摘要:

Over the past decade, the biotechnology/pharmaceutical industry has been diligently working on the development of immunomodulatory agents for the treatment of shock and sepsis, and the literature is rife with descriptions of novel and innovative molecules that promise to become the panacea for these conditions. Unfortunately, despite promising preclinical evidence, dozens of these new agents have failed to demonstrate clinical efficacy in controlled, randomized clinical trials, abandoning the bedside physician to the traditional armamentarium of drugs and therapeutics for the treatment of patients with these complex, progressive, and life-threatening conditions. The reasons for this quandary are controversial, complex, and multifactoral. This review focuses on the concept that the preclinical trials of many of these agents were conducted using models of sepsis and shock that do not adequately reflect the clinical realities of these conditions. As a result, it is not surprising that clinical trials of agents based on clinically flawed models failed to demonstrate clinical efficacy. The lack of clinical insight during preclinical development of these agents has contributed to the current impasse of the development of safe, efficacious, and potentially lifesaving agents for the treatment of shock and sepsis. Thus, the goal of this review article is to review the advantages and disadvantages of commonly used sepsis and shock models in light of lessons learned from these clinical trials.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The influence of coronary artery bypass grafting (CABG) on spontaneous and lipopolysaccharide (LPS)-stimulated release of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 as well as its modulation by pentoxifylline (PTF) were studied in a prospective, randomized, double-blinded study. 12 patients undergoing elective CABG were randomly assigned to receive either saline or PTF (1 mg/kg as a loading dose followed by 1 mg/kg/h) intraoperatively. Blood samples were obtained (A) preoperatively, (B) 20 min after CABG, and (C) 24 h after CABG. Cytokine plasma levels as well as LPS-stimulated cytokine secretion were measured in a whole blood culture systemex vivoand correlated with mRNA expression in peripheral blood mononuclear cells. In addition, the dose-response characteristics of modulation of the cytokine response by PTF were studied in cultured whole bloodin vitro.Plasma IL-6 and IL-10-levels were significantly elevated after CABG, whereas neither TNF-α nor IL-1β were detectable. In contrast to the spontaneous release of IL-6 and IL-10, the expression of all cytokines studied was significantly reduced uponex vivoLPS stimulation early after CABG. Proinflammatory cytokine response upon LPS stimulation was restored 24 h after CABG for the group mean, however, with substantial interindividual heterogeneity. Therapeutic doses of PTFin vitroattenuated LPS-induced TNF-α (-50.5%) and most notably IL-10 (-83.9%) release, whereas IL-1β was even increased (+45.7%). However, application of PTF during CABG neither inhibited the spontaneous production of IL-10 nor modulated cytokine productionex vivo.These results suggest a biphasic response of stimulated peripheral blood mononuclear cell cytokine gene expression during CABG with an initial tolerance to LPS stimulation. The application of PTF during CABG in doses that are primarily based on its use in occlusive arterial disease do not seem to modulate the release of the cytokines studied.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The aim of the study was to investigate the time course of neutrophil activation after skeletal muscle ischemia in humans and to assess the effect of xanthine oxidase inhibitor allopurinol or cyclooxygenase inhibitor indomethacin. In patients undergoing tourniquet ischemia of the upper limb, polymorphonuclear neutrophils (PMN) were simultaneously isolated from antecubital vein blood of both the contralateral control arm and the tourniquet arm. PMN-superoxide production (PMN-SOP) was determined by a cytochrome C reduction assay, PMN-myeloperoxidase activity (PMN-MPO) by guaiacol oxidation and serum PMN-elastase concentration by an enzyme immunoassay. At 60 min after release of the tourniquet, significant increases of PMN-SOP, PMN-MPO, and serum elastase concentrations were observed in tourniquet arms as compared with control arms (p< .05). Allopurinol (300 mg orally, 12 and 2 h before ischemia) significantly inhibited the increase of PMN-SOP, PMN-MPO, and serum elastase (p< .05). Indomethacin (50 mg orally, 2 h before ischemia) prevented increased PMN-MPO and serum elastase, but prevented increased PMN-SOP only when neutrophils were incubated in the presence of their autologous plasma. These findings suggest that ischemia/reperfusion of human skeletal muscle involves both xanthine oxidase-dependent oxygen free radicals and cyclooxygenase metabolites. These pathways could activate circulating neutrophils which potentially inflict local and remote endothelial injury.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We studied the effect of water-soluble antioxidants geared at restoring glutathione levels on oxygen consumption, cell energetics as measured by energy charge potential (ECP), glutathione levels, and mortality, in response to a 20% total body surface area (TBSA) third degree burn injury combined with endotoxemia, five days after burn in a rat model. The 20% TBSA third degree burn injury was not fatal for the six day study period. Oxygen consumption as well as red blood cell ECP remained unchanged from control values. Liver ECP was significantly reduced; however, liver glutathione was significantly increased. The 20% TBSA burn injury combined with endotoxemia produced a 60% mortality rate. Twenty-four hour survivors (40%) demonstrated a significant decrease in oxygen consumption, red blood cell ECP, and liver ECP. Liver glutathione was significantly decreased compared with burn but was not significantly decreased compared with control. Nonsurvivors of the burn injury combined with endotoxin (60%) demonstrated a significant reduction in liver glutathione levels compared with survivors. Oxygen consumption and ECP could not be measured in the nonsurvivors due to the rapid loss of ATP in the moribund state that occurred by 4 h postinjury. Antioxidants produced 100% survival, attenuated in the fall in liver ECP, and restored red blood cell ECP and liver glutathione levels to normal values. We conclude that a modest burn injury combined with endotoxemia produces a liver glutathione debt, oxygen debt, an energy deficit, and 60% mortality. The mechanism of injury is oxidant related as antioxidants prevented mortality restored liver glutathione levels, and prevented or attenuated the decrease in ECP. A decrease in ECP and glutathione levels appear to be more sensitive indicators of outcome than the presence of an oxygen debt. The survivors, in both burn plus endotoxin groups treated with or without antioxidants was comparable, indicating a critical value for oxygen consumption exists before death occurs.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Hypertonic colloid solutions reportedly exert protective effects on the microcirculation. The present study investigated the effects of a hypertonic saline hydroxyethyl starch (HES) solution on the oxygen extraction capabilities in an endotoxic shock model in the dog. Fourteen anesthetized and mechanically ventilated dogs received 2 mg/kg ofEscherichia coliendotoxin before being randomly divided into two groups to receive a 4 mL/kg infusion in 10 min of either hypertonic (7.5%, n = 7), or isotonic (.9%, n = 7) HES solution. Thereafter, each animal received isotonic HES titrated to restore cardiac index to baseline levels, followed by a constant infusion of normal saline at 20 mL/kg throughout the study. The amount of fluid required to restore cardiac index to baseline levels was approximately one-half in the hypertonic saline HES group as compared with the isotonic group (123 ± 12 vs. 291 ± 62 mL/kg,p< .05). The two groups of dogs had similar mean arterial pressure and cardiac index values. Hypertonic saline HES-treated animals had a higher sodium concentration than the control group (144.4 ± 4.0 vs. 138.7 ± 3.1 mM/L,p< .05). There were no significant differences in blood gases or lactate concentrations between the groups. When cardiac tamponade was induced to study the tissue oxygen extraction capabilities, hypertonic saline HES-treated dogs had a slightly lower critical oxygen delivery (11.1 ± 1.6 vs. 14.2 ± 3.3 mL/kg·min,p= NS), and a significantly higher critical oxygen extraction ratio (61.9 ± 17.1 vs. 44.0 ± 11.5%,p< .05) than the isotonic group. We conclude that during endotoxic shock in dogs, hypertonic saline HES solution can increase whole body oxygen extraction capabilities, probably by an improvement in microvascular perfusion in septic conditions.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We hypothesized that endothelin (ET) may be released in response to tumor necrosis factor-α (TNF) and that platelet-activating factor (PAF) and cyclooxygenase products modulate TNF-induced ET-1 releasein vivo.Anesthetized and instrumented pigs were randomly assigned to receive: 1) saline + TNF (n = 8); 2) saline + heat-inactivated TNF (control group, n = 5); 3) WEB 2086 (PAF receptor antagonist) + TNF (n = 7); or 4) indomethacin + TNF (n = 6). Infusion of TNF was associated with increases in mean aortic, mean pulmonary artery, and intratracheal pressures, increases in systemic and pulmonary vascular resistances, and elevated plasma thromboxane B2concentration. Plasma ET-1 concentrations were unchanged in controls and significantly increased in TNF-treated pigs at 2 to 4 h. WEB 2086 did not modify plasma levels of ET-1 during exogenous infusion of TNF. In contrast, the cyclooxygenase inhibitor, indomethacin, mildly, but not significantly, reduced plasma ET-1 levels. In addition, indomethacin (but not WEB 2086) blocked or attenuated the TNF-induced increases in mean aortic pressure, systemic vascular resistance, mean pulmonary artery pressure, pulmonary vascular resistance, and intratracheal pressure. We conclude that in the pig, cyclooxygenase products modulate some of the cardiovascular responses to TNF and may mildly affect ET-1 biosynthesis. On the other hand, PAF neither significantly influences TNF-induced biosynthesis of ET-1 nor its associated cardiovascular responses.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The time sequence and the mechanisms leading to the development of the hypertriglyceridemia of bacteremic sepsis are not fully understood. This study was conducted to determine the mechanisms leading to the early rise in serum triglycerides (TG). Bacteremic sepsis was induced in fasted and parenterally fed rats by intravenous infusion of liveEscherichia colicolonies over a 1 h period every 24 h up to 96 h. Body temperature was elevated from 12 to 48 h afterE. coliinfusion in fasted rats and from 24 to 72 h afterE. coliinfusion in fed rats. The initial rise in serum TG was observed at 3 h afterE. coliinfusion; in fasted rats this elevation was maintained over 72 h. In the parenterally fed rats, hypertriglyceridemia was evident only at the 3 h time point. Serum concentrations of tumor necrosis factor α (TNF-α) were elevated significantly at 60 min after initiating theE. coliinfusion, peaked at 90 min, and declined by 120 min. Immunization with neutralizing goat anti-TNF-α IgG did not block the initial increase in serum TG induced byE. coli.This early rise in TG in fastedE. coli-treated rats was accompanied by a 33% increase in TG secretion in comparison with control rats. TG secretion declined by 27% at 9 h and remained depressed at 12 and 24 h in comparison with time-matched control rats. By 24 h lipid accumulation was evident in the livers of the fasted and fedE. coli-treated rats. Most of the fastedE. coli-treated rats died by 72 h. Parenteral feeding extended survival ofE. coli-treated rats until 120 h. These findings along with the observation that two mechanisms are involved in maintaining the elevation of serum TG duringE. colisepsis suggests that the hypertriglyceridemia may be important in host survival.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Portal hypertension is characterized by splanchnic vasodilation and diminished arterial vasoconstrictor response to hemorrhage. Angiotensin-II and arginine vasopressin are critical modulators of the splanchnic response to hemorrhage in normal animals. We hypothesized that alterations in endogenous renin, angiotensin-II, or arginine vasopressin production or release could contribute to the abnormal response to hemorrhage in portal hypertension. Hemodynamics were studied in normal and portal hypertensive rabbits following either graded isovolumetric or single large volume hemorrhage, followed by reinfusion of blood. Hemodynamic and renin-angiotensin-II, and arginine vasopressin activities were determined. The experiments demonstrated a significantly diminished appearance in angiotensin-II (110.87 ± 30 vs. 245 ± 51.0 pg/mL) and aldosterone (54.2 ± 9.5 vs. 119.4 ± 13.5 ng/dL), and plasma renin activity (19.4 ± 4.2 vs. 29.1 ± 2.8 ng/mL/h) in portal hypertension compared with normal, but an appropriate rise in arginine vasopressin levels following hemorrhage in portal hypertension. These findings suggest a diminished angiotensin-II production or release in portal hypertension, which may mediate the failure of the appropriate splanchnic vasoconstrictive response to hemorrhage.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

We previously demonstrated that platelet-activating factor (PAF) when injected intravenously decreases renal sympathetic nerve activity in anesthetized dogs. Recently, nitric oxide (NO) has been shown to inhibit renal sympathetic nerve activity. The present study was designed to determine, using the NO synthase inhibitorNG-nitro-L-arginine methyl ester (L-NAME), whether endogenous NO contributes to the PAF-induced renal sympathoinhibition in anesthetized dogs. We also determined the role of NO in systemic and pulmonary hemodynamics during PAF-induced hypotension. In response to PAF (10 μg · kg−1, intravenously), renal sympathetic nerve activity showed similar responses in animals pretreated with L-NAME (n = 7; 20 mg · kg−1bolus and .05 mg · kg−1· min−1), D-NAME (n = 7), and phenylephrine (n = 7), as characterized by an initial increase (230%) followed by a decrease (56%). The depressor response to PAF was also similar as early as 10 min after injection in all PAF-injected groups. In contrast, L-NAME pretreatment potentiated PAF-induced pulmonary hypertension. Pulmonary arterial pressure 10 min after PAF in the L-NAME group (25 ± 2 mmHg) was significantly greater than that in the D-NAME group (12 ± 3 mmHg). In conclusion, endogenously produced NO is not involved in PAF-induced renal sympathetic nerve response or hypotension but attenuates PAF-induced pulmonary hypertension at the early stage in anesthetized dogs.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Diaspirin cross-linked hemoglobin (DCLHbTM), a hemoglobin-based blood substitute, has been found to improve systemic hemodynamics, cutaneous oxygen tension, and normalization of blood lactate levels and acid-base equilibrium after hemorrhage in animals. The present study was conducted to determine the dose-dependent effect of a 10% solution of DCLHb (20, 50, and 100% of shed blood volume; SBV) on regional blood circulation in hemorrhaged rats. Hemorrhage was induced in urethane-anesthetized rats by bleeding them at a rate of approximately .5 to 1 mL/min until a mean arterial pressure of 35–40 mmHg was achieved. This was maintained for up to 90 min to reach a base deficit of more than −12 mmol/L. Hemorrhage significantly decreased oxygen consumption, mean arterial pressure, cardiac output, stroke volume, and regional blood circulation, but increased total peripheral resistance. The vehicle Ringer's lactate (RL at 20% of SBV, intravenously) did not produce any improvements in oxygen consumption, base deficit, systemic hemodynamics, and regional blood circulation. DCLHb increased oxygen consumption, decreased base deficit, and produced significant improvements in systemic hemodynamics and regional blood flow in a dose-dependent manner. The increase in blood flow was highly significant until 60 min, but was less marked at 120 min, after resuscitation with DCLHb. Resuscitation with RL (300% of SBV) significantly improved systemic and regional blood circulation. However, the improvement was greater after resuscitation with DCLHb (50 or 100% of SBV) as compared with RL at 300% SBV. DCLHb in the dose of 50% of SBV produced maximal resuscitative effects, which were comparable to a DCLHb dose of 100% of SBV. The effect of DCLHb at 50% of SBV on renal cortical blood perfusion, concentration of moving red blood cells (CMBC), and blood velocity was also studied using laser Doppler flowmetry. Hemorrhage produced a decrease in renal cortical blood perfusion (85.3%), which was due to a decrease in the CMBC (61.0%) and their velocity (64.2%). Resuscitation with the RL did not produce any improvement in renal cortical perfusion. However, resuscitation with DCLHb significantly increased renal cortical perfusion (364.7%) due to an increase in both CMBC (123.4%) and their velocity (109.9%). It is concluded that DCLHb in a dose of 50% of SBV produces maximal improvement in regional blood circulation of hemorrhaged rats.

ISSN:1073-2322    

出版商:OVID    

年代:1998

数据来源: OVID