Simultaneous administration of multiple model substrates to assess hepatic drug clearance

We have evaluated a method to simultaneously assess three major processes involved in hepatic drug clearance using three model substrates administered simultaneously as a 5-minute intravenous injection. Lorazepam, indocyanine green, and antipyrine are used to assess conjugation, liver blood flow, and microsomal oxidative metabolism, respectively. These substrates were administered individually and as a mixture to 10 healthy adult male volunteers to determine if clearances of any of the compounds were affected by simultaneous administration. Mean clearances of the substrates were not different when administered alone (9.97, 0.78, and 0.53 ml/min/kg) vs. together (11.5, 0.89, and 0.52 ml/min/kg), using a paired t test. Since we were using this method to assess hepatic drug clearance in children with leukemia, the effect of short-term allopurinol was assessed. The three model substrates were administered to the volunteers after 0, 1, 8, and 22 days of treatment with allopurinol, 200 mg t.i.d. There was no change in mean clearance of any of the three compounds at any point during allopurinol treatment (repeated-measures ANOVA). We conclude that this technique is a simple and valid method to simultaneously assess three major processes involved in hepatic drug clearance and is not affected by up to 22 days of oral allopurinol treatment. This simple technique, requiring a single set of blood samples, has potential applications in the assessment of developmental changes in hepatic drug clearance, as well as the effects of environmental, therapeutic, and pathophysiologic factors on three major processes involved in hepatic drug clearance.     

Methods for studying the hepatic metabolism of drugs in man

Various methods can be used to investigate human hepatic drug metabolism in vivo. a) Indirect methods based on the assessment of atoxic substances metabolism in order to investigate: --hepatic oxidative activity by antipyrine or caffeine clearance and aminopyrine breath test determination. Such an activity can be modified by drug-induced enzyme induction or inhibition and in case of hepatic disease; --genetic polymorphism of hepatic drug metabolism assessed by the determination of debrisoquine or dextrometorphane metabolic ratio and of N-acetylation phénotype. Unusual therapeutic or adverse effects could be explained by such a polymorphism; --hepatic blood flow, which variations could modify hepatic clearance of drugs with a high hepatic extraction ratio, by the assessment of indocyanine green clearance. b) Direct methods based on pharmacokinetics data and their alterations under various circumstances: simultaneous administration of other drugs, liver disease.     

Hepatic drug clearance in children with leukemia: changes in clearance of model substrates during remission-induction therapy

We administered a "cocktail" of three model substrates for hepatic processes: antipyrine for oxidation, lorazepam for glucuronidation, and indocyanine green for hepatic blood flow, to children with acute lymphocytic leukemia (ALL). The plasma clearance of these substrates was determined before and after remission-induction therapy in 14 children with ALL. We found an improvement in clearance of antipyrine (0.65 to 0.95 ml/min/kg; P less than 0.01) and lorazepam (0.93 to 1.20 ml/min/kg; P less than 0.05) in 12 of 14 patients, with a mean increase of 67% and 52%, respectively, from before to after remission. There was no significant difference in mean indocyanine green clearance from before to after induction (14.8 vs. 14.4 ml/min/kg). There were no significant differences in liver function test results (SGOT, prothrombin time, or serum bilirubin) from before to after induction. Plasma concentrations of albumin, alpha 1-acid glycoprotein, and apolipoprotein A changed by a mean of +11.1%, -38.2%, and +68.6%, respectively, from before to after remission. However, these changes did not account for the changes in total plasma clearance of lorazepam, because lorazepam free fraction did not change and lorazepam free clearance increased by a mean of 83%. Our hypothesis is that eradication of hepatic leukemic infiltration by ALL remission therapy resulted in an improvement in microsomal metabolism of antipyrine and lorazepam.     

Regional flow during experimental hemorrhage and crystalloid resuscitation: persistence of low flow to the splanchnic organs.

BACKGROUND AND METHODS. Rapid changes in cardiac output (CO) and organ perfusion occur with hemorrhagic shock and fluid resuscitation. To assess regional alterations of flow, 40 Sprague-Dawley male rats were subjected to hemorrhagic shock and crystalloid resuscitation under halothane anesthesia. Polyethylene microspheres were injected before and after hemorrhage and after resuscitation. At sacrifice, brain, lungs, heart, liver, intestine, spleen and kidneys were harvested, weighed and radioactivity counted. Changes in mean arterial pressure, oxygen consumption, organ flow and CO were also measured. RESULTS: Cardiac output decreased during hemorrhage (P less than 0.01), it increased with resuscitation but did not return to baseline even with infusion of fluid volumes of three times the blood loss. Flow decreased during hemorrhage in all organs, but the difference was not statistically significant in the liver (P greater than 0.05), since a larger percentage of CO was maintained as hepatic perfusion. During resuscitation, flow to brain and kidneys increased over the percentage values expected by increased CO (P less than 0.01), but flow to the liver did not increase significantly. Flow to small bowel remained depressed (P less than 0.005). CONCLUSIONS: Following hemorrhage there is hypoperfusion of all splanchnic organs; however, flow to the liver decreases least. Crystalloid resuscitation in our model failed to return CO to baseline. Blood supply to intestine remained depressed in disproportion to CO both after hemorrhage and resuscitation and hepatic blood flow remained decreased after resuscitation.     

Comparison of epinephrine with vasopressin on bone marrow blood flow in an animal model of hypovolemic shock and subsequent cardiac arrest

OBJECTIVE: The intraosseous route is an emergency alternative for the administration of drugs and fluids if vascular access cannot be established. However, in hemorrhagic shock or after vasopressors are given during resuscitation, bone marrow blood flow may be decreased, thus impairing absorption of intraosseously administered drugs. In this study, we evaluated the effects of vasopressin vs. high-dose epinephrine in hemorrhagic shock and cardiac arrest on bone marrow blood flow. DESIGN: Prospective, randomized laboratory investigation that used an established porcine model for measurement of hemodynamic variables and organ blood flow. SETTING: University hospital laboratory. SUBJECTS: Fourteen pigs weighing 30 +/- 3 kg. INTERVENTIONS: Radiolabeled microspheres were injected to measure bone marrow blood flow during a prearrest control period and during hypovolemic shock produced by rapid hemorrhage of 35% of the estimated blood volume. In the second part of the study, ventricular fibrillation was induced; after 4 mins of untreated cardiac arrest and 4 mins of standard cardiopulmonary resuscitation, a bolus dose of either 200 microg/kg epinephrine (n = 6) or 0.8 units/kg vasopressin (n = 6) was administered. Defibrillation was attempted 2.5 mins after drug administration, and blood flow was assessed again at 5 and 30 mins after successful resuscitation. MEASUREMENTS AND MAIN RESULTS: Mean +/- sem bone marrow blood flow decreased significantly during induction of hemorrhagic shock from 14.4 +/- 4.1 to 3.7 +/- 1.8 mL.100 g-1.min-1 in the vasopressin group and from 18.2 +/- 4.0 to 5.2 +/- 1.0 mL.100 g-1.min-1 in the epinephrine group (p =.025 in both groups). Five minutes after return of spontaneous circulation, mean +/- sem bone marrow blood flow was 3.4 +/- 1.1 mL.100 g-1.min-1 after vasopressin and 0.1 +/- 0.03 mL.100 g-1.min-1 after epinephrine (p =.004 for vasopressin vs. epinephrine). At the same time, bone vascular resistance was significantly (p =.004) higher in the epinephrine group when compared with vasopressin (1455 +/- 392 vs. 43 +/- 19 mm Hg. mL-1.100 g.min, respectively). CONCLUSIONS: Bone blood flow responds actively to both the physiologic stress response of hemorrhagic shock and vasopressors given during resuscitation after hypovolemic cardiac arrest. In this regard, bone marrow blood flow after successful resuscitation was nearly absent after high-dose epinephrine but was maintained after high-dose vasopressin. These findings emphasize the need for pressurized intraosseous infusion techniques, because bone marrow blood flow may not be predictable during hemorrhagic shock and drug therapy.     

Melatonin pretreatment improves liver function and hepatic perfusion after hemorrhagic shock

Exogenous administration of pineal hormone melatonin (MEL) has been demonstrated to attenuate organ damage in models of I/R and inflammation by antioxidative effects. However, specific organ-protective effects of MEL with respect to hemorrhagic shock have not been investigated yet. In the present study, we evaluated the role of MEL pretreatment for hepatic perfusion, redox state, and function after hemorrhage and resuscitation, with emphasis on MEL receptor activation. In a model of hemorrhagic shock (MAP 35 +/- 5 mmHg for 90 min) and reperfusion (2 h), we measured nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) autofluorescence, hepatic microcirculation, and hepatocellular injury by intravital microscopy, as well as plasma disappearance rate of indocyanine green (PDRICG) as a sensitive maker of liver function in rat. Pretreatment with 10 mg kg(-1) MEL (i.v.) 15 min before induction of hemorrhage resulted in a significantly improved PDR(ICG) compared with controls (MEL/shock, 15.02% min(-1) +/- 2.9 SD vs. vehicle/shock, 6.18 +/- 4.6 SD; P = 0.001). Intravital microscopy after reperfusion revealed an improved hepatic perfusion index, redox state, and reduced hepatocellular injury in pretreated animals compared with the vehicle group. Melatonin receptor antagonist luzindole (LZN; 2.5 mg kg(-1)) almost completely abolished the protective effects of MEL pretreatment with respect to liver function (MEL + LZN/shock PDR(ICG), 7.31% min(-1) +/- 3.4 SD). Beneficial effects regarding hepatic perfusion, redox state, and cellular injury were not influenced by LZN, indicating that they may depend on antioxidative effects of MEL. However, liver function after hemorrhage is effectively maintained by MEL pretreatment via receptor-dependent pathways.     

Beta-adrenergic blockade affects initial drug distribution due to decreased cardiac output and altered blood flow distribution

Beta-adrenergic receptor blockers decrease intravenous anesthetic dose requirements. The present study determined the effect of propranolol on indocyanine green and antipyrine disposition from the moment of rapid intravenous injection. Anti-pyrine is a physiological marker that distributes to a volume as large as total body water in a blood flow-dependent manner and is a pharmacokinetic surrogate for many lipophilic drugs, including intravenous anesthetics. Antipyrine and indocyanine green disposition were determined twice in five healthy adult males in this Institutional Review Board-approved study, once during propranolol infusion. After rapid indocyanine green and antipyrine injection, arterial blood samples were collected frequently for 2 min and less frequently thereafter. Plasma indocyanine green and antipyrine concentrations were measured by high-performance liquid chromatography. Indocyanine green and antipyrine disposition were characterized, using SAAM II, by a recirculatory pharmacokinetic model that describes drug disposition from the moment of injection. Parameters were compared using the paired t test. The disposition of indocyanine green demonstrated that propranolol decreased cardiac output at the expense of the fast peripheral (nonsplanchnic) intravascular circuit. The area under the antipyrine concentration versus time relationship was doubled for at least the first 3 min after injection due to both decreased cardiac output and maintenance of nondistributive blood flow at the expense of a two-thirds reduction of blood flow (intercompartmental clearance) to the rapidly equilibrating (fast, splanchnic) tissue volume. The increase in antipyrine area under the curve due to propranolol-induced alteration of initial antipyrine disposition could explain decreased intravenous anesthetic dose requirements in the presence of beta-adrenergic receptor blockade.     

不同时间输注红细胞悬液对大鼠失血性休克复苏的影响

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

Protective effect of crocetin on hemorrhagic shock-induced acute renal failure in rats

Multiple organ failure is a common outcome of hemorrhagic shock followed by resuscitation, and the kidney is one of the prime target organs involved. The main objective of the study was to evaluate whether crocetin, a natural product from Gardenia jasminoides Ellis, has beneficial effects on renal dysfunction caused by hemorrhagic shock and resuscitation in rats. Anesthetized rats were bled to reduce mean arterial blood pressure to 35 (SD, 5) mmHg for 60 min and then were resuscitated with their withdrawn shed blood and normal saline. Crocetin was administered via the duodenum at a dose of 50 mg/kg 40 min after hemorrhage. The increase in creatinine and blood urea nitrogen was significantly reduced at 2 h after hemorrhage and resuscitation in crocetin-treated rats. The increases in renal nitric oxide, tumor necrosis factor α, and interleukin 6 were also attenuated by crocetin. Hemorrhagic shock resulted in a significant elevation in malondialdehyde production and was accompanied by a reduction in total superoxide dismutase activity, activation of nuclear factor κB, and overexpression of inducible nitric oxide synthase. These changes were significantly attenuated by crocetin at 2 h after resuscitation. These results suggested that crocetin blocks inflammatory cascades by inhibiting production of reactive oxygen species and restoring superoxide dismutase activity to ameliorate renal dysfunction caused by hemorrhage shock and resuscitation.     

The Effects of Lansoprazole on the Disposition of Antipyrine and Indocyanine Green in Normal Human Subjects

This study was designed to evaluate the potential effects of acute and chronic daily oral doses of lansoprazole (60 mg) on the disposition of antipyrine, an almost completely metabolized low hepatic extraction compound, and indocyanine green, a hepatically secreted compound with high extraction ratio. The study utilized a randomized, placebo-controlled, double-blind, two-period crossover design. Sixteen of 18 subjects completed all phases of the study. Both antipyrine (10 mg kg(minus sign1)) and indocyanine green (0.5 mg kg(minus sign1)) were administered as single intravenous bolus doses on Days 1 and 7 of lansoprazole or placebo dosing. Acute exposure to lansoprazole had no statistically significant effects on the plasma pharmacokinetics of indocyanine green or antipyrine. After the seventh dose, there was a small but statistically significant reductions in indocyanine green total body clearance (CL), and elimination rate constant of 10.6% and 8%, respectively. Additionally, a small statistically significant reduction (8.6%) in antipyrine volume of distribution was detected. No other plasma antipyrine pharmacokinetic parameters were changed with concomitant lansoprazole administration. About a 12% increase in the recovery of one of the major antipyrine urine metabolites (NORA) was detected. Overall, this study demonstrates little or no effect of lansoprazole on the pharmacokinetics of antipyrine and indocyanine green.     

Hepatic clearances of antipyrine, indocyanine green, and galactose in normal subjects and in patients with chronic liver diseases

Blood clearance of antipyrine, indocyanine green, and galactose were measured to evaluate the alterations of effective hepatic blood flow and hepatic intrinsic clearances in chronic liver diseases. Galactose blood clearance, which may be taken as effective hepatic blood flow, decreased by approximately 30% in patients with cirrhosis (12.49 +/- 0.76 ml/min/kg; mean +/- SE; n = 17) compared with normal subjects (18.17 +/- 1.03 ml/min/kg; n = 5). In patients with cirrhosis, intrinsic clearances of antipyrine (0.178 +/- 0.014 ml/min/kg; n = 17) and indocyanine green (6.19 +/- 1.38 ml/min/kg; n = 7) showed 61% and 85% reduction, respectively, compared with those of normal subjects (0.462 +/- 0.048 ml/min/kg; n = 5; 41.72 +/- 7.75 ml/min/kg; n = 5). Considering that indocyanine green and antipyrine are eliminated by different hepatic mechanism, these mechanisms may not be equally sensitive to decrements in hepatic function. In addition, fractional reductions of intrinsic clearances for these compounds are thus much greater than that of effective hepatic blood flow.     

The effect of dehydroepiandrosterone on hemorrhage-induced suppression of cellular immune function

OBJECTIVE: To determine whether the steroid hormone dehydroepiandrosterone (DHEA) improves cellular immune functions after hemorrhagic shock. DESIGN AND SETTING: Prospective controlled study in a research laboratory at an university medical center. SUBJECTS: Male NMRI mice. INTERVENTIONS: Animals received 0.9% saline or DHEA (20 mg/kg subcutaneously) before induction of a volume-controlled hemorrhagic shock (55% of estimated circulating blood volume) by retro-orbital puncture. One hour after hemorrhage mice underwent fluid resuscitation by intravenous infusion of lactated Ringer's solution (300% of the shed blood). Separate groups of mice were killed to obtain whole blood and spleen 1 h after hemorrhage, 1 h after fluid resuscitation, and 24 h after hemorrhage to determine lymphocyte distribution (CD4(+), CD8(+), NK1.1-AG(+)), splenocyte apoptosis, and plasma concentrations of tumor necrosis factor-alpha and interleukin-10. MEASUREMENTS AND RESULTS: Hemorrhage in control mice was associated with a rapid increase in circulating NK cell numbers. Elevated splenocyte apoptosis, an increased CD4/CD8 ratio, and decreased number of circulating CD8(+) T-cells was observed 24 h after hemorrhagic shock. DHEA administration was accompanied by a normalization of splenocyte apoptosis and lymphocyte migration. Induction of hemorrhagic shock did not affect TNF-alpha or IL-10 plasma concentrations in either treatment group. CONCLUSIONS: DHEA administration improves cellular immune function after hemorrhage and may therefore be beneficial in patients with hemorrhagic shock.     

Changes in antipyrine and indocyanine green kinetics during nifedipine, verapamil, and diltiazem therapy

Ten healthy subjects received oral antipyrine and intravenous indocyanine green (ICG) alone and after 5 days of oral nifedipine, diltiazem, and verapamil. Antipyrine clearance decreased during verapamil (range 4% to 26%) and diltiazem (6% to 24%) therapy (P less than 0.001) but did not change during nifedipine treatment. Antipyrine t1/2 also increased during verapamil and diltiazem treatment (P less than 0.001). ICG clearance did not change during diltiazem therapy but increased during dosing with nifedipine and verapamil (P less than 0.05). Estimated liver blood flow (derived from ICG clearance and hematocrit) also increased during verapamil (mean 33%) and nifedipine (mean 27%) treatment (P less than 0.05). Drug interactions with other liver-metabolized drugs may occur during therapy with these calcium antagonists. Nifedipine appears to increase liver blood flow whereas diltiazem inhibits oxidative drug metabolism. Drug interactions with verapamil could involve both mechanisms.     

Microcirculation follows macrocirculation in heart and gut in the acute phase of hemorrhagic shock and isovolemic autologous whole blood resuscitation in pigs

BACKGROUND: Disparity between the macro‐ and microcirculation is thought to occur as a result of (micro)vascular dysfunction in some types of shock. Whether this occurs during hemorrhagic shock, however, is unknown. We therefore investigated both macro‐ and microcirculatory variables in the heart as a vital organ and the gut as a nonvital organ. We hypothesized that the microcirculation in the gut would follow the macrocirculation in the acute phase of hemorrhagic shock and isovolemic autologous whole blood resuscitation, but that the microcirculation in the heart would be preserved even under conditions of macrocirculatory depression. STUDY DESIGN AND METHODS: Eleven pigs (23 ± 4 kg) were anesthetized and subjected to a controlled hemorrhagic shock (30 and 45% reduction of total blood volume) and isovolemic resuscitation with autologous blood. Quantitative measurement of microvascular oxygen pressures (µpO₂) was performed by phosphorimetry on the gut and heart simultaneously. Measurements of systemic hemodynamic and regional oxygen‐derived variables as well as µpO₂ were performed at baseline, after the first and second phases of hemorrhage, and after resuscitation. RESULTS: Five pigs responded to resuscitation, while six pigs died spontaneously within 20 to 30 minutes after reinfusion of the withdrawn blood, without significant differences in macro‐ or microcirculatory variables at baseline and after hemorrhage. Correlation analysis showed that microvascular pO₂ in the heart and the gut were closely related to macrocirculatory variables (cardiac index, mean arterial pressure, and oxygen delivery) during hemorrhage and resuscitation. CONCLUSIONS: This study demonstrated that the microcirculation in the gut (being a nonvital organ) and heart (being a vital organ) follow the macrocirculation in the acute phase of hemorrhagic shock and isovolemic autologous whole blood resuscitation.     

Perflubron emulsion improves hepatic microvascular integrity and mitochondrial redox state after hemorrhagic shock

Hemorrhagic shock is associated with decreased systemic oxygen delivery, but also with impaired microvascular perfusion, which can result in diminished local oxygen availability even in the presence of adequate cardiac output after resuscitation. Beside surgical interventions to control blood loss, transfusion of stored packed red blood cells represents the current standard of care in the management of severe hemorrhagic shock. Because stored red blood cells are less deformable and show a higher O2 affinity that affects the O2 off-load to tissues, perfluorocarbon-based artificial oxygen carriers might improve local O2 delivery under these conditions. To test this, rats were subjected to hemorrhagic shock (1 h, mean arterial pressure [MAP] 30-35 mmHg) and were resuscitated with fresh whole blood, pentastarch, stored red blood cells, perflubron emulsion (2.7 and 5.4 g/kg body weight) together with pentastarch, or stored red blood cells together with 2.7 g/kg perflubron emulsion. Hepatic microcirculation, tissue oxygenation, and mitochondrial redox state were investigated by intravital microscopy. In addition, hepatocellular function and liver enzyme release were determined. After hemorrhagic shock and resuscitation with perflubron emulsion, volumetric sinusoidal blood flow was significantly increased compared with resuscitation with stored red blood cells. Furthermore, resuscitation with perflubron emulsion resulted in higher hepatic tissue PO2 and normalized mitochondrial redox potential, which was accompanied by lessened hepatocellular injury as well as improved liver function. These results indicate that, in this model of hemorrhagic shock, asanguineous fluid resuscitation with addition of perflubron emulsion is superior to stored blood or pentastarch alone with respect to increased local O2 availability on the cellular level. This effect is primarily due to improved restoration of hepatic microcirculatory integrity.     

大鼠失血性休克继发凝血活化的实验治疗

为了探讨不同复苏液对失血性休克大鼠凝血功能的影响和可能机制,将50只SD大鼠随机分为5组：对照组、假手术组、休克组、复苏1组（输林格液）和复苏2组（输林格液＋万汶液）,每组10只大鼠。建立失血性休克大鼠模型后,复苏组在失血性休克1小时后给予不同复苏液（林格液、6%中分子羟乙基淀粉130/0.4即万汶液）,复苏2小时后采血,检测血浆组织型纤溶酶原激活剂（t-PA）、组织型纤溶酶原激活剂抑制物-1（PAI-1）、组织因子（TF）的变化。研究结果表明：与对照组、假手术组比较,休克组和复苏1组的t-PA、t-PA/PAI-1、TF水平均明显升高（P〈0.01）;复苏1组t-PA、t-PA/PAI-1水平明显高于休克组（P〈0.01）;而复苏2组t-PA、t-PA/PAI-1、TF均明显低于休克组和复苏1组（P〈0.01）。结论：大鼠失血性休克可使纤溶功能亢进,血小板和凝血系统被活化;采用万汶液加林格液复苏在调节凝血功能方面优于单用林格液。     

Differential cardiopulmonary recruitment of neutrophils during hemorrhagic shock: a role for ICAM-1?

Hemorrhagic shock and subsequent resuscitation can result in acute lung injury and cardiac dysfunction. Previous studies have demonstrated that tissue neutrophil accumulation contributes to cardiopulmonary injury associated with trauma. Thus, suppression of tissue neutrophil recruitment in an early therapeutic window after hemorrhagic shock may protect the cardiopulmonary system. It is unclear whether hemorrhagic shock induces cardiopulmonary recruitment of neutrophils before resuscitation. Intercellular adhesion molecule-1 (ICAM-1) is one of the important factors that mediate tissue neutrophil recruitment. The physiologic significance of ICAM-1 expression after hemorrhage before resuscitation is not well delineated. The present study examined the role of ICAM-1 in neutrophil accumulation in the heart and lung after severe hemorrhage without resuscitation. Mice were subjected to hemorrhagic shock by removal of 30% of total blood volume. Lung neutrophil number as determined by immunofluorescent staining increased by 1 h after hemorrhage and was maximal at 4 h whereas myocardial neutrophil number was not changed. Lung neutrophil accumulation was not associated with an up-regulation of ICAM-1 expression or an alteration in ICAM-1 subcellular distribution. Surprisingly, deletion of the ICAM-1 gene enhanced hemorrhagic shock-induced lung neutrophil accumulation. These results suggest that hemorrhagic shock induces preferential neutrophil accumulation to the lung that appears to occur independent of ICAM-1-expression.     

延迟液体复苏对失血性休克大鼠炎性反应的影响

目的:探讨延迟液体复苏对失血性休克大鼠炎性反应的影响。方法:将40只大鼠随机分为休克后即刻复苏组、休克后延迟30 min复苏组、休克后延迟60 min复苏组、未复苏组。采用Wiggers方法制备可控性失血性休克模型。记录复苏开始即刻(0 min),30、90、150、210、270、330 min平均动脉压水平,并采血测定IL-6、TNF-α和IL-10浓度。结果:液体复苏组复苏开始后各时点平均动脉压水平无明显差异。与未复苏组相比,休克后延迟30、60 min复苏组IL-6、TNF-α浓度明显增加,休克后延迟60 min复苏组IL-10浓度显著降低(P<0.01)。结论:在控制性失血性休克动物模型,延迟液体复苏可使促炎细胞因子生成增加,其增加的程度与延迟复苏时间密切相关。     

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.