Improved survival after resuscitation with norepinephrine in a murine model of uncontrolled hemorrhagic shock

BACKGROUND: Recent studies have challenged current guidelines on fluid resuscitation. However, studies on resuscitation using norepinephrine in uncontrolled hemorrhagic shock are lacking. The authors examined the effects of norepinephrine in combination with saline infusion in uncontrolled hemorrhage in rats. METHODS: Rats subjected to a 15-min controlled hemorrhage (withdrawal of 3 ml blood/100 g body mass) followed by a 60-min uncontrolled hemorrhage (75% tail amputation) were randomly assigned to one of several treatment groups (10 rats/group) receiving different doses of norepinephrine (0 [NE0], 5 [NE5], 50 [NE50], or 500 [NE500] microg.100 g(-1).h(-1)). In the four hypotensive resuscitation groups (n = 40), mean arterial pressure was not allowed to fall below 40 mmHg by titrated infusion of normal saline. In the four normotensive resuscitation groups (n = 40), it was not allowed to fall below 80 mmHg. The endpoint was survival at 210 min. RESULTS: There was a significant difference (P < 0.05) in survival rate among groups. Among the hypotensive rats, 6 (60%) survived in the NE0 and NE5 dose groups, 9 (90%) survived in the NE50 dose group, and none survived in the NE500 dose group. Among the normotensive rats, none survived in the NE0 group, 4 (40%) survived in the NE5 dose group, all 10 (100%) survived in the NE50 group, and none survived in the NE500 group. CONCLUSIONS: The early use of norepinephrine in uncontrolled hemorrhagic shock in rats significantly improved survival when infused at a rate of 50 microg.100 g(-1).h(-1) in normotensive and hypotensive resuscitation strategies.     

低血压复苏对失血性休克鼠肠损伤及肺损伤的影响

目的 观察低血压复苏对出血未控制的失血性休克鼠肠及肺损伤的影响.方法 16只雄性出血未控制的失血性休克Sprague-Dawley(SD)大鼠随机分成正常血压复苏组(Ⅰ组)及低血压复苏组(Ⅱ组).复苏3 h后,分别比较肠损伤及肺损伤的程度.结果 Ⅰ组肠黏膜绒毛受损率为(33.13±2.17)%,而Ⅱ组为(12.38±1.69)%(P＜0.05);Ⅰ组肠道菌群移位发生率为87.5%(7/8),而Ⅱ组为25.0%(2/8)(P＜0.05);Ⅰ组及Ⅱ组伊文思蓝(EBD)漏出率分别为(3.03±0.28)%和(1.25±0.17)%(P＜0.05),肺通透指数(LPI)分别为0.140±0.018和0.085±0.004(P＜0.05),肺组织髓过氧化物酶(MPO)的浓度分别为(16.4±2.6)u/g和(33.8±2.1)u/g(P＜0.05).结论 低血压复苏可以减轻出血未控制的失血性休克鼠肠道及肺的损伤.     

Recombinant activated factor VII increases survival time in a model of incompressible arterial hemorrhage in the anesthetized pig

BACKGROUND: Hemorrhage is the leading cause of death in battlefield casualties and the second leading cause of death after civilian trauma. Evacuation time for military casualties to surgical care can be prolonged and improved hemostasis could greatly reduce mortality. There are several anecdotal reports that recombinant activated factor VII (rFVIIa) may arrest uncontrolled bleeding after trauma. However, the majority of prospective randomized controlled trials show little benefit in survival. The aim of this study was to determine whether rFVIIa could increase survival time within a clinically relevant time scale for military practice and reduce the volume of blood loss in a model of incompressible arterial hemorrhage. A secondary aim was to determine the effects of hypotensive versus normotensive resuscitation on the effectiveness of rFVIIa. METHODS: Terminally anaesthetized Large White pigs were randomly allocated to one of four treatment groups. All animals received a controlled hemorrhage of 40% of the total estimated blood volume. They were given either rFVIIa (180 microg/kg) or placebo (saline 0.3 mL/kg) intravenously and a 4 to 5 mm longitudinal aortotomy created in the infra renal aorta before resuscitation commenced with 0.9% saline to one of two target systolic arterial blood pressures (SBPs): 110 mm Hg (normotensive) or 80 mm Hg (hypotensive). Group sizes were as follows: placebo/normotensive (6), placebo/hypotensive (7), rFVIIa/normotensive (7), and rFVIIa/hypotensive (7). Survival was monitored for a maximum of 6 hours after the onset of resuscitation. RESULTS: rFVIIa was associated with a significantly prolonged survival time in animals managed hypotensively (214 [79-349] vs. 35 [19-52] minutes mean [95% confidence interval] rFVIIa vs. placebo, p = 0.03 Peto log rank test). There was no significant difference in survival time between those given rFVIIa and placebo in groups managed normotensively (128 [6-249] vs. 40 [15-66] minutes respectively, p = 0.27). Both rFVIIa and hypotensive management were associated with reduced uncontrolled hemorrhage volumes. There was no evidence of inappropriate intravascular thrombi or microthrombi associated with the use of rFVIIa. CONCLUSIONS: rFVIIa, combined with hypotensive resuscitation, can increase survival time and reduce hemorrhage in a model of arterial hemorrhage. The increase in survival time is clinically relevant for military evacuation of battlefield casualties to surgical care.     

Fluid resuscitation strategies: a systematic review of animal trials

OBJECTIVES: Our objective was to systematically review randomized, controlled trials of fluid resuscitation in animal models of uncontrolled hemorrhage and to explore potential sources of heterogeneity. METHODS: We conducted an electronic bibliographic search of published research, reviewed reference lists of included trials, and contacted authors about unpublished studies. We included all unconfounded, randomized, controlled trials of fluid resuscitation (timing, volume, or resuscitation targets) in animal models of uncontrolled hemorrhage. The outcome measure was mortality at the end of the scheduled follow-up period of the trial. Two reviewers independently applied the selection criteria to the trial reports. A third reviewer resolved disagreements. RESULTS: Forty-four trials compared fluid versus no fluid resuscitation. There was marked heterogeneity in the effect of fluid resuscitation on the risk of death, much of which was explained by the hemorrhage model used. In aortic injury models, the adjusted relative risk of death with fluid resuscitation was 0.48 (95% confidence interval [CI], 0.33-0.71). In organ incision models, the adjusted relative risk of death was 0.76 (95% CI, 0.49-1.18). In tail resection models, the adjusted relative risk of death was 0.69 (95% CI, 0.38-1.25) if 50% or more was removed and 1.86 (95% CI, 1.13-3.07) if less than 50% was removed. In other vascular injury models, the adjusted relative risk of death with fluid resuscitation was 1.70 (95% CI, 1.01-2.85), respectively. Nine trials compared hypotensive versus normotensive resuscitation. The relative risk of death with hypotensive resuscitation was 0.37 (95% CI, 0.27-0.50). CONCLUSION: Fluid resuscitation appears to reduce the risk of death in animal models of severe hemorrhage but increases the risk of death in those with less severe hemorrhage. Excessive fluid resuscitation could therefore be harmful in some situations. Hypotensive resuscitation reduced the risk of death in all the trials investigating it. An evaluation of the potential impact of hypotensive resuscitation in humans could now be warranted.     

Nimodipine reduces the toxicity of intravenous bupivacaine in rats.

We examined nimodipine modification of bupivacaine toxicity in anesthetized male rats. Three minutes after pretreatment, group 1 (n = 11), group 3 (n = 10), and their respective control groups (n = 11 and n = 9) received intravenous bupivacaine LD50 (median lethal dose). After pretreatment, group 2 (n = 10), group 4 (n = 8), and their respective control groups (n = 10 and n = 8) received intravenous bupivacaine LD90 (90% lethal dose). Pretreatment was 200 micrograms/kg intravenous nimodipine in groups 1 and 2 and 500 micrograms/kg in groups 3 and 4. Control animals were pretreated with intravenous saline solution. Data were analyzed by chi 2-analysis and analysis of variance. Survival increased after 200 micrograms/kg nimodipine (P less than 0.05). In group 1, 9 (81%) of 11 survived compared with control animals (4 [36%] of 11). In group 2, 8 (80%) of 10 survived compared with control animals (2 [20%] of 10). Survival was not increased after 500-micrograms/kg nimodipine pretreatment. In group 3, 2 (22%) of 9 survived compared with control animals (4 [40%] of 10). In group 4, 4 (50%) of 8 survived compared with control animals (2 [25%] of 8). We conclude that nimodipine pretreatment with 200 micrograms/kg protects against fatal toxicity from LD50 and LD90 bupivacaine, but 500 micrograms/kg does not.     

Target blood pressure for hypotensive resuscitation

Background

Good outcomes have resulted from hypotensive resuscitation of hemorrhagic shock patients. We hypothesized that mean arterial pressure (MAP) 60 mmHg is the target blood pressure for hypotensive resuscitation during uncontrolled hemorrhagic shock in trauma.

Methods

To determine the effective target MAP for hypotensive resuscitation during uncontrolled hemorrhagic shock, we randomly assigned 80 rats to one of 8 treatment groups (n = 10 for each group). We then observed the effects of different target MAPs (control, 40, 50, 60, 70, 80, 90 mmHg, and sham) on fluid resuscitation of uncontrolled hemorrhagic shock. Blood pressure, serum lactate, hematocrit, fluid therapy, blood loss, and plasma cytokine levels were measured at 0, 30, 90, 120, 180, 240, 300 min after the start of the surgical procedure.

Results

A target MAP of 90, 80 and 70 mmHg had increased blood loss and decreased hematocrit and IL-6 and TNF-α production. A target MAP of 60, 50 and 40 mmHg had lower blood loss, good hematocrit, higher IL-6 and TNF-α production, and decreased animal survival. Only target MAPs of 40 and 50 had and decreased animal survival. The differences in blood loss, hematocrit, lactate, post-resuscitation MAP, survival, IL-6, IL-10, and TNF-α production between rats with a target MAP of 60 mmHg and those with a target MAP of 70 mmHg were not significant. The amount of fluid therapy in the BP 60 groups was less than in the BP 70 groups (P < 0.001).

Conclusion

A MAP of 60 mmHg should be considered for evaluation in human studies as a target for hypotensive resuscitation.     

Isotonic saline resuscitation in uncontrolled hemorrhage under various anesthetic conditions.

OBJECTIVE: The authors evaluated the effect of early fluid resuscitation with isotonic saline (NaCl, 0.9%) on uncontrolled hemorrhage in rats under different anesthetic conditions. SUMMARY/BACKGROUND DATA: Recently, it has been suggested that administration of fluids to patients during uncontrolled hemorrhage may produce adverse effects, and a postponement of resuscitation until surgical control of bleeding was recommended. Past clinical trials were inconclusive, and the results of recent experimental studies were affected by use of vasoactive anesthetics. METHODS: One hundred thirty-five female Sprague-Dawley rats were randomly divided into three groups: group 1--unanesthetized; group 2--anesthetized with sodium pentobarbital; and group 3--anesthetized with a mixture of droperidol and ketamine. Uncontrolled hemorrhage was initiated with a 75% tail resection, and each group was further subdivided into three subgroups for the following treatment: (A) no resuscitation; (B) 40 mL/kg of isotonic saline; or (C) 80 mL/kg of isotonic saline, administered 15 minutes after the initiation of hemorrhage. Blood loss volume and survival time were recorded, and animals were observed up to 360 minutes. RESULTS: At 6 hours, nonresuscitated animals of all groups exhibited the highest mortality rates (93%, 73%, 100% in groups 1, 2, and 3, respectively). Resuscitation significantly improved the survival; lowest mortality rates were observed after resuscitation with 80 mL/kg in groups 1 and 3 (33%) and 40 mL/kg in group 2 (40%). Fluid infusion increased hemorrhage rates in all anesthetized rats. No such increases in bleeding were observed in group 1. CONCLUSIONS: Resuscitation with isotonic saline improved mortality in uncontrolled hemorrhage, even with concomitant increases in hemorrhage rates, under all three anesthetic conditions tested. Unanesthetized rats bled less than the animals under anesthesia and did not exhibit an increased blood loss in response to fluid infusion.     

Permissive hypotension does not reduce regional organ perfusion compared to normotensive resuscitation: animal study with fluorescent microspheres

Introduction

The objective of this study was to investigate regional organ perfusion acutely following uncontrolled hemorrhage in an animal model that simulates a penetrating vascular injury and accounts for prehospital times in urban trauma. We set forth to determine if hypotensive resuscitation (permissive hypotension) would result in equivalent organ perfusion compared to normotensive resuscitation.

Methods

Twenty four (n=24) male rats randomized to 4 groups: Sham, No Fluid (NF), Permissive Hypotension (PH) (60% of baseline mean arterial pressure - MAP), Normotensive Resuscitation (NBP). Uncontrolled hemorrhage caused by a standardised injury to the abdominal aorta; MAP was monitored continuously and lactated Ringer’s was infused. Fluorimeter readings of regional blood flow of the brain, heart, lung, kidney, liver, and bowel were obtained at baseline and 85 minutes after hemorrhage, as well as, cardiac output, lactic acid, and laboratory tests; intra-abdominal blood loss was assessed. Analysis of variance was used for comparison.

Results

Intra-abdominal blood loss was higher in NBP group, as well as, lower hematocrit and hemoglobin levels. No statistical differences in perfusion of any organ between PH and NBP groups. No statistical difference in cardiac output between PH and NBP groups, as well as, in lactic acid levels between PH and NBP. NF group had significantly higher lactic acidosis and had significantly lower organ perfusion.

Conclusions

Hypotensive resuscitation causes less intra-abdominal bleeding than normotensive resuscitation and concurrently maintains equivalent organ perfusion. No fluid resuscitation reduces intra-abdominal bleeding but also significantly reduces organ perfusion.

     

Controlled resuscitation for uncontrolled hemorrhagic shock

OBJECTIVE: To test the hypothesis that controlled resuscitation can lead to improved survival in otherwise fatal uncontrolled hemorrhage. METHODS: Uncontrolled hemorrhage was induced in 86 rats with a 25-gauge needle puncture to the infrarenal aorta. Resuscitation 5 minutes after injury was continued for 2 hours with lactated Ringer's solution (LR), 7.3% hypertonic saline in 6% hetastarch (HH), or no fluid (NF). Fluids infused at 2 mL x kg(-1) x min(-1) were turned on or off to maintain a mean arterial pressure (MAP) of 40, 80, or 100 mm Hg in six groups: NF, LR 40, LR 80, LR 100, HH 40, and HH 80. Blood loss was measured before and after 1 hour of resuscitation. RESULTS: Survival was improved with fluids. Preresuscitation blood loss was similar in all groups. NF rats did not survive 4 hours. After 72 hours, LR 80 rats (80%) and HH 40 rats (67%) showed improved survival over NF rats (0%) (p < 0.05). Rebleeding increased with MAP. Attempts to restore normal MAP (LR 100) led to increased blood loss and mortality. CONCLUSION: Controlled resuscitation leads to increased survival compared with no fluids or standard resuscitation. Fluid type affects results. Controlled fluid use should be considered when surgical care is not readily available.     

Effect of methylene blue on resuscitation after haemorrhagic shock.

OBJECTIVE: To compare prehospital hypotensive resuscitation with volume resuscitation, and find out whether reagents that inhibit free-oxygen radical formation, such as methylene blue, can improve resuscitation and survival. DESIGN: Randomised controlled trial. SETTING: Animal laboratory, Israel. ANIMALS: 48 adult male Wistar rats. INTERVENTIONS: After 30 minutes of controlled haemorrhage, rats were subjected to 60 minutes of uncontrolled haemorrhage with simultaneous resuscitation. Hartmann's solution alone, or with blood or with a bolus of methylene blue were infused to maintain the mean arterial pressure (MAP) at 80 or 40 mm Hg. Then haemorrhage was stopped and Hartmann's solution plus whole blood were infused to obtain a MAP that was within normal limits. MAIN OUTCOME MEASURES: Volumes of shed blood and resuscitation fluids, MAP, packed cell volume, blood pH and base deficit, and survival. RESULTS: During uncontrolled haemorrhage. a MAP of 80 mm Hg could not be reached in animals resuscitated with Hartmann's solution alone, and all died. All the rats given Hartmann's solution with a bolus of methylene blue or with whole blood achieved a higher MAP. MAP of 40 mm Hg was attained in all animals regardless of the resuscitation fluid. Only 15 of 24 animals resuscitated to a MAP of 80 mm Hg survived, compared with 22 survivors of the 24 rats resuscitated to a MAP of 40 mm Hg (p <0.04). Methylene blue or whole blood drastically reduced the volumes of shed blood and of fluids required, and moderated the reduction in packed cell volume, particularly during hypotensive resuscitation. CONCLUSION: Hypotensive protocols should be used to improve survival. Methylene blue given with the electrolyte solutions could negate their detrimental effects during resuscitation.     

Blood loss after fluid resuscitation with isotonic or hypertonic saline for the initial treatment of uncontrolled hemorrhage induced by spleen rupture

BACKGROUND: It has been suggested that fluid resuscitation for the prehospital management of hypotensive trauma victims increases bleeding. In a model of uncontrolled hemorrhage induced by complete splenic laceration with a hilar vascular injury, we hypothesized that small-volume hypertonic saline or large-volume lactated Ringer's solution may provide sustained hemodynamic benefits despite promoting increases in intra-abdominal bleeding. METHODS: Forty anesthetized, spontaneously breathing dogs (18 +/- 1 kg) underwent laparotomy. A suture line was placed around the spleen to produce a splenic rupture with hilar vascular injury by pulling the exteriorized lines after incision closure. Intra-abdominal blood loss was measured directly, immediately after the animal was killed. Dogs were randomly assigned to four groups (n = 10 per group): Untreated controls were killed 20 (CT20) or 40 (CT40) minutes after splenic rupture to measure blood loss directly. Treatment groups received (20 minutes after spleen rupture) lactated Ringer's (LR), 33 mL/kg over 15 minutes, or 7.5% NaCl/6% dextran 70 (HSD), 4 mL/kg over 4 minutes. Blood loss was measured 40 minutes after spleen rupture. RESULTS: Mean arterial pressure dropped from an average value of 103 +/- 3 mm Hg to 67 +/- 5 mm Hg during the first 20 minutes and was partially restored afterward in all groups, with no significant differences between them. No resuscitation was associated with low cardiac output, whereas HSD restored and LR overshot baseline cardiac output. Intra-abdominal blood loss was 30 +/- 4, 38 +/- 4, 43 +/- 5, and 42 +/- 5 mL/kg for groups CT20, CT40, HSD, and LR, respectively, with no statistical significance between groups. CONCLUSION: No-fluid resuscitation in uncontrolled hemorrhage from splenic rupture resulted in a low-flow state, whereas resuscitation with small volumes of HSD or large volumes of LR produced hemodynamic benefits without significant increases in bleeding.     

Hepatocellular dysfunction occurs early after hemorrhage and persists despite fluid resuscitation

The liver is a major organ involved in multiple organ failure (MOF) following hemorrhage and trauma. However, it is not known if active hepatocellular membrane transport, measured by in vivo indocyanine green (ICG) clearance, is depressed after hemorrhage and if it persists after resuscitation. To study this, rats were bled to and maintained at a mean BP of 40 mm Hg until 40% of maximum bleedout (MB) volume was returned in the form of Ringer's lactate (RL). The rats were then resuscitated with 2X or 3X the volume of MB with RL and hepatocellular function was determined at various intervals. ICG, two to four doses (0.167-1.667 mg/kg BW), was given intravenously and [ICG] was continuously recorded without the need of blood sampling, using an in vivo hemoreflectometer with computer-assisted data acquisition. Initial velocity of clearance (V0) was calculated from [ICG] vs time (t) according to [ICG] = e (a + bt + ct 2), where eab is V0. Maximal velocity of clearance (Vmax) and Km, a kinetic constant representing the efficiency of the active transport process, were determined from the Lineweaver-Burk plot. The results indicate that Vmax decreased by 66% at MB and remained depressed despite fluid resuscitation. Km, decreased by 58% at MB, returned to prehemorrhage level after 3X RL but was not maintained and it decreased by 60% at 4 hr after resuscitation. This in vivo study demonstrates that active hepatocellular function is significantly depressed early after hemorrhage and persists despite resuscitation with RL and may form the basis of the MOF observed after severe and prolonged hemorrhage.     

NMR monitoring of phosphate metabolism of rat skeletal muscle during hemorrhage and resuscitation

Phosphorus nuclear magnetic resonance (NMR) spectroscopy allows noninvasive monitoring of intracellular high-energy metabolites. In the present study we used topical NMR to monitor intracellular levels of ATP, creatine phosphate (CrP), inorganic phosphate (Pi), and pH in the biceps femoris muscle of rats during hemorrhagic shock and resuscitation. Twelve rats weighing 300-500 gm were anesthetized and bled to a mean arterial pressure (MAP) of 50-55 mm Hg for 90 minutes. Then they were resuscitated with lactated Ringers' until MAP returned to normal or resuscitation fluid equaled four times the shed blood volume. During resuscitation, the rats fell into one of two groups: survivor group (n = 5) which could be successfully resuscitated for 60 minutes or longer; or nonsurvivor group (n = 7) which died during resuscitation. In both groups, ATP levels were maintained during hemorrhage and resuscitation. Intramuscular pH dropped about 0.2 pH units in both groups at the end of hemorrhage; however, pH was restored back toward baseline in the survivor group. CrP levels were lower in the nonsurvivor group at the end of hemorrhage. After resuscitation, CrP returned to nearly baseline levels in the survivor group; in the nonsurvivor group, CrP was further depleted after resuscitation. Pi levels were increased in both groups at the end of hemorrhage, but in the survivor group Pi decreased during the first 15 minutes of resuscitation; in the nonsurvivor group Pi increased further to four times baseline levels. This study demonstrated that topical NMR can quantitate a metabolic deficit in skeletal muscle during hemorrhage and resuscitation. The results show that improvement of intracellular Pi and CrP levels correlated with survival.     

Exogenous nitric oxide donor and related compounds protect against lung inflammatory response after hemorrhagic shock and resuscitation

BACKGROUND: Resuscitation from hemorrhagic shock triggers an inflammatory response characterized by upregulation of cytokine and adhesion molecule expression, increased leukocyte activity, and accumulation of polymorphonuclear neutrophils in a variety of tissues. This study investigated the capability of an exogenous nitric oxide (NO) donor, sodium nitroprusside (NP); a NO substrate, L-arginine; and an inducible NO synthase inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL) to reduce lung injury in an animal model of mixed controlled and uncontrolled hemorrhagic shock. METHODS: For this study, 72 Sprague-Dawley rats weighing 250 to 300 g were subjected to a model of uncontrolled hemorrhagic shock for 150 minutes. Six groups of animals were included in this study (12 per group): sham-saline, sham-NP, shock-saline, shock-NP, shock-L-arginine, and shock-L-N6-(1-iminoethyl)lysine. After the period of hemorrhagic shock, resuscitation of the groups was accomplished using normal saline (groups 1 and 3), NP (0.5 mg/kg) (groups 2 and 4), L-arginine (300 mg/kg) (group 5), or L-NIL (50 mg/kg) (group 6). The following indices were evaluated: fluid requirements for resuscitation, mean arterial pressure (MAP), arterial po2, pco2, and pH, lung wet-to-dry weight ratio, lung histology and cytokine (interleukin [IL]-1 alpha, IL-beta 1, tumor necrosis factor-beta [TNF beta], IL-3, IL-4, IL-5, IL-6, IL-10, TNF alpha, IL-2, interferon-gamma [IFN gamma]), and mRNA expression in the lung by a ribonuclease protection assay (RPA). RESULTS: Sodium nitroprusside significantly increased MAP and reduced fluid requirements during resuscitation after hemorrhage. There also was a significant improvement in lung function, as expressed by improvements in po2, pco2, and pH, and reduction of the wet-to-dry weight ratio. In addition, a significant reduction in acute lung injury was observed in the histologic studies. Furthermore, the expression of cytokines was reduced by NP treatment. The use of L-arginine and L-NIL offered similar protective results for the injured lung. CONCLUSIONS: These data suggest that limiting inducible NO synthase-generated NO availability with the exogenous NO donor, sodium nitroprusside, may reduce lung injury after severe hemorrhage, possibly, among other effects, by downregulating the expression of inflammatory cytokines. L-arginine and L-NIL also had a beneficial effect on lung function and structure.     

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目的　探讨限制性液体复苏对出血未控制性休克后续救治的影响。方法　应用脾组织和血管损伤制作重度未控制出血性休克模型 ,比较早期限制液体复苏 [平均动脉压 (MAP)分别维持在 4 0mmHg(NS4 0组 ,1mmHg =0 .133kPa)、5 0mmHg(NS5 0组 )和 6 0mmHg(NS6 0组 ) ]和大量液体复苏 [MAP分别维持在 80mmHg(NS80组 )和 10 0mmHg(NS10 0组 ) ]对MAP、血乳酸 (BL)、红细胞压积 (HCT)、出血量、输液量及存活率的影响。结果　NS4 0、NS5 0和NS6 0组的出血量、液体用量和存活率明显低于NS80和NS10 0组 (P均 <0 .0 5 ) ;伤后4 5min ,NS80和NS10 0组HCT明显低于NS4 0、NS5 0和NS6 0组 (P均 <0 .0 5 ) ;伤后 4 0 5min ,NS80和NS10 0组的HCT明显低于NS5 0和NS6 0组 ,MAP明显低于NS4 0、NS5 0和NS6 0组 ,血乳酸明显高于NS4 0、NS5 0和NS6 0组 (P均 <0 .0 5 )。结论　在出血未控制条件下 ,早期限制性液体复苏可明显降低出血量 ,减轻酸中毒 ,为后续救治创造条件 ,并有利于最终存活率的提高     

特布他林对去甲肾上腺素和烧伤血清诱导大鼠神经胶质细胞血管内皮生长因子基因表达的影响

目的了解β2肾上腺素能受体激动剂特布他林对烧伤血清和去甲肾上腺素（NE）诱导神经胶质细胞血管内皮生长因子（VEGF）基因表达的影响。方法制备烧伤大鼠及正常大鼠血清。取出生1～3d乳鼠脑组织行原代神经胶质细胞培养，并在培养液中加入不同的刺激物，分为：（1）对照组：加入体积分数10％的正常大鼠血清；（2）NE1、NE2、NE3组：分别加入体积分数10％烧伤血清＋10、20、50μmol／LNE；（3）TBN1、TBN2、TBN3组：分别加入10、20、50μmol／L特布他林＋体积分数10％烧伤血清＋10、20、50μmol／LNE。采用蛋白质印迹法检测各组VEGF蛋白的表达；实时荧光定量PCR法检测VEGFmRNA的表达。结果对照组VEGF蛋白的表达处于较低水平，NE1、NE2、NE3组其表达随NE浓度的增大逐渐增加，而TBN1、TBN2、TBN3组的表达明显增加。对照组神经胶质细胞VEGF mRNA表达量[（5．72±0．12）拷贝数／g]较低，NEl、NE2、NE3组VEGF mRNA的表达[（13．26±0．03）、（10．37±0．04）、（14．87±0．55）拷贝数／g]均高于对照组（P〈0．01）。而TBN1、TBN2、TBN3组VEGF mRNA表达量[（13．39±0．19）、（15．77±0．11）、（16．00±0．07）拷贝数／g]也逐渐增加，除TBN1组外其余2组与各NE组比较，差异有统计学意义（P〈0．01）。结论特布他林可增强烧伤血清和NE诱导神经胶质细胞VEGF基因的表达。     

Hypotensive resuscitation in patients with ruptured abdominal aortic aneurysm.

BACKGROUND: The technique of hypotensive resuscitation in haemorrhagic shock involves resuscitation to below normotensive blood pressures achieving the minimum perfusion pressure that will adequately perfuse vital organs until definitive arrest of haemorrhage. AIM: To summarise the evidence for the use of hypotensive resuscitation in patients with uncontrolled haemorrhagic shock and ruptured abdominal aortic aneurysm (AAA). METHODS: A MEDLINE (1966-2004) and Cochrane library search for articles relating to hypotensive resuscitation was undertaken; see text for further details. RESULTS: Several animal studies exist using an abdominal aortotomy model of ruptured AAA. These have demonstrated improved tissue perfusion, decreased blood loss and improved survival associated with hypotensive resuscitation compared with aggressive resuscitation. There are several human studies advocating delayed rather than immediate resuscitation in trauma patients but careful review of the literature reveals no prospective studies of hypotensive resuscitation in patients with ruptured AAA. CONCLUSIONS: Animal studies demonstrate superiority of hypotensive resuscitation over aggressive resuscitation but further research is required to assess its efficacy in patients with ruptured AAA.     

Hospital profitability per hour of operating room time can vary among surgeons

In rats subjected to closed head trauma (CHT) plus uncontrolled hemorrhage, giving 0.3 mL of 0.9% saline per 0.1 mL of blood lost did not restore mean arterial blood pressure (MAP) or improve neurological severity score (NSS). In CHT without hemorrhage, giving 20% albumin or 10% hetastarch improved NSS. We hypothesized that these latter treatments would also improve NSS after CHT plus uncontrolled hemorrhage. Rats were randomly assigned to one of seven groups. Experimental conditions were CHT (yes or no), uncontrolled hemorrhage (yes or no), and fluid given to replace blood loss (none; 10% hetastarch, 20% albumin, or 3% saline [0.1 mL per 0.1 mL of blood lost]; or 0.9% saline [0.3 mL per 0.1 mL of blood lost]). NSS (0--25 scale, where 0 = no impairment) was determined at 1, 4, and 24 h, and brain water content was determined at 24 h after CHT. NSS (median +/- range) at 24 h was 11 +/- 6 when no fluid was given; 16 +/- 5 with 10% hetastarch; 14 +/- 5 with 20% albumin; 12 +/- 4 with 3% saline; and 13 +/- 4 with 0.9% saline given (not significant). In addition, brain water content and MAP did not differ among the groups receiving CHT with or without uncontrolled hemorrhage. In our model of CHT plus uncontrolled hemorrhage in rats, giving 10% hetastarch, 20% albumin, 3% saline, or 0.9% saline failed to improve NSS, brain water content, or MAP. IMPLICATIONS: In previous studies of closed head trauma (CHT) without hemorrhage, giving 20% albumin or 10% hetastarch improved neurological severity scores (NSSs). We hypothesized that these treatments also might be beneficial in CHT plus uncontrolled hemorrhage. We found that giving 10% hetastarch, 20% albumin, 3% saline, or 0.9% saline failed to improve NSS, brain water content, or mean arterial blood pressure.     

Mechanism of the beneficial effects of pentoxifylline on hepatocellular function after trauma hemorrhage and resuscitation.

BACKGROUND. The purpose of this study was to determine whether pentoxifylline administration restores the depressed hepatocellular function after trauma hemorrhage and crystalloid resuscitation and, if so, whether this is the result of the down-regulation of inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-6 (IL-6). METHODS. After laparotomy rats were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximum shed blood volume was returned in the form of Ringer's lactate. They were then resuscitated with Ringer's lactate to four times the shed blood volume. Pentoxifylline (50 mg/kg body weight) or saline solution was infused intravenously for 95 minutes during and after resuscitation. One and a half hours and 4 hours after resuscitation, hepatocellular function (maximal velocity [Vmax] and the efficiency of the active transport [Km] of indocyanine green clearance) and plasma. TNF and IL-6 levels were determined with in vivo hemoreflectometer and cellular assays, respectively. RESULTS. Circulating TNF and IL-6 levels increased significantly after hemorrhage and resuscitation. Pentoxifylline treatment, however, markedly decreased the levels of these cytokines, and the values were similar to those of sham rats. The decreased Vmax and Km values were also restored by pentoxifylline treatment. Moreover, there was a significant correlation between Vmax and TNF or IL-6 levels. CONCLUSIONS. The down-regulation of inflammatory cytokines by pentoxifylline may be the mechanism by which this agent restores the depressed hepatocellular function after trauma hemorrhage and resuscitation.     

Influence of Hemorrhagic Shock Followed by Crystalloid Resuscitation on Propofol: A Pharmacokinetic and Pharmacodynamic Analysis

Background: Previous work has demonstrated that ongoing hemorrhagic shock dramatically alters the distribution, clearance, and potency of propofol. Whether volume resuscitation after hemorrhagic shock restores drug behavior to baseline pharmacokinetics and pharmacodynamics remains unclear. This is particularly relevant because patients suffering from hemorrhagic shock are typically resuscitated before surgery. To investigate this, the authors studied the influence of an isobaric bleed followed by crystalloid resuscitation on the pharmacokinetics and pharmacodynamics of propofol in a swine model. The hypothesis was that hemorrhagic shock followed by resuscitation would not significantly alter the pharmacokinetics but would influence the pharmacodynamics of propofol.

Methods: After approval from the Animal Care Committee, 16 swine were randomly assigned to control and shock-resuscitation groups. Swine randomized to the shock-resuscitation group were bled to a mean arterial blood pressure of 40 mm Hg over a 20-min period and held there by further blood removal until 42 ml/kg of blood had been removed. Subsequently, animals were resuscitated with lactated Ringer's solution to maintain a mean arterial blood pressure of 70 mm Hg for 60 min. After resuscitation, propofol (750 [mu]g[middle dot]kg-1[middle dot]min-1) was infused for 10 min. The control group underwent a sham hemorrhage and resuscitation and received propofol at the same dose and approximate time as the shock-resuscitation group. Arterial samples (20 from each animal) were collected at frequent intervals until 180 min after the infusion began and were analyzed to determine drug concentrations. Pharmacokinetic parameters for each group were estimated using a three-compartment model. The electroencephalogram Bispectral Index Scale was used as a measure of drug effect. Pharmacodynamics were characterized using a sigmoid inhibitory maximal effect model.

Results: The raw data demonstrated minimal differences in the mean plasma propofol concentrations between groups. The compartment analysis revealed some subtle differences between groups in the central and slow equilibrating volumes, but the differences were not significant. Hemorrhagic shock followed by resuscitation shifted the concentration effect relationship to the left, demonstrating a 1.5-fold decrease in the effect-site concentration required to achieve 50% of the maximal effect in the Bispectral Index Scale.