摘要:

Two recent studies have examined the efficacy of interferon-gamma in reducing infection and death in patients sustaining severe injury. Both included multi-center, randomized, double-blinded placebo-control design. The first trial, conducted at four university trauma centers, enrolled 213 patients, while the second trial involved nine university trauma centers and 416 subjects. Recombinant human interferon-gamma (100 μg) was administered subcutaneously daily for 10 days in the first trial and 21 days in the second, in addition to standard supportive therapy. In both trials infection rates were similar in the treatment arms. Although the death rate related to infection was not affected in the first study, the second trial suggested an improved outcome from this complication. The outcome of the larger trial was flawed by dominant findings at one center that had the highest enrollment, infection, and death rates. Confounding variable analysis presented here explains much of the difference between center findings in the larger trial. Thus, the benefit of interferon-gamma as an immune adjuvant in severe injury is clouded by study design flaws evaluating its use and by the inability to identify appropriate subjects using clinical criteria.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The effect of methylprednisolone on the myocardial beta-adrenergic receptors after long term (>;72 h) catecholamine infusion was studied. In 56 patients with pulmonary arterial catheter, 10 mg/kg of methylprednisolone was given as an intravenous bolus. Significant increases could be seen in cardiac output and blood pressure in patients who were simultaneously treated with vasopressors like dopamine and/or dobutamine. In patients who were on dopamine infusion higher than 10 μg/kg/min methylprednisolone there was an increase in the systemic vascular resistance. Patients who were not on vasopressors but received methylprednisolone, had no similar changes in hemodynamic parameters. In an in vitro analysis of tissue from the myocardium in 12/56 patients who succumbed and in four additional patients who expired after multiple trauma, a beta-adrenergic receptor assay was performed. It was found that the long term infusion of catecholamines decreased the receptor number and the methylprednisolone abolished or caused the decrease to be less pronounced. In this study we could not control the selection of the patients; a randomized study needs to be conducted in the future.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

This study assessed sepsis-induced changes in the contents of calpain and cathepsin B in rat soleus muscle. Sepsis was induced in rats by intra-abdominally implanting fecal pellets containing Escherichia coli and Bacteroides fragilis. Intact soleus muscles were isolated from non-operated control rats, and from rats sacrificed 1 and 2 days after they were implanted with bacteria-free (sterile implanted) or bacteria-laden (septic implanted) pellets. Western blot analyses of muscle homogenates were performed to identify and quantitate these proteinases using specific antibodies. No significant differences in cathepsin B contents were observed between the septic and nonseptic animals on days 1 and 2, post-implantation. Among the three distinct bands recognized by anti-calpain, two prominent bands of 80 and 76 kDa, representing calpain subunits, did not seem to be altered in septic rats compared to the nonseptic groups. The content of the 45-kDa subunit decreased in both the septic and sterile groups compared with non-operated control. These results along with our previous observations suggest that although Gram-negative sepsis does not appear to have an effect on Ca2+-insensitive lysosomal cathepsin B content or activity, it upregulates the activity of the Ca2+-dependent calpain but not its content in the skeletal muscle during sepsis.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Sepsis is characterized by decreased peripheral vascular resistance, however, discrepancies exist regarding the specific secondary mediators involved. This study examined whether the presence of endotoxin (ET) is a requirement for tumor necrosis factor-α (TNF-α) to induce vasodilation of isolated skeletal muscle arterioles. First order cremasteric arterioles were isolated from male Sprague-Dawley rats, cannulated with glass micropipettes, superfused in physiologic saline, and allowed to achieve spontaneous basal tone in the absence of intraluminal flow. A 2 min exposure to TNF-α (.01–100 ng/mL) had no apparent effect on arteriolar diameter (95 ± 5% after .01 ng/mL and 92 ± 6% after 100 ng/mL, p >; .05 compared with basal). However, arterioles superfused with 2.5 μg/mL Salmonella enteritidis ET for 1 h followed by a 2 min exposure to 100 ng/mL TNF-α demonstrated a dilation (to 128 ± 12%) that became statistically significant 10 min after TNF-α washout (to 142 ± 12%, p < .05). This effect was eliminated by combined inhibition of cycooxygenase (with indomethacin) and nitric oxide synthase (L-NAME). The data indicate that neither ET or TNF-α alone elicit a direct vasomotor effect on the isolated arteriole preparation used in these studies. However, pretreatment of the vessels with ET results in the ability of TNF-α to cause arteriolar dilation, possibly through a mechanism involving both cyclooxygenase and nitric oxide synthase.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Nitric oxide (NO) produced by the inducible isoform of nitric oxide synthase contributes to the hypotension and vascular hyporeactivity in shock. Nicotinamide is protective against the cytotoxic effects of exogenous and endogenous NO in vitro. We investigated the effect of nicotinamide on the cellular energetic and vascular failure in a rat model of endotoxin shock. Administration of nicotinamide to rats, starting at 1 h after bacterial lipopolysaccharide, maintained higher blood pressure levels, without affecting induction of nitric oxide synthase. Nicotinamide treatment prevented the lipopolysaccharide-induced decrease in mitochondrial respiration and intracellular NAD+levels in peritoneal macrophages and improved the contractility of the thoracic aorta ex vivo. Thus, nicotinamide protects against the delayed, NO-mediated vascular failure in endotoxic shock. Its actions are unrelated to inhibition of NO biosynthesis but may be related to inhibition of the NO-mediated activation of an energy-consuming DNA repair cycle triggered by polyADP ribose synthetase.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50of .047 ± .01 μM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n = 7). ABT-299 was given at 1.0 mg/kg from −0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 μg/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

The procoagulant activity of mononuclear cells (MNCs) may play an important role in the disseminated intravascular coagulation seen in septic shock. This study compares the capacity of Escherichia coli (E. coli) and recombinant human TNF-α (rhTNF-α) to induce procoagulant activity by baboon MNCs. In vivo studies showed that MNC procoagulant activity was significantly increased at T + 120 min after LD100E. coli infusion into baboons. Most of this procoagulant activity was attributable to tissue factor. In contrast, a bolus infusion of rhTNF-α (150 μg/kg) and a monoclonal antibody to activated protein C (2 mg/kg) did not induce any increase of MNC procoagulant activity at T + 120 min even though the plasma TNF-a level was 10 times higher than that seen following infusion of E. coli. In vitro studies showed that E. coli at concentrations comparable to that observed in the in vivo study and LPS at a concentration of 2.5 ng/mL induced more intense tissue factor expression by both human and baboon monocytes than rhTNF-α in the concentrations ranging from 10 to 1,000 ng/mL. These results suggest that TNF-α alone is not sufficient to induce noticeable MNC procoagulant activity, at least, in the early stage of this septic shock model.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Oxygen free radicals have been shown to be implicated in ischemic tissue injury, and free radical-induced reactions may also play an important role in the pathophysiology of circulatory shock. The present study was designed to investigate the potential use of ascorbic acid as an exogenous antioxidant on the liver's recovery from hemorrhagic shock in situ. Rats (fasted overnight) were subjected to 60 min of hemorrhagic shock (HS) (mean arterial pressure = 40 mmHg) under pentobarbital anesthesia, followed by retransfusion of the shed blood. One-half of the animals (n = 6) were injected with 10 mg/kg of ascorbic acid prior to induction of shock, while untreated animals (n = 6) received the same volume of saline solution. In untreated animals, systemic plasma levels of malondialdehyde rose from 1.07 ± .08 during normotension (NT) to 1.36 ± .18*60 min after resuscitation (RS), documenting oxygen free radical-induced lipid peroxidation. Accordingly, plasma levels of alanine aminotransferase (16.5 ± 2.5; 34.9 ± 12.3*; 105.8 ± 68.7*U/L; NT/HS/RS) and ammonia (127 ± 40; 532 ± 160*; 304 ± 244*μg/dL) rose significantly during the experiment. Hepatic ATP content of the liver fell from 4.8 ± .83 to .56 ± .27*after HS and recovered partially to 2.7 ± 1.6*μmol/g after RS. Leukocyte infiltration in the liver, indicated by tissue levels of myeloperoxidase, remained constant during HS but rose during RS (37.9 ± 18.5; 38.6 ± 16.4; 81.4 ± 30.7*; arbitrary units), thus documenting an inflammatory reaction after HS. In the ascorbic acid group, plasma levels of malondialdehyde were comparable to those of untreated animals after RS, as were enzyme concentrations and ammonia. No differences were observed with regard to the tissue concentrations of ATP or myeloperoxidase. Mean arterial blood pressure as well as liver tissue perfusion, as measured by Laser Doppler flowmetry, did not show significant differences between the groups. It was concluded that, although an effect of oxygen free radicals on liver tissue could be found during and after HS, treatment with ascorbic acid alone, in our model, failed to ameliorate the recovery of the animals upon resuscitation (values are mean ± SD;*,p < .05 vs. NT; one-way ANOVA)

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

We studied whether dibutyryl cyclic adenosine monophosphate (DbcAMP), which freely penetrates into the cells, improves systemic vasoconstriction caused by endotoxin in dogs. Thirteen anesthetized dogs were randomized into three groups. The endotoxin (ETX) group (n = 5) received only Escherichia coli endotoxin (3 mg-kg-1, intravenously). The ETX + DbcAMP group (n = 5) received DbcAMP (6 mg-kg-1, intravenously) 30 min before the administration of endotoxin. The DbcAMP group received the same dose of DbcAMP 30 min after administration of saline. In the ETX group, systemic blood pressure and cardiac index significantly decreased, and systemic vascular resistance significantly increased, while in the ETX + DbcAMP group, increases in systemic and pulmonary vascular resistances after the administration of endotoxin were attenuated. DbcAMP did not cause hemodynamic changes in normal dogs. Plasma concentrations in thromboxane B2in the ETX group were higher than in the ETX + DbcAMP group. Also, the change in plasma cyclic AMP concentrations showed a good logarithmic correlation with the change in plasma thromboxane B2concentrations after the administration of endotoxin (r = .908, Log (ΔTxB2) = -.002*(ΔcAMP) + 3.786). We conclude that DbcAMP improves systemic vasoconstriction caused by endotoxin in dogs. The beneficial mechanism of DbcAMP on systemic vasoconstriction after the administration of endotoxin may be partially due to inhibition of thromboxane B2.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

A small volume of 7.5% NaCI/6% Dextran-70 (HSD) can rapidly expand the plasma volume, but concerns exist regarding its adverse effects on renal function in the dehydrated state. Sheep were thirsted for 4 days (13% plasma volume contraction), and subjected to a fixed-pressure shock model (mean arterial pressure of 50 mmHg for 2 h), followed by resuscitation with either HSD (4 mL/kg) or lactated Ringer's solution (LR; 37 mL/kg). Mean arterial pressure was restored to 90%, cardiac output to 125% and 120%, and plasma volume to 78% and 72% of baseline in LR and HSD groups, respectively. Glomerular filtration rate improved to 100% of baseline following HSD compared with 82% following LR. No significant urinary 70,000 molecular weight dextran was observed, suggesting an intact renal glomerular membrane. These data suggest that small volume HSD resuscitation is effective, even with pre-existing dehydration. In addition, renal function is not compromised by HSD resuscitation of hemorrhaged, dehydrated animals.

ISSN:1073-2322    

出版商:OVID    

年代:1996

数据来源: OVID