摘要:

ABSTRACTCritically ill patients characteristically exhibit a pronounced catabolism in addition to a down-regulation of normal anabolic activity, leading to major complications from loss of body protein stores. The marked decrease in lean body mass and protein stores leads to the loss of essential structural and functional proteins required for restoring and maintaining homeostasis. The standard management of the catabolic response to injury and illness has centered on optimizing nutrient intake that modulates but does not reverse the process. Complications of ongoing catabolism therefore remain a major cause of morbidity. Addition of anticatabolic and anabolic agents that may counteract “the stress response to injury or illness” may be of significant clinical benefit. Agents currently available for clinical use, which will be described, can be divided into two groups. The first group are nutrients and nutrient metabolites, namely protein and the specific amino acids, glutamine, arginine, and branched chain amino acids, especially leucine. The second group are anabolic hormones, namely growth hormone, testosterone, and the testosterone analog oxandrolone. The pros and cons of these agents, as to their anabolic and anticatabolic value, are described.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTMajor liver resections are associated with considerable morbidity and mortality. Gut-derived bacteria and bacterial endotoxin (LPS) are considered to play a central role in the pathophysiology of these complications. Like human BPI, rBPl21binds to LPS from Gram-negative bacteria. By binding and clearing of LPS, rBPI21can inhibit a number of endotoxin-induced humoral and cellular responses. Because of this capacity, rBPI21could partially compensate for the loss of hepatic mononuclear phagocytic system function after liver resection. However, the liver is also thought to be an important organ for the clearance of BPI, and reduction of liver mass could result in a decreased clearance and exceedingly high plasma levels of rBPI21. In this study we therefore investigated the pharmacokinetics of rBPI21in rats and in patients undergoing a major liver resection. Rats were administered an intravenous (i.v.) bolus of rBPI21after undergoing a 60% or 80% hepatectomy (with sham-operated controls). Patients undergoing a hemihepatectomy and healthy volunteers received rBPI21or placebo by continuous i.v. infusion for 48 h. Plasma concentrations were measured by sandwich ELISA. In rats, 60% hepatectomy did not consistently change the clearance of rBPI21, whereas 80% hepatectomy decreased the clearance of rBPI21severalfold. In hemihepatectomized patients, the clearance of rBPI21after major hepatectomy was also slower, when compared with healthy volunteers, but this difference had disappeared within 24 h. Our data indicate that the administration of rBPI21in patients undergoing liver resection is well tolerated and does not result in exceedingly high plasma levels. Additional studies on the efficacy of rBPI21in the prevention of complications after hepatectomy are needed.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTMacrophage overproduction of inflammatory mediators is detrimental in the progression of acute pancreatitis. Although inhibition of inflammatory mediators has been shown to decrease the severity of experimental pancreatitis and improve overall survival, less is known about the mechanism by which blockade produces these benefits. Prior to the induction of lethal acute pancreatitis, rats were randomized to receive a single dose (.01, .1, 1.0, or 10 mg/kg) of a macrophage-pacifying compound (CNI-1493) or vehicle. Escalating doses provided incremental increases in survival from 10% (vehicle) to a maximum of 70% (CNI-1493,1.0 mg/kg). To evaluate the physiologic mechanism responsible for the improved survival, continuous arterial blood pressure, serial hematocrit, ascites volume, pancreatic edema, bronchoalveolar leukocytes and protein, and pancreatic histology were determined in additional rats receiving CNI-1493 (1.0 mg/kg). Serum tumor necrosis factor-± and nitrites were also determined to assess the mechanism of action of CNI-1493. Macrophage pacification decreased pancreatitis severity as determined by enzyme release and pancreatic histology score. Ascites volume and bronchoalveolar protein levels were also decreased, indicating that CNI-1493 prevents the loss of circulating blood volume and maintains hematocrit and mean arterial pressure, thus improving survival. CNI-1493 prevented the increase of serum tumor necrosis factor-± but not serum nitrites, implicating macrophage-derived cytokines and not nitric oxide in the pathogenesis of physiologic decompensation and death in this model of pancreatitis.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTThe effects of hypertonic (7.5%) saline/6% dextran 70 (HSD) on central and regional hemodynamics were studied during uncontrolled intra-abdominal bleeding in 16 anesthetized pigs. Ultrasonic flow probes were placed proximally and distally to an aortic injury to indicate the incidence and extent of rebleeding after injecting 4 mL kg-1(N = 8) and 2.65 mL kg-1(N = 8) of HSD 10min after the vascular injury was induced. The initial aortic bleeding reduced the blood flow rates to 71% of baseline in the skin, 53% in the splanchnic region, 42% in the upper aorta, and 15% in the kidney. Cardiac output dropped to 46% and the mean arterial pressure to 57% of baseline. The injection of HSD was followed by a prompt increase in all blood flow rates, but rebleeding started within 2 min in 13 of the pigs (81%). A second period of rebleeding occurred in six of them. The rebleeding averaged 300 mL, which is 62% of the blood lost when the aortic injury was induced. There was no significant difference between the treatment groups with respect to these blood losses or to the oxygen consumption, which was not restored by HSD. Five animals in each treatment group died after about 70 min, while the remaining six pigs (38%) survived the 120 min study period. These results suggest that HSD in the recommended dose, and even two-thirds thereof, promotes rebleeding when given shortly after a low energy intra-abdominal aortic injury. The fluid seems to have no beneficial effect on this type of uncontrolled hemorrhage.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTTumor necrosis factor (TNF) is released during hepatic ischemia/reperfusion (I/R) and plays an important role in the ensuing neutrophil-mediated lung and liver injury. Since TNF is not a direct neutrophil chemotaxin, we hypothesized that TNF may up-regulate neutrophil adhesion molecules, specifically intercellular adhesion molecule-1 (ICAM-1), following hepatic I/R, and that this molecule then plays an important role in tissue neutrophil influx. Rats underwent 90 min of lobar hepatic ischemia with reperfusion. Pulmonary and hepatic ICAM-1 expression were assessed by reverse transcription-poly-merase chain reaction, Western blot analysis, and immunohistochemical staining. Increases in hepatic ICAM-1 were demonstrated within 1 h of reperfusion, while increases in pulmonary ICAM-1 were not seen until 6 h of reperfusion. Next, rats were treated with anti-TNF antibody or control antibody without TNF neutralizing properties prior to hepatic I/R. Pretreatment with anti-TNF antibody significantly decreased pulmonary and hepatic ICAM-1 expression after hepatic I/R. We next investigated the effects of pretreatment with anti-ICAM-1 antibodies on the lung and liver injury that follows hepatic I/R. Lung injury was assessed by changes in pulmonary capillary permeability as estimated by extravasation of Evans Blue dye and pulmonary neutrophil influx as measured by lung myeloperoxidase levels. Liver injury was assessed by hepatic neutrophil morphometrics and plasma liver enzymes (alanine aminotransferase). Pretreatment with anti-ICAM-1 antibodies significantly decreased pulmonary capillary permeability, pulmonary myeloperoxidase, hepatic neutrophil influx, and plasma alanine aminotransferase, as compared to animals pretreated with control antibody. These data suggest that TNF is a proximal trigger for pulmonary and hepatic ICAM-1 up-regulation following hepatic ischemia with reperfusion, and that ICAM-1 is important for pulmonary and hepatic neutrophil influx, with the resultant tissue injury, following hepatic I/R.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTAnticoagulants can influence production of cytokines in whole blood, but the effects vary depending on the type of anticoagulant and the immunological stimulus. We examined this further by anticoagulating normal blood with either unfractionated (UF) heparin or low molecular weight heparin (Fragmin) and stimulating each sample with lipopolysaccharide, zymosan A, phytohemagglutinin, immune complexes, H2O2, or RPMI. After incubating 24 h, the combination of lipopolysaccharide and Fragmin induced significantly greater concentrations of interleukin 1 (IL)-1 ± (25 ± 10 ng/mL; ± ± standard error), IL-8 (21 ± 6), and tumor necrosis factor (TNF)± (.48 ± .24) compared with heparinized blood (p < .05). The combination of Fragmin and zymosan also induced significantly greater concentrations of IL-1 ± (97 ± 24) and TNF± (2.9 ± .8), but not IL-8 (2.0 ± 15). Average levels of proinflammatory cytokines (IL-1±, IL-6, IL-8, and TNF±) were greater with Fragmin anticoagulation for 36 of 40 comparisons, and patterns were similar for 6 h and 24 h incubations. Statistical difference was established in 33% of these comparisons. A composite score of proinflammatory cytokines for Fragmin-anticoagulated blood was significantly greater than expected for UF heparinized blood (p < .0001) after 24 h. Expression of one anti-inflammatory cytokine (IL-10) was only slightly elevated for Fragmin anticoagulation. Proinflammatory cytokines are produced in greater quantities with Fragmin anticoagulation, which may be a disadvantage for ischemic conditions (e.g., cardiac surgery) but advantageous for long-term treatment of thrombosis.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTBecause platelet-activating factor (PAF) is an important mediator of inflammation and heparin has anti-inflammatory effects, we hypothesized that low molecular weight heparin (LMWH) would inhibit PAF-induced activation and chemotaxis in porcine neutrophils. Citrated blood was obtained from pento-barbital-anesthetized pigs, and neutrophils were isolated over a 55%/65% Percoll gradient. The effect of LMWH on basal phorbol myristate acetate (PMA)-induced superoxide (SO) release, as well as its effect on PAF priming for PMA-induced SO release, were investigated. Additionally, the effect of LMWH on PAF-induced chemotaxis of neutrophils across transwell membranes was evaluated. Baseline SO release in response to PMA was .351 ± .046 nmol/106cells/min, and this was decreased to .289 ± .034 nmol/106cells/min by pretreatment with 50 U/mL LMWH. PMA-induced SO production was increased by .240 ± .042 nmol/106cells/min when cells were primed with 10±M PAF. This priming effect of PAF was reduced significantly by pretreatment of neutrophils with LMWH at 10 and 50 U/mL. Chemotaxis of neutrophils in response to 100±M PAF was significantly decreased to 70.02 ± 6.4% (n = 8) of the control response by pretreatment of cells with 50 U/mL LMWH. We conclude that LMWH has anti-inflammatory effects on porcine neutrophils, which includes attenuation of cell activation and chemotaxis in response to the lipid-derived inflammatory mediator, PAF.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTIntestinal ischemia and reperfusion injury (I/R) is probably involved in the pathogenesis of intestinal barrier dysfunction, associated with the concomitant translocation of enteric bacteria and toxins and the potential development of multiple organ failure. The intestinal endothelial and epithelial layers play a major role preventing the entry of toxic substances from the gut, but the influence of protease-antiprotease systemic balance on these barrier functions and the relationship between epithelial DNA synthesis, apoptosis, and endothelial and epithelial barrier macromolecule permeability are not fully investigated. Endothelial and epithelial barrier macromolecular permeability, epithelial DNA synthesis, the endothelial and epithelial plasma membrane system, apoptosis and oncosis, plasma levels of proteinase inhibitors, and proenzymes were measured in rats subjected to 20 and 40 min intestinal ischemia and 1, 3, 6, or 12 h reperfusion. Endothelial permeability increased after both 20 and 40 min intestinal ischemia. Epithelial permeability significantly increased during 1–6 h reperfusion after 20 min ischemia and during 1–12 h reperfusion after 40 min ischemia. Epithelial DNA synthesis increased in animals with 20 min ischemia followed by 12 h reperfusion. Plasma levels of prekallikrein, C1-esterase inhibitor, and ±1-macroglobulin were significantly lower following both 20 and 40 min ischemia from 3 h reperfusion and on. Apoptotic epithelial cells significantly increased in animals subjected to 20 min ischemia followed by 12 h reperfusion. The severity of reperfusion injury in the intestinal endothelial and epithelial barrier seems to correlate with the period of ischemia and the pathway of cell damage and death, together with proteinase-antiproteinase imbalance.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

ABSTRACTFluid resuscitation is the usual therapy for hemorrhagic shock, and frequently consists of the infusion of large volumes of electrolyte solutions. However, to be successful, this therapy should be implemented soon after injury. A new treatment method in which the infusion could be delayed might result in a greater survival rate. Reducing the volume of fluid needed is also important. Both of these aspects of fluid resuscitation therapy were addressed in this study by supplementing the electrolyte solution with trans-sodium crocetinate (TSC). Rats were subjected to a severe hemorrhage, with 55% (or greater) of the estimated blood volume being removed over a period of approximately 10 min. There were five animals in each treatment group, and two types of experiments were done. In one, a bolus injection of TSC (or saline control) was given immediately after hemorrhage, followed 30 min later with an infusion of isotonic saline. In the other experiments, reduced infusion volumes of a TSC-saline infusion fluid were used. In both cases, TSC resulted in the survival of the animals while the controls all died. Whole-body oxygen consumption also increased with TSC, reaching 75% of the normal resting value after about 15 min. This correlates well with the increased survival rates seen, since mortality after hemorrhagic shock is associated with decreased oxygen consumption. These results suggest that the use of TSC could allow for later implementation of fluid resuscitation therapy as well as reducing the volume needed.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID