Male Sprague-Dawley rats (200-300 g body weight, n = 5-12/group). INTERVENTIONS: Twenty-four hours after different doses of DCLHb, HbG (each 1, 2, or 3 g/kg of body weight), or HAR (5, 25, or 75 mg/kg of body weight), the protein expression of HO-1 and heat shock protein-70 in liver, kidney, heart, lungs, and aorta was determined. Twenty-four hours after pretreatment with DCLHb, HbG, or HAR, rats were subjected to hemorrhage (mean arterial blood pressure, 35-40 mm Hg for 1 or 2 hrs)/resuscitation (5 or 4 hrs, respectively). Animals treated with Ringer's solution (30 mL/kg of body weight) served as controls. In additional experiments, HO activity was blocked with tin mesoporphyrin-IX. MEASUREMENTS AND MAIN RESULTS: DCLHb, HbG, and HAR dose-dependently induced HO-1 protein but not heat shock protein-70. Pretreatment with DCLHb or HbG shortened the onset of decompensation in shock (DCLHb, 40 +/- 11 mins; HbG, 36 +/- 4 mins) compared with vehicle (68 +/- 4 mins, p < .05) and HAR pretreatment (81 +/- 7 mins, p < .05). High doses of DCLHb pretreatment increased mortality (2 hrs of shock, 80%; p < .05 vs. vehicle or HAR). Pretreatment with HAR led to higher shed blood volumes (p < .05) and higher hepatocellular ATP levels (2 hrs of shock, p < .05 vs. DCLHb and HbG). Blockade of HO activity by tin mesoporphyrin-IX abolished the protection mediated by HAR. CONCLUSIONS: Although DCLHb, HbG, and HAR induce HO-1 in the absence of an unspecific stress response, only HAR pretreatment protects against shock-induced organ failure. Although the underlying mechanisms of positive HAR priming are not completely understood, the induction of HO-1 expression and the lack of nitric oxide scavenging through HAR may play an important role.     

一氧化氮合酶抑制剂对大鼠创伤性休克的治疗作用

目的：评价选择性诱导型一氧化氮合酶(iNOS)抑制剂氨基胍(AG)和非选择性一氧化氮合酶抑制剂L—硝基精氨酸甲酯(L—NAME)对创伤性休克的治疗效果。方法：30只SD大鼠制作创伤性休克动物模型。双侧股骨干砸伤后并经股动脉放血至平均动脉压(MAP)35—45mmHg(1mmHg＝0．133kPa)，维持30min，然后回输失血和等量的林格氏液。随机分为休克组(10只)、AG组(10只，复苏时静脉注射AG8mg／kg)、L—NAME组(10只，复苏时静脉注射L—NAME 8mg／kg)，观察休克前后血浆一氧化氮(NO)浓度的动态变化，观察24h大鼠存活率，24h后留取肺、肝、肾、小肠组织，观察病理改变。结果：大鼠创伤性休克后，血浆NO水平明显高于休克前；AG组动物复苏后血浆NO的水平明显降低，各脏器的病理损害亦显著减轻，存活率明显提高：L—NAME组动物复苏后血浆NO的水平也明显降低，各脏器的病理损害无明显变化，存活率无明显提高。结论：NO在创伤性休克的病理发展过程中起着重要作用，应用AG有助于创伤性休克的纠正，而L—NAME能降低NO的水平，但对休克的预后无明显改善。     

Dextran 70 administration after trauma-hemorrhagic shock does not impair cellular immune functions

: Although the effects of the colloid dextran 70 on induction of anaphylactoid reactions or reticulo-endothelial phagocytosis have been examined previously, its effects on specific cell-mediated immunity after trauma-hemorrhage shock remain unknown.

: Nonheparinized C3H/HeN mice underwent a laparotomy, were bled, and then maintained at a blood pressure of 35 mm Hg for 60 minutes. Then they were resuscitated with either 4 × the shed blood volume as lactated Ringer's solution (LRS) or 2 × LRS + 1 × dextran 70. Control mice underwent all operative protocols but were neither hemorrhaged, nor resuscitated. At 2 or 24 hours posthemorrhage, serum, splenocytes (SPL), and peritoneal macrophages (pMø, splenic Mo (sMø) were obtained. Bioassays were used to determine interleukin-2 (IL-2), IL-3, IL-6, and SPL proliferation.

: Trauma-hemorrhage markedly depressed lymphokine release, splenocyte proliferation, and IL-6 release at 2 hours after the insult. The combination of LRS + dextran did not restore lymphocyte functions, but also did not further suppress them. The release of IL-6 by pMø and sMø at 2 and 24 hours after dextran infusion and serum IL-6 remained at the same level as in LRS-treated animals.

: The combination of LRS and colloid dextran 70 does not adversely affect ex vivo cell-mediated immune functions during the first 24 hours after its administration after trauma-hemorrhage. Thus, from the immunological standpoint, dextran is a safe resuscitation adjunct.     

Caspase inhibition does not protect against liver damage in hemorrhagic shock

This study was aimed to determine whether administration of an inhibitor of caspase-3 protects hepatocellular function in rats with hemorrhagic shock and whether caspases are important pharmacological targets in attenuating liver injury induced by hemorrhagic shock and resuscitation. Male adult rats were subjected to hemorrhagic shock by bleeding to a mean arterial blood pressure of 35-40 mmHg for 1 h and were then resuscitation with 60% shed blood and lactated Ringers solution. A subgroup of animals was injected i.v. with 2 mg/kg caspase inhibitor, Z-DEVD-FMK, prior to blood withdrawal. Fas ligand expression was markedly elevated and caspase-3 activity increased by 3-fold in hemorrhagic untreated rats. The increase in caspase-3 activity was prevented by administration of Z-DEVD-FMK prior to shock and resuscitation. Poly (adenosine diphosphate ribose) polymerase proteolysis was reduced in rats treated with the caspase-3 inhibitor compared with hemorrhagic untreated animals. Plasma aspartate aminotransferase and alanine aminotransferase values showed a significant increase at 6 h of shock in untreated animals (+360% and +515% as compared with sham-operated animals, respectively). Administration of the caspase-3 inhibitor did not prevent the increase in plasma transaminases. The cytosolic concentration of thiobarbituric acid-reactive substances (TBARS) and the oxidized:reduced glutathione ratio increased in the animals with hemorrhagic shock (+94% and +170%, respectively). These parameters were not significantly modified by pretreatment with Z-DEVD-FMK. It appears that caspase inhibition does not attenuate hepatocellular depression and liver injury induced by hemorrhagic shock and resuscitation.     

Monkey model of severe volume-controlled hemorrhagic shock with resuscitation to outcome.

Seventeen cynomolgus monkeys under N2O analgesia and sedation were subjected to severe volume-controlled hemorrhagic shock (shed blood volume of 21 or 27 ml/kg). In 12 monkeys, resuscitation was started after increasing periods of hemorrhagic shock from 30 min to 5 h. In five additional monkeys, volume-controlled hemorrhage was modified at hemorrhagic shock 30 min to control MAP at 30 mmHg: resuscitation was started at hemorrhagic shock of 2 h. A clinically relevant resuscitation protocol consisted of a field phase from 0 to 6 h (lactated Ringer's solution, spontaneous breathing), and a hospital intensive care phase from 6 h to 48 h (blood, lactated Ringer's solution to mean arterial pressure (MAP) greater than or equal to 70 mmHg, controlled ventilation, advanced life support). Fifteen of the 17 monkeys survived. After outcome evaluation at 4 or 7 days, the eight monkeys with "moderate insult" had only transient functional impairment. Of the nine with "severe insult," three showed signs of moderate transient non-oliguric renal failure. Eight of the 12 monkeys studied morphologically showed scattered liver cell damage. None of the monkeys developed pulmonary dysfunction or functional or morphologic evidence of cerebral damage. This study establishes a new hemorrhagic shock-resuscitation model simulating field-to-hospital life support. Severe hemorrhagic shock with MAP 30-40 mmHg for 90-120 min (without trauma or sepsis) can lead to complete functional recovery after transient malfunction of liver and kidneys.