Fetal hepatic drug elimination

The majority of studies of fetal hepatic elimination have concentrated on the expression and activity of the metabolizing enzymes, but the unique physiologic milieu of the fetal liver should also be considered. The basic structure of the liver is formed by the end of the first trimester. The fetal hepatic circulation differs substantially from that of the adult in that there is an extra input vessel, the umbilical vein, and there is shunting of 30-70% of hepatic blood flow via the ductus venosus. The left and right lobes of the fetal liver seem to function independently with respect to a variety of biochemical parameters, due at least in part to the lower oxygen supply to the right lobe. The zonation of drug-metabolizing enzymes along the hepatic acinus, which is prominent in the adult liver, is absent in the fetal liver. Unlike rodent species, the human fetal liver has a significant capacity for drug metabolism. Of the oxidative enzymes, CYP3A7 accounts for up to 50% of total fetal hepatic cytochrome P450 content. Expression of this enzyme decreases dramatically after birth. CYP1A1 and CYP2D6 have also been detected in human fetal liver, but whether CYP2E1 is expressed remains controversial. Several other cytochrome P450s have been identified and await characterization. Fetal hepatic drug conjugation may prolong fetal exposure to the metabolites produced, which, being more water soluble, do not readily cross the placenta back to the mother and, if excreted in fetal urine, can be recycled in the fetus via amniotic fluid and fetal swallowing. Limited activity of glucuronidation enzymes has been demonstrated in human fetal liver in contrast to the activity of sulfation enzymes, which is significant. Limited in vivo studies in fetal sheep have demonstrated significant fetal hepatic drug elimination, and this has been confirmed in studies of the isolated perfused fetal sheep liver. Our understanding of fetal hepatic elimination processes has advanced steadily over the years. Future developments, however, should consider more fully the influence of the unique physiological milieu of the fetal liver, in addition to the expression and activity of drug metabolizing enzymes.     

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.     

Effects of route of administration and blood flow on hepatic drug elimination.

The effects of route of administration and blood flow on the elimination of lidocaine, diphenylhydantoin and propranolol have been investigated in the isolated perfused rat liver. After administration directly into the portal vein, drug concentrations in the reservoir were the same at a given flow rate as concentrations in the hepatic vein after drug was placed directly into the reservoir. The apparent clearance of the drug calculated from these concentrations gave an estimate of intrinsic drug clearance, which is an estimate of the activity of the drug-metabolizing enzymes. Intrinsic clearance is defined as drug clearance when flow is not rate limiting and therefore should be independent of flow. This was confirmed by showing that, at steady state, neither hepatic venous drug concentrations nor concentrations in the reservoir after portal venous administration of lidocaine were affected by altering hepatic blood flow from 10 to 20 ml/min. Propranolol was given as a single dose into the reservoir at flows of 10 and 20 ml/min. The area under the concentration-time curve (AUC) in the reservoir was decreased by increased flow, but AUC for hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged. Although AUC in hepatic venous blood was unchanged, higher peak concentrations and a more rapid half-life was seen in keeping with the clearance of drug from the reservoir. These data suggest that after oral drug administration, steady-state concentrations or AUC in systemic blood is dependent only on the activity of the enzymes involved (i.e., intrinsic clearance) and unaffected by flow, provided drug is completely absorbed and eliminated only by the liver. Furthermore, this will apply even to drugs whose systemic clearance and drug half-life after i.v. administration is profoundly affected by altered hepatic blood flow.     

低温复苏对大鼠失血性休克肝损伤的影响

目的探讨低温复苏对大鼠失血性休克肝损伤的保护作用及其机制。方法 24只成年雄性Wistar大鼠随机平均分为3组,对照组(S)、常温复苏组(N)(37~38℃)和低温复苏组(H)(33~34℃)。S组只进行外科插管操作,不建立失血性休克模型及复苏,N组和H组在建立失血性休克模型后分别在预定温度下进行复苏。Real-time PCR法检测复苏240 min肝组织PPAR-γ、HSP70和TNF-αm RNA表达变化。ELISA法检测血清TNF-α浓度变化。生化法检测血清ALT和AST浓度变化。结果 (1)休克复苏240 min大鼠血清TNF-α浓度为S组(8.53±1.90)ng/ml,N组(74.08±8.81)ng/ml,H组(32.13±5.82)ng/ml,两个实验组差异具有统计学意义(P<0.05);(2)休克复苏240 min大鼠血清ALT和AST浓度分别为是S组(61±11)U/L、(47±9)U/L,N组(187±20)U/L、(139±15)U/L,H组(141±11)U/L、(97±11)U/L,两个实验组差异有统计学意义(P<0.05);(3)与S组比较,休克复苏240 min N组肝组织PPAR-γm RNA表达量为0.50±0.11,H组PPAR-γm RNA表达量为2.01±0.48(P<0.05);(4)与S组比较,休克复苏240 min N组肝组织HSP70 m RNA表达量为4.12±1.36,H组HSP70 m RNA表达量为11.69±3.88(P<0.05);(5)与S组比较,休克复苏后240 min N组肝组织TNF-αm RNA表达量为15.10±4.99,H组TNF-αm RNA表达量为10.10±2.95(P<0.05)。结论失血性休克后的低温复苏能够上调大鼠肝组织内PPAR-γ和HSP70基因的表达,同时抑制TNF-α基因表达,降低血清中TNF-α、ALT和AST的浓度,减轻肝脏损伤,利于休克的复苏。     

美蓝对家兔失血性休克作用的实验研究

目的　探讨美蓝在家兔失血性休克中的作用。方法　复制不可逆失血性休克家兔模型 ,2 8只雄性家兔随机分为美蓝组 (MB ,n =15 )和生理盐水组 (NS ,n =13) ,监测两组休克前后SBP、DBP、MAP的动态变化及血清NO的水平。结果　 (1)MB组与NS组相比 ,静注开始 10min之后SBP、DBP、MAP显著升高 (P <0 0 1) ,其升高效应维持约 4 0min。 (2 )失血性休克后 ,两组的血清NO水平均有一定程度上升。两组间相比 ,仅休克 4 5′点 ,MB组较NS组显著降低 (P <0 0 5 )。 (3)MB组存活时间 (10 9 6 7± 2 2 2 4 )min显著长于NS组 (6 7 85± 17 77)min ,90min存活率显著高于NS组。结论　在家兔不可逆失血性休克时早期应用 7 5mg/kg的美蓝 ,能快速升高血压 ,延长动物的存活时间 ,并能一过性降低血清NO水平。推测美蓝的升压效应可能有部分是通过降低NO水平而起作用。     

Effect of hemorrhagic shock on cefazolin and gentamicin pharmacokinetics in dogs.

The physiologic response to traumatic injury may alter the disposition of drugs and thereby affect their therapeutic or toxic potential. A study was conducted in 10 mongrel dogs to determine the effect of experimental hemorrhagic shock with resuscitation on the pharmacokinetics of gentamicin and cefazolin. Single simultaneous intravenous doses of gentamicin (3 mg/kg) and cefazolin (25 mg/kg) were administered to each animal on an initial study day, after which serial blood and urine collections were performed. After 1 week, a standard hemorrhagic shock model was applied to each animal. Shock was continued for 1 h, after which the animal was resuscitated with either whole blood or saline. After stabilization for 20 min, a second dose of gentamicin and cefazolin was administered, and blood and urine were again collected. Drug clearance was not significantly altered, except for that of cefazolin after saline resuscitation, for which there was a significant increase in drug clearance. After both methods of resuscitation an increase in the volume of distribution was noted for cefazolin and gentamicin. Drug half-life was noted to be increased after shock for cefazolin by both resuscitation methods and for gentamicin after shock by saline resuscitation. Although alterations of pharmacokinetic parameters were noted, mean concentrations of gentamicin and cefazolin in serum were similar for pre- and postshock phases.     

N-乙酰半胱氨酸对休克鼠肠屏障的保护作用

目的通过大鼠失血性休克模型,研究探讨抗氧化剂N-乙酰半胱氨酸(NAC)是否具有减轻肠缺血-再灌注损伤(IRS)及保护肠屏障的作用。方法SD大鼠56只,分正常组、NAC干预组(休克 NAC)和对照组(休克 生理盐水),后两组又分为休克复苏后1h、3h和6h小组,每小组大鼠8只;动物实验前30min尾静脉注入NAC250mg/kg或5%葡萄糖;颈动脉和颈静脉插管,通过放血使大鼠的平均动脉压降至40mmHg,持续60min后回输血和生理盐水使动物复苏,血压平稳后分别以各时点取血和回肠标本进行组织学、肠黏膜损伤度检查和D-乳酸(D-LAC)、二胺氧化酶(DAO)活性及肠源性内毒素(LPS)测定。结果(1)对照组:大鼠失血性休克后,肠黏膜明显受损,组织学检查主要为黏膜的水肿、灶性坏死、绒毛脱落及炎性细胞浸润,复苏后1h、3h、6h肠黏膜损伤指数分别达3.0、2.4、1.6;外周血及肠DAO活性、门静脉LPS明显升高(与正常组相比,1h、3h和6h组P均<0.05);D-LAC于复苏后1h后显著升高(与对照组相比,P<0.05)。(2)NAC干预组:肠黏膜的损伤程度较对照组明显减轻,肠黏膜损伤指数分别为2.2、1.6、1.2;DAO活性、门静脉LPS及D-LAC均明显低于NAC非干预组(P<0.05),但部分仍高于正常组。结论NAC可减轻鼠肠IRS,并可抑制由于肠黏膜损伤后的肠渗透性增加。     

Effect of naloxone on immune responses after hemorrhagic shock

OBJECTIVE: To determine whether naloxone administration after hemorrhagic shock has any beneficial or deleterious effect on immune responses. BACKGROUND DATA: Hemorrhagic shock is known to produce immunodepression in both humans and experimental animals. Although studies suggest that endogenous opioids play a role in immune regulation in adverse circulatory conditions, it remains controversial whether these opioids exert beneficial or detrimental effects on immunity after shock. Moreover, little information is available concerning the effects of opioid receptor blockade using naloxone on cell-mediated immunity and endocrine responses after shock. METHODS: Male C3H/HeN mice (25 g) were bled to and maintained at a mean arterial blood pressure of 35+/-5 mm Hg for 1 hr. The shed blood was then returned along with lactated Ringer's solution (two times the shed blood volume) to provide fluid resuscitation. The animals were randomized to receive either naloxone (1 mg/kg i.v.) or an equal volume of vehicle (saline) after the shed blood was returned, i.e., immediately before crystalloid resuscitation, and were killed at 2 hrs after resuscitation to obtain splenocytes, macrophages (peritoneal and splenic), and blood. MEASUREMENTS AND MAIN RESULTS: Bioassays revealed significantly decreased release of all studied interleukins (interleukins-1, -2, -3, and -6) by peritoneal and splenic macrophages as well as significantly decreased splenocyte proliferative capacity after shock in vehicle-treated mice. Naloxone administration after hemorrhage resulted in either similar or even more decreased levels of interleukin release compared with vehicle-treated hemorrhaged mice. Significantly increased plasma corticosterone concentrations were observed in vehicle-treated animals compared with control animals. Naloxone administration did not have any significant effects on corticosterone plasma concentrations after hemorrhage. CONCLUSIONS: These findings indicate the importance of the endogenous opioid system for the maintenance of immunity in adverse circulatory conditions, i.e., hemorrhage. Although additional studies involving different doses and/or times of naloxone administration may provide different results, the present findings raise the concern that naloxone administration in the traumatized host may have deleterious effects because it decreases peritoneal macrophage and splenic immune functions.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

目的 探讨限制性液体复苏对失血性休克大鼠肝脏缺血-再灌注损伤的影响.方法 54只Wistar大鼠应用Krausz等人工制作的标准脾脏损伤+切断脾中部一动脉分支制作重度未控制出血性休克模型,当平均动脉压(MAP)降至40 mmHg时开始应用平衡盐液复苏,依据维持MAP的不同随机分为40,50,60,80和100 mmHg组(分别记为RS40,RS50,RS60,RS80,RS100组)和假手术组(SS组).脾损伤前记为TO时点.在45 min时(T45时点)结扎止血,再应用平衡盐液+全血(2:1)复苏,使MAP尽量维持在100 mmHg,2 h后(T165时点)停止输液,观察4 h(T405时点).于TO,T45,T165和T405时点抽血测定血乳酸;于T405时点取部分肝组织测定组织血流量、ATP酶、丙二醛(MDA)和总抗氧化能力(TAOC).统计学采用单因素方差分析(SNK-q检验).结果 随着维持MAP的提高,肝组织ATP酶、TAOC和肝组织血流量逐渐降低,而MDA和血乳酸却逐渐增高.在T405时点:血乳酸在RS80和RS100组[(3.60 ±0.68)mmol/L,(3.84±1.09)mmol/L]均明显高于SS,RS40,RS50和RS60组[(2.00±0.66)mmol/L,(2.74±1.45)mmol/L,(2.43±0.94)mmol/L,(2.07±0.95)mmol/L](P<0.05);MDA在RS80和RS100组[(7.32±0.31)mmol/mg,(7.71±0.23)nmol/mg]均明显高于SS,RS40,RS50和RS60组[(4.95±0.80)nmol/mg,(6.14±0.94)nmol/mg,(6.42±0.48)mnol/mg,(6.84±0.36)nmol/mg](P<0.05);肝组织ATP酶活性和TAOC在RS各组均明显低于SS组(P<0.05),而在RS80和RS100组则明显低于RS40,RS50和RS60组(P<0.05);肝组织血流量在RS80和RS100组均明显低于其他4组(P<0.05).结论 在出血未控制条件下,限制性液体复苏明显提高肝组织的血液灌注、改善微循环、减轻酸中毒和肝组织的脂质过氧化损伤,减轻了肝脏缺血-再灌注损伤.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.     

限制性液体复苏对肝脏缺血-再灌注损伤的影响

Objective To investigate the effects of limited resuscitation on hepatic ischernia-reperfusion in-jury in rots with hemorrhagic shock. Method Uncontrolled hemorrhagic shock was induced in 54 rats by transect-ing the middle branch of the splenic artery to produce standardized massive splenic injury. Resuscitation started when the mean arterial pressure (MAP) reached 40 mmHg. The rats were randomly divided (n = 9per group) in-to sham-operated group (SS), or one of five treatment groups in which infusion of Ringer' s solution was continually administrated to maintain MAP at 40 (RS40), 50 (RS50), 60 (RS60), 80 (RS80) or 100 mmHg (RS100) for 45 minutes (T45 point). After the bleeding was controlled, resuscitation was continued with Ringer's solution and whole blood (2:1) to increase the MAP to 100 mmHg for 120 minutes (T165 point), which was followed by obser-vation for 240 minutes (T405 point). All animals were observed for 240 minutes or until death. Blood specimens were collected at TO, T45, T165 and T405 for determination of blood lactate levels. At the end of the experiment,a small amount of hepatic tissue was collected to measure tissue blood perfusion, total antioxidative capacity (TAOC), Na+K+ ATPase activity and malondialdehyde (MDA) levels. Results At T405, the blood lactate lev-els in the RS80 and RS100 groups [(3.60±0.68) and (3.84 ± 1.09) mmol/L, respectively] were significantly higher than those in the SS, RS40, RS50 and RS60 groups [(2.00±0.66),(2.74±1.45),(2.43 +0.94) and (2.07±0.95) mmol/L, respectively;all:P < 0.05]. The MDA levels were significantly higher in the RS80 and RS100[(7.32±0.31) and (7.71±0.23) nmol/mg,respectively] than those in the SS, RS40, RS50 and RS60 groups[(4.95±0.80),(6.14±0.94),(6.42±0.48) and (6.84±0.36) nmol/mg, respeetively;all: P <0.05]. The Na+ K+ ATPase and TAOC levels were significantly lower in all of the RS groups than those in the SS group (all: P < 0.05), and those in the RS80 and RS100 groups was significantly lower than those in the RS40,RS50 and RS60 groups (all: P <0.05). Blood perfusion in the RS80 and RS100 groups was significantly lower than that in the other groups (all: P < 0.05). Conclusions If hemorrhage is uncontrolled, limited resuscitation appears to balance the needs for organ perfusion, improve the microcircttlation and decrease lactate levels. Fur-thermore, limited resuscitation could decrease ischemia-reperfusion injury in liver tissue.