羟乙基淀粉溶液在复苏肠缺血-再灌注休克中的作用
涂自智 孙庆华 George Dimopoulos Suzana M Lobo Daniel de Backer 肖献忠 Jean-Louis Vincent
【摘要】 目的 比较不同剂量羟乙基淀粉溶液(HES)对兔肠缺血-再灌注损伤所致休克的复苏作用。方法32只新西兰白兔随机分为4组：模型对照、乳酸林格液复苏组(LRS，20 ml·kg-1·h-1)，小剂量HES复苏组(HES 2 ml·kg-1·h-1+LRS 18 ml·kg-1·h-1)，大剂量HES复苏组(HES 20 ml·kg-1·h-1)。采用肠系膜上动脉夹闭60 min后松夹行再灌注制备肠缺血-再灌注休克模型，松夹再灌注时同步进行液体复苏。观测各时间点的血流动力学参数(平均动脉压、心率、心排血量、肠系膜上动脉血流)，并通过测定肠黏膜CO2分压和动脉血CO2分压的差值(动脉二氧化碳间隙)、肠黏膜pH值、动脉血乳酸浓度和氧输送等指标间接评估组织氧合情况。实验结束后累计动物死亡数。结果 HES能明显提高肠缺血-再灌注休克时的血流动力学参数，与对照组和LRS组比较差异均有显著性(P均<0.05)；小剂量HES比大剂量HES改善血流动力学参数的作用更平稳(P均<0.05)，且较其他3组能明显降低血乳酸浓度和动脉二氧化碳间隙，减轻pHi的降低(P均<0.05)；而大剂量HES对上述参数的影响不明显，并可见动物口鼻出血及死亡；小剂量或大剂量HES与其他两组比较均能使氧输送回升(P均<0.05)。结论小剂量HES加LRS复苏，既能提高血流动力学参数，又能明显改善组织氧合状况，比单用LRS或大剂量HES对兔肠缺血-再灌注休克的复苏效果更好。
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关键词: 羟乙基淀粉； 缺血-再灌注损伤，肠； 休克； 液体复苏
Roles of hydroxyethyl starch solution in resuscitation for shock induced by ischemia/reperfusion inJury of the intestine
TU Zi-zhi, SUN Qing-hua△, George Dimopoulos△, Suzana M Lobo△, Daniel de Backer△, XIAO Xian-zhong, Jean-Louis Vincent△.
Department of Pathophysiology, Xiangya Medical College, Central South University, Changsha 410078, Hunan, China;△Department of Intensive Care Medicine, Erasme Hospital, Free University of Brussels, Belgium
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【Abstract】 ObJective To compare the effects of high and low doses of 6% hydroxyethyl starch solution (HES) on resuscitation for shock induced by ischemia/reperfusion injury of the intestine in rabbits. Methods Thirty-two anesthetized rabbits were randomized into four groups of eight animals each. The animals in the control group received no fluid resuscitation, animals in group 2 received lactated Ringer's solution (LRS, 20 ml·kg-1·h-1), those in group 3 received LRS+HES (LRS 18 ml·kg-1·h-1+HES 2 ml·kg-1·h-1, low dosage of HES), and those in group 4 received HES only in high dosage of HES (20 ml·kg-1·h-1). All these rabbits underwent intestinal ischemia/reperfusion inJury developed by occluding superior mesenteric artery (SMA) with a noncrushing vascular clamp for 60 minutes and then the clamp was loosened for 240 minutes. The fluid resuscitation began at the same time of reperfusion. Hemodynamic parameters including mean artery pressure, heart rate, aortic velocity (as cardiac output), and SMA blood flow were measured. Tissue oxygenation was assessed indirectly by measuring the tonometric parameter of the gut, including difference between partial pressure of carbon dioxide in intestinal intramucosal and partial pressure of carbon dioxide in arterial blood (Pt-aCO2 gap), intestinal intramucosal pH (pHi), arterial blood lactate acid concentration and oxygen delivery. Mortality of the rabbits was counted at the end of the experiment. Results Hemodynamic parameters as measured in low and high doses of HES groups were significantly higher in values than LRS group(LRS) and control (all P<0.05). Low dose of HES was better in restoring hemodynamic parameters than high dose of HES (all P<0.05). Low dose of HES could greatly decrease lactate and Pt-aCO2 gap, significantly improve pHi compared with other three groups (all P<0.05), but high dose of HES did not do so, and oral and nasal bleeding even death of some animals were seen. Low dose and high dose of HES significantly improved oxygen delivery while LRS did not (all P<0.05). Conclusion Low dose of HES together with LRS is more effective than only high dose of HES or LRS in the resuscitation for shock induced by ischemia/reperfusion inJury of the intestine in rabbits, resulting in better hemodynamic parameters and tissue oxygenation.
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Key words: hydroxyethyl starch； intestinal ischemia/reperfusion inJury； shock； fluid resuscitation
肠缺血-再灌注后，氧自由基、腺苷、激肽以及局部酸性代谢产物等可随血流进入全身循环，使得毛细血管壁通透性增高、组织水肿、有效循环血量减少，引起低血容量性休克；甚至可因肠壁受损而引起肠源性细菌或者内毒素移位，导致败血症休克或全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)而危及患者生命( 1，2)。及时进行液体复苏是防治肠缺血-再灌注休克的重要措施。但是，临床上一般对创伤失血性休克会进行积极的液体复苏(3)，而对这种由于肠缺血-再灌注所引起的休克，如何进行有效液体复苏未给予足够的重视。中分子质量、质量分数为6%的羟乙基淀粉溶液(HES，Elohaes, Fresenius,Germany)作为一种有效的人工胶体液已用于临床。本研究拟通过兔肠缺血-再灌注损伤模型，比较晶体液(乳酸林格液，LRS)和不同剂量HES对休克的复苏作用，为临床上对肠缺血-再灌注休克患者实施最佳的液体复苏方案提供依据。
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1 材料与方法
1.1 动物模型与分组：新西兰白兔32只，比利时布鲁塞尔自由大学Erasme医院实验动物中心提供，体质量2.8~3.5 kg，雌雄不限。随机分为4组：①模型对照组，LRS 4 ml·kg-1·h-1；②LRS组，LRS 20 ml·kg-1·h-1复苏；③小剂量HES组，LRS 18 ml·kg-1·h-1+6%HES 2 ml·kg-1·h-1复苏;④大剂量HES组，6%HES20 ml·kg-1·h-1复苏。实验前动物常规饲养，自由饮水。肌肉注射氯胺酮20 mg/kg(ketamine,Warner-Lambert Manufacturing Ltd.Dublin,Ireland)和赛拉嗪5 mg/kg(xylazine,Bayer,Lever Kusen,Germany) 麻醉，然后从左耳缘静脉用输液泵(Braun,Melsungen AG,Germany) 持续输入氯胺酮70 mg·kg-1·h-1和赛拉嗪1.5 mg·kg-1·h-1混合液维持静脉麻醉效果。气管插管，呼吸机通气(Servo ventilator 900B;Siemens-Elema,Solna,Sweden)，维持潮气量7～8 ml/kg，呼吸频率35～40次/min。分离右侧颈总动脉，插管监测血压，并取动脉血样；左侧颈外静脉插管输液。腹部正中切口，无损伤动脉夹夹闭肠系膜上动脉(SMA)根部，阻断血流60 min后，松夹恢复肠系膜血流，制成肠缺血-再灌注损伤模型。同时在SMA根部及膈下腹主动脉处放置超声血流探针(Transonic Systems Inc.,Ithaca,NY)监测血流，将张力计导管(TRIP，NGS Catheter;Tonometrics,Helsinki,Finland)插入中段回肠腔内，监测肠腔内二氧化碳分压(PtCO2)和肠黏膜pH(pHi)。实验中，必要时给予肌松剂泮库溴铵0.1 mg·kg-1·h-1(pancuronium bromide)。术中及术后稳定和缺血期间，各组均进行基础输液(LRS 4 ml·kg-1·h-1)以保持输液导管通畅。松开动脉夹后，模型组继续维持基础输液，其他各组进行液体复苏。1.2 监测指标：手术结束后稳定60 min开始测量正常基础值。在缺血60 min(I60)及再灌注30 min(R30)、60 min(R60)、120 min(R120)、180 min(R180)和240 min(R240)各时间点测量血流动力学指标，包括平均动脉压(MAP)、心率(HR)、腹主动脉血流(AoV，作为心排血量( 4,5)、肠系膜上动脉血流(Qsma，缺血时无此指标)。同时取动脉血样立即进行血气分析(用血气分析仪，ABL625，Radiometer,Copenhagen,Denmark)，计算氧输送(oxygen delivery,DO2)，并测定血乳酸浓度。此外，在上述各时间点使用标准技术测定PtCO2和pHi( 6-8)。用温生理盐水1 ml充填肠张力计气束，平衡60 min，然后抽出前面0.7 ml液体弃去，再抽出余下的0.3 ml液体立即进行血气分析，计算动脉二氧化碳间隙(Pt-aCO2间隙),实验结束后累计动物死亡数。Pt-aCO2间隙=PtCO2- PaCO2
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1.3 统计学处理：数据用均数±标准差(x±s)表示，差异显著性用t检验；动物死亡率用R×2 χ2检验，P<0.05为差异有统计学意义。
2 结 果
2.1 死亡率(表1)：各组动物于R60后开始死亡，HES较LRS能降低动物的死亡率，两者合用效果较好，动物死亡率为0。
2.2 血流动力学参数(表2)：对照组动物均具有典型的肠缺血-再灌注损伤模型特征( 9)，MAP、HR、AoV和Qsma于再灌注后逐渐下降，有3只动物死亡。LRS组各参数的变化趋势与对照组基本相似，无显著性差异(P>0.05)。小剂量HES组及大剂量HES组的MAP下降程度减轻或有一定程度回升，而AoV和Qsma均明显回升，HR下降不明显，与另两组相比差异均有显著性(P均<0.05)。小剂量表2 各组各时间点血流动力学参数的变化(x±s,n=8)HES组MAP回升程度较平稳，大剂量HES组再灌注后MAP呈先上升后下降趋势，两组于R60、R120和R240点比较，有明显差异(P均<0.05)；而再灌注后小剂量HES组的AoV和Qsma比大剂量HES组回升程度要低(P均<0.05)。
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2.3 动脉血乳酸浓度(图1)：4组血乳酸浓度均呈上升趋势，但大剂量HES可轻度降低乳酸浓度，仅在R60和R120时与对照组和LRS组相比差异有显著性(P均<0.05)；而小剂量HES则可明显降低血乳酸浓度，与其他3组相比，再灌注后各时间点均有显著性差异(P均<0.05)。
3 讨 论
肠缺血-再灌注损伤是常见的临床危重病症,可因休克、SIRS甚至多器官功能衰竭(MOF)而导致死亡，应尽早进行液体复苏，以阻断这一病理过程的恶化。本研究结果发现，对肠缺血-再灌注损伤不处理的对照组于再灌注240 min内因休克而死亡的动物数占37.5%；LRS复苏组死亡率为25.0%；大剂量HES复苏组为12.5%；而小剂量HES组没有动物死亡，且其平均动脉压、心率、心排血量、肠系膜上动脉血流等血流动力学指标平稳。说明对肠缺血-再灌注损伤所致休克的复苏，仅用LRS或大剂量HES效果欠佳；而用LRS加小剂量HES(每只兔约为60 ml左右)复苏效果较好，特别是小剂量HES对肠系膜上动脉血流的较好维持，说明它已有效地改善了内脏器官的血液灌流状况。在研究不同液体对肠缺血-再灌注后肠黏膜灌注及氧合作用的影响时发现，与对照组和仅使用LRS复苏相比，6%HES可使再灌注后血乳酸浓度和Pt-aCO2间隙降低，pHi升高，并增强氧输送能力。说明HES不仅能改善缺血-再灌注休克的血流动力学参数，而且也能有效地改善缺血-再灌注后的内脏灌注和组织氧合状态,与Friedman等(10)在复苏未控制的狗失血性休克研究中所得结果基本一致。其机制可能与HES能增加有效循环血量、改善内脏微循环有关(11)。休克时的微循环障碍与大量细胞因子和血管活性物质的产生释放，使毛细血管灌注不足、细胞黏附、血液黏滞度增高密切相关。Collis等(12)和Boldt等( 13)所做的研究表明，HES可抑制内皮细胞激活和黏附分子P-选择素表达，减少败血症患者循环血中黏附分子的浓度。Morisaki等在羊腹膜炎休克模型中证实，HES可保护毛细血管的完整性，降低毛细血管渗漏综合征的液体漏出( 14-18)；并能稀释血液、降低血黏度，改善组织微循环，提高氧运送能力，改善组织缺氧和累积性组织氧债 ( 19,20)。本实验中观察到HES改善内脏灌注和组织氧合作用，可能与上述作用有关。此外，Kupiotis( 21)和Baldassarre等( 22)也先后报道指出，HES可抑制血小板聚集，损伤凝血功能而引起出血。本实验中大剂量HES组可见部分动物口鼻出血，可能与此有关。6%HES作为一种人造胶体液，平均相对分子质量为200 000，半衰期为3.35 h，经静脉输入后，主要保留在血管里而不渗出，故能有效地增加胶体渗透压( 23)和血浆容量，限制血管内液体的外漏，提高有效循环血量，从而降低单独输晶体液所致组织间隙水肿的程度(11)，改善内脏血液灌注和氧合作用( 24,25)。HES因能有效地恢复血流动力学和氧输送参数，而被广泛用于复苏大多数急性低血容量性休克( 26,27)。但是，大剂量输入HES，除了直接损伤凝血功能外( 21，22)，还可能因血管内胶渗压的升高、大量组织液回流，致使血压很快上升，使保护性的血管痉挛解除，血管扩张( 28)；同时，组织液回流降低了血液黏滞度，使血流加快，已形成的微小血栓碎裂被冲走，凝血因子被稀释，凝血功能降低而引起再出血 ( 29)。本实验中对不同剂量HES的复苏效果比较发现，大剂量HES组心排血量、肠系膜上动脉血流量明显上升，平均动脉血压在缺血60 min再灌注120 min前明显升高，然后下降，甚至出现动物死亡；而pHi回升程度不大，Pt-aCO2间隙和乳酸浓度也呈先低后高形态，可能也与HES降低凝血功能引起出血有关。小剂量HES加LRS的混合液体复苏，既克服了晶体液易外漏导致组织水肿的缺陷，又减弱了大剂量HES易引起凝血功能障碍的副作用。因此，与大剂量HES相比，该组动物血流动力学参数上升平稳，血乳酸和Pt-aCO2间隙明显下降，pHi和氧输送明显回升，且没有动物死亡，收到了较好的复苏效果。
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作者单位：410078 长沙，中南大学湘雅医学院病理生理教研室(涂自智，肖献忠)；比利时布鲁塞尔自由大学Erasme医院危重病医学系(孙庆华，George Dimopoulos, Suzana M Lobo,Daniel de Backer,Jean-Louis Vincent)
作者简介：涂自智(1959- )，男(汉族)，湖南省石门县人，医学硕士，副教授(Email:tuzizhi93@yahoo.com)。, http://www.100md.com
【摘要】 目的 比较不同剂量羟乙基淀粉溶液(HES)对兔肠缺血-再灌注损伤所致休克的复苏作用。方法32只新西兰白兔随机分为4组：模型对照、乳酸林格液复苏组(LRS，20 ml·kg-1·h-1)，小剂量HES复苏组(HES 2 ml·kg-1·h-1+LRS 18 ml·kg-1·h-1)，大剂量HES复苏组(HES 20 ml·kg-1·h-1)。采用肠系膜上动脉夹闭60 min后松夹行再灌注制备肠缺血-再灌注休克模型，松夹再灌注时同步进行液体复苏。观测各时间点的血流动力学参数(平均动脉压、心率、心排血量、肠系膜上动脉血流)，并通过测定肠黏膜CO2分压和动脉血CO2分压的差值(动脉二氧化碳间隙)、肠黏膜pH值、动脉血乳酸浓度和氧输送等指标间接评估组织氧合情况。实验结束后累计动物死亡数。结果 HES能明显提高肠缺血-再灌注休克时的血流动力学参数，与对照组和LRS组比较差异均有显著性(P均<0.05)；小剂量HES比大剂量HES改善血流动力学参数的作用更平稳(P均<0.05)，且较其他3组能明显降低血乳酸浓度和动脉二氧化碳间隙，减轻pHi的降低(P均<0.05)；而大剂量HES对上述参数的影响不明显，并可见动物口鼻出血及死亡；小剂量或大剂量HES与其他两组比较均能使氧输送回升(P均<0.05)。结论小剂量HES加LRS复苏，既能提高血流动力学参数，又能明显改善组织氧合状况，比单用LRS或大剂量HES对兔肠缺血-再灌注休克的复苏效果更好。
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关键词: 羟乙基淀粉； 缺血-再灌注损伤，肠； 休克； 液体复苏
Roles of hydroxyethyl starch solution in resuscitation for shock induced by ischemia/reperfusion inJury of the intestine
TU Zi-zhi, SUN Qing-hua△, George Dimopoulos△, Suzana M Lobo△, Daniel de Backer△, XIAO Xian-zhong, Jean-Louis Vincent△.
Department of Pathophysiology, Xiangya Medical College, Central South University, Changsha 410078, Hunan, China;△Department of Intensive Care Medicine, Erasme Hospital, Free University of Brussels, Belgium
, 百拇医药
【Abstract】 ObJective To compare the effects of high and low doses of 6% hydroxyethyl starch solution (HES) on resuscitation for shock induced by ischemia/reperfusion injury of the intestine in rabbits. Methods Thirty-two anesthetized rabbits were randomized into four groups of eight animals each. The animals in the control group received no fluid resuscitation, animals in group 2 received lactated Ringer's solution (LRS, 20 ml·kg-1·h-1), those in group 3 received LRS+HES (LRS 18 ml·kg-1·h-1+HES 2 ml·kg-1·h-1, low dosage of HES), and those in group 4 received HES only in high dosage of HES (20 ml·kg-1·h-1). All these rabbits underwent intestinal ischemia/reperfusion inJury developed by occluding superior mesenteric artery (SMA) with a noncrushing vascular clamp for 60 minutes and then the clamp was loosened for 240 minutes. The fluid resuscitation began at the same time of reperfusion. Hemodynamic parameters including mean artery pressure, heart rate, aortic velocity (as cardiac output), and SMA blood flow were measured. Tissue oxygenation was assessed indirectly by measuring the tonometric parameter of the gut, including difference between partial pressure of carbon dioxide in intestinal intramucosal and partial pressure of carbon dioxide in arterial blood (Pt-aCO2 gap), intestinal intramucosal pH (pHi), arterial blood lactate acid concentration and oxygen delivery. Mortality of the rabbits was counted at the end of the experiment. Results Hemodynamic parameters as measured in low and high doses of HES groups were significantly higher in values than LRS group(LRS) and control (all P<0.05). Low dose of HES was better in restoring hemodynamic parameters than high dose of HES (all P<0.05). Low dose of HES could greatly decrease lactate and Pt-aCO2 gap, significantly improve pHi compared with other three groups (all P<0.05), but high dose of HES did not do so, and oral and nasal bleeding even death of some animals were seen. Low dose and high dose of HES significantly improved oxygen delivery while LRS did not (all P<0.05). Conclusion Low dose of HES together with LRS is more effective than only high dose of HES or LRS in the resuscitation for shock induced by ischemia/reperfusion inJury of the intestine in rabbits, resulting in better hemodynamic parameters and tissue oxygenation.
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Key words: hydroxyethyl starch； intestinal ischemia/reperfusion inJury； shock； fluid resuscitation
肠缺血-再灌注后，氧自由基、腺苷、激肽以及局部酸性代谢产物等可随血流进入全身循环，使得毛细血管壁通透性增高、组织水肿、有效循环血量减少，引起低血容量性休克；甚至可因肠壁受损而引起肠源性细菌或者内毒素移位，导致败血症休克或全身炎症反应综合征(systemic inflammatory response syndrome,SIRS)而危及患者生命( 1，2)。及时进行液体复苏是防治肠缺血-再灌注休克的重要措施。但是，临床上一般对创伤失血性休克会进行积极的液体复苏(3)，而对这种由于肠缺血-再灌注所引起的休克，如何进行有效液体复苏未给予足够的重视。中分子质量、质量分数为6%的羟乙基淀粉溶液(HES，Elohaes, Fresenius,Germany)作为一种有效的人工胶体液已用于临床。本研究拟通过兔肠缺血-再灌注损伤模型，比较晶体液(乳酸林格液，LRS)和不同剂量HES对休克的复苏作用，为临床上对肠缺血-再灌注休克患者实施最佳的液体复苏方案提供依据。
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1 材料与方法
1.1 动物模型与分组：新西兰白兔32只，比利时布鲁塞尔自由大学Erasme医院实验动物中心提供，体质量2.8~3.5 kg，雌雄不限。随机分为4组：①模型对照组，LRS 4 ml·kg-1·h-1；②LRS组，LRS 20 ml·kg-1·h-1复苏；③小剂量HES组，LRS 18 ml·kg-1·h-1+6%HES 2 ml·kg-1·h-1复苏;④大剂量HES组，6%HES20 ml·kg-1·h-1复苏。实验前动物常规饲养，自由饮水。肌肉注射氯胺酮20 mg/kg(ketamine,Warner-Lambert Manufacturing Ltd.Dublin,Ireland)和赛拉嗪5 mg/kg(xylazine,Bayer,Lever Kusen,Germany) 麻醉，然后从左耳缘静脉用输液泵(Braun,Melsungen AG,Germany) 持续输入氯胺酮70 mg·kg-1·h-1和赛拉嗪1.5 mg·kg-1·h-1混合液维持静脉麻醉效果。气管插管，呼吸机通气(Servo ventilator 900B;Siemens-Elema,Solna,Sweden)，维持潮气量7～8 ml/kg，呼吸频率35～40次/min。分离右侧颈总动脉，插管监测血压，并取动脉血样；左侧颈外静脉插管输液。腹部正中切口，无损伤动脉夹夹闭肠系膜上动脉(SMA)根部，阻断血流60 min后，松夹恢复肠系膜血流，制成肠缺血-再灌注损伤模型。同时在SMA根部及膈下腹主动脉处放置超声血流探针(Transonic Systems Inc.,Ithaca,NY)监测血流，将张力计导管(TRIP，NGS Catheter;Tonometrics,Helsinki,Finland)插入中段回肠腔内，监测肠腔内二氧化碳分压(PtCO2)和肠黏膜pH(pHi)。实验中，必要时给予肌松剂泮库溴铵0.1 mg·kg-1·h-1(pancuronium bromide)。术中及术后稳定和缺血期间，各组均进行基础输液(LRS 4 ml·kg-1·h-1)以保持输液导管通畅。松开动脉夹后，模型组继续维持基础输液，其他各组进行液体复苏。1.2 监测指标：手术结束后稳定60 min开始测量正常基础值。在缺血60 min(I60)及再灌注30 min(R30)、60 min(R60)、120 min(R120)、180 min(R180)和240 min(R240)各时间点测量血流动力学指标，包括平均动脉压(MAP)、心率(HR)、腹主动脉血流(AoV，作为心排血量( 4,5)、肠系膜上动脉血流(Qsma，缺血时无此指标)。同时取动脉血样立即进行血气分析(用血气分析仪，ABL625，Radiometer,Copenhagen,Denmark)，计算氧输送(oxygen delivery,DO2)，并测定血乳酸浓度。此外，在上述各时间点使用标准技术测定PtCO2和pHi( 6-8)。用温生理盐水1 ml充填肠张力计气束，平衡60 min，然后抽出前面0.7 ml液体弃去，再抽出余下的0.3 ml液体立即进行血气分析，计算动脉二氧化碳间隙(Pt-aCO2间隙),实验结束后累计动物死亡数。Pt-aCO2间隙=PtCO2- PaCO2
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1.3 统计学处理：数据用均数±标准差(x±s)表示，差异显著性用t检验；动物死亡率用R×2 χ2检验，P<0.05为差异有统计学意义。
2 结 果
2.1 死亡率(表1)：各组动物于R60后开始死亡，HES较LRS能降低动物的死亡率，两者合用效果较好，动物死亡率为0。
2.2 血流动力学参数(表2)：对照组动物均具有典型的肠缺血-再灌注损伤模型特征( 9)，MAP、HR、AoV和Qsma于再灌注后逐渐下降，有3只动物死亡。LRS组各参数的变化趋势与对照组基本相似，无显著性差异(P>0.05)。小剂量HES组及大剂量HES组的MAP下降程度减轻或有一定程度回升，而AoV和Qsma均明显回升，HR下降不明显，与另两组相比差异均有显著性(P均<0.05)。小剂量表2 各组各时间点血流动力学参数的变化(x±s,n=8)HES组MAP回升程度较平稳，大剂量HES组再灌注后MAP呈先上升后下降趋势，两组于R60、R120和R240点比较，有明显差异(P均<0.05)；而再灌注后小剂量HES组的AoV和Qsma比大剂量HES组回升程度要低(P均<0.05)。
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2.3 动脉血乳酸浓度(图1)：4组血乳酸浓度均呈上升趋势，但大剂量HES可轻度降低乳酸浓度，仅在R60和R120时与对照组和LRS组相比差异有显著性(P均<0.05)；而小剂量HES则可明显降低血乳酸浓度，与其他3组相比，再灌注后各时间点均有显著性差异(P均<0.05)。
3 讨 论
肠缺血-再灌注损伤是常见的临床危重病症,可因休克、SIRS甚至多器官功能衰竭(MOF)而导致死亡，应尽早进行液体复苏，以阻断这一病理过程的恶化。本研究结果发现，对肠缺血-再灌注损伤不处理的对照组于再灌注240 min内因休克而死亡的动物数占37.5%；LRS复苏组死亡率为25.0%；大剂量HES复苏组为12.5%；而小剂量HES组没有动物死亡，且其平均动脉压、心率、心排血量、肠系膜上动脉血流等血流动力学指标平稳。说明对肠缺血-再灌注损伤所致休克的复苏，仅用LRS或大剂量HES效果欠佳；而用LRS加小剂量HES(每只兔约为60 ml左右)复苏效果较好，特别是小剂量HES对肠系膜上动脉血流的较好维持，说明它已有效地改善了内脏器官的血液灌流状况。在研究不同液体对肠缺血-再灌注后肠黏膜灌注及氧合作用的影响时发现，与对照组和仅使用LRS复苏相比，6%HES可使再灌注后血乳酸浓度和Pt-aCO2间隙降低，pHi升高，并增强氧输送能力。说明HES不仅能改善缺血-再灌注休克的血流动力学参数，而且也能有效地改善缺血-再灌注后的内脏灌注和组织氧合状态,与Friedman等(10)在复苏未控制的狗失血性休克研究中所得结果基本一致。其机制可能与HES能增加有效循环血量、改善内脏微循环有关(11)。休克时的微循环障碍与大量细胞因子和血管活性物质的产生释放，使毛细血管灌注不足、细胞黏附、血液黏滞度增高密切相关。Collis等(12)和Boldt等( 13)所做的研究表明，HES可抑制内皮细胞激活和黏附分子P-选择素表达，减少败血症患者循环血中黏附分子的浓度。Morisaki等在羊腹膜炎休克模型中证实，HES可保护毛细血管的完整性，降低毛细血管渗漏综合征的液体漏出( 14-18)；并能稀释血液、降低血黏度，改善组织微循环，提高氧运送能力，改善组织缺氧和累积性组织氧债 ( 19,20)。本实验中观察到HES改善内脏灌注和组织氧合作用，可能与上述作用有关。此外，Kupiotis( 21)和Baldassarre等( 22)也先后报道指出，HES可抑制血小板聚集，损伤凝血功能而引起出血。本实验中大剂量HES组可见部分动物口鼻出血，可能与此有关。6%HES作为一种人造胶体液，平均相对分子质量为200 000，半衰期为3.35 h，经静脉输入后，主要保留在血管里而不渗出，故能有效地增加胶体渗透压( 23)和血浆容量，限制血管内液体的外漏，提高有效循环血量，从而降低单独输晶体液所致组织间隙水肿的程度(11)，改善内脏血液灌注和氧合作用( 24,25)。HES因能有效地恢复血流动力学和氧输送参数，而被广泛用于复苏大多数急性低血容量性休克( 26,27)。但是，大剂量输入HES，除了直接损伤凝血功能外( 21，22)，还可能因血管内胶渗压的升高、大量组织液回流，致使血压很快上升，使保护性的血管痉挛解除，血管扩张( 28)；同时，组织液回流降低了血液黏滞度，使血流加快，已形成的微小血栓碎裂被冲走，凝血因子被稀释，凝血功能降低而引起再出血 ( 29)。本实验中对不同剂量HES的复苏效果比较发现，大剂量HES组心排血量、肠系膜上动脉血流量明显上升，平均动脉血压在缺血60 min再灌注120 min前明显升高，然后下降，甚至出现动物死亡；而pHi回升程度不大，Pt-aCO2间隙和乳酸浓度也呈先低后高形态，可能也与HES降低凝血功能引起出血有关。小剂量HES加LRS的混合液体复苏，既克服了晶体液易外漏导致组织水肿的缺陷，又减弱了大剂量HES易引起凝血功能障碍的副作用。因此，与大剂量HES相比，该组动物血流动力学参数上升平稳，血乳酸和Pt-aCO2间隙明显下降，pHi和氧输送明显回升，且没有动物死亡，收到了较好的复苏效果。
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, 百拇医药
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作者单位：410078 长沙，中南大学湘雅医学院病理生理教研室(涂自智，肖献忠)；比利时布鲁塞尔自由大学Erasme医院危重病医学系(孙庆华，George Dimopoulos, Suzana M Lobo,Daniel de Backer,Jean-Louis Vincent)
作者简介：涂自智(1959- )，男(汉族)，湖南省石门县人，医学硕士，副教授(Email:tuzizhi93@yahoo.com)。, http://www.100md.com