摘要:

ObjectiveSepsis is the leading cause of death in critically ill surgical patients. Septic hepatic dysfunction, an important determinant of outcome, is poorly understood but includes inappropriate transcriptional down-regulation. This may be modulated by proinflammatory cytokines. We hypothesized that intrahepatic changes in tumor necrosis factor (TNF)/interleukin (IL)-1-linked processes, such as the activation of the p50 homodimeric and the p65/p50 heterodimeric isoforms of the transcription factor nuclear factor (NF)-&kgr;B or transcription of the acute phase reactant &agr;1-acid glycoprotein (AGP), would correlate with recovery from sepsis.DesignProspective experimental comparison of sham operation and nonlethal and lethal sepsis in male Sprague-Dawley rats.InterventionsNonlethal sepsis was induced by using single-puncture cecal ligation and puncture (CLP). Lethal sepsis was induced via double-puncture CLP. NF-&kgr;B DNA binding activity was determined by using electrophoretic mobility shift analysis with differentiation of p50/p50 and p50/p65 isoforms by using appropriate antibodies. AGP transcription was assessed with transcription elongation analysis, intrahepatic IL-1&bgr;, and TNF-&agr; abundance by using immunohistochemistry, and serum IL-1&bgr; was assessed by using ELISA.Main ResultsOverall NF-&kgr;B activity increased equivalently over time after both single- and double-puncture CLP, with a peak occurring 3 hrs after intervention. In single-puncture CLP, there was an increase in the binding of the p50 homodimer form over time. After double-puncture CLP, no such change was observed. AGP transcription was increased equivalently in both models. Intrahepatic IL-1&bgr; was detected 16 and 24 hrs after single-puncture CLP and 6 hrs after double-puncture CLP. After double-puncture CLP, intrahepatic TNF-&agr; was detected at 6, 16, and 24 hrs. Serum IL-1&bgr; was undetectable after both single- and double-puncture CLP.ConclusionsAlthough AGP transcription was similar in mild and fulminant sepsis, double-puncture CLP increased the binding activity of the p50 homodimer relative to binding of the p50/p65 NF-&kgr;B heterodimer. These results imply that transcriptional activity not linked to acute phase responses is an important determinant of outcome in sepsis.

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo test the effects of dobutamine and dopexamine on hepatic portal and sinusoidal blood flow in a model of normodynamic endotoxemia.DesignRandomized, controlled trial.SettingExperimental laboratory.SubjectsMale Wistar rats (250–350 g).InterventionsA total of 40 male Wistar rats were randomized into four groups: a control group, which only received Ringer’s solution; an endotoxin group, which received a continuous infusion of 2 mg/kg body weight (bw)/hr of endotoxin; a dobutamine group, which received endotoxin and a continuous infusion of dobutamine (3 &mgr;g/kg bw/min); and a dopexamine group, which received endotoxin and dopexamine (2 &mgr;g/kg bw/min). The experimental period was 120 min.Measurements and Main ResultsMean arterial blood pressure (MAP), heart rate (HR), and cardiac output (CO) were detected. Portal blood flow was measured using an ultrasonic flow probe positioned around the portal vein, and sinusoidal blood flow was detected in the left liver lobe using intravital microscopy. All detected variables remained stable in the control group. In the endotoxin group, HR increased significantly and MAP decreased significantly from 111 ± 10 mm Hg to 95 ± 8 mm Hg at 120 mins, whereas CO remained unchanged. Both in the dobutamine and the dopexamine group HR increased and MAP decreased more than in the endotoxin group. CO increased in both groups significantly. Portal blood flow (23 ± 4 mL/min to 16 ± 3 mL/min) and sinusoidal blood flow (38.6 ± 2.5 to 22.8 ± 1.2 103&mgr;m3/sec) decreased significantly in the endotoxin group. In the dobutamine and the dopexamine group portal and sinusoidal blood flow remained at baseline values.ConclusionsIn our model of endotoxemia, dobutamine and dopexamine preserved systemic and hepatic blood flow. These preservations of hepatic blood flow during endotoxemia could portend beneficial effects but need to be studied further.

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivePartial liquid ventilation with the perfluorochemical, perflubron, has been shown to improve lung mechanics and enhance gas exchange in the treatment of severe acute lung injury. However, the most effective strategy to provide optimal intrapulmonary distribution of perflubron has not been fully accessed. The objective of this study was to examine the effect of body position (supine vs. rotational) and mode of ventilation (conventional mechanical ventilation [CMV] vs. high-frequency oscillatory ventilation [HFOV]) on perflubron distribution and oxygenation improvement.DesignProspective, randomized, animal trial.SettingResearch laboratory at a university medical center.SubjectsTwenty healthy piglets (4.5–6.6 kg).InterventionsSubjects underwent repetitive saline lavage to achieve a uniform degree of lung injury and then were randomized to either CMV or were converted to HFOV. Within each ventilator group, animals were randomized to supine positioning (S) or rotational positioning with alternation between supine and prone position (R) during incremental dosing of three 5-mL/kg doses of perflubron.Measurements and Main ResultsArterial blood gas tensions, hemodynamic variables, and the oxygenation index were recorded after each dose of 5 mL/kg. Lateral cinefluoroscopic images after each dose were digitized for computer analysis of density. A density index was calculated for a 2-cm2window in three dorsal and three ventral lung regions. Uniformity of distribution was calculated by comparing the mean density among the six regions. Oxygenation improvements were compared between groups. There were no significant differences in hemodynamic variables or gas exchange after lung injury in the four groups. Rotational positioning produced significantly more uniform perflubron distribution during both CMV and HFOV. This effect was independent of the mode of ventilation. The mean ventral density index was affected by rotating position and HFOV mode of ventilation after 10 mL/kg of perflubron, and rotating position was affected only after 15 mL/kg of perflubron. There was a significant reduction in the oxygenation index from baseline to end lavage in both CMV groups, as well as all of the animals that were rotated.ConclusionPerflubron is more uniformly dispersed when dosed in a rotational fashion with alternation between supine and prone position during incremental dosing. This effect is independent of mode of ventilation. There was no relationship between oxygenation improvements and nondependent perflubron distribution. CMV and rotating dosing both led to a significant decrease in the oxygenation index after a 15 mL/kg dose of perflubron. This information has important impact on the future development of dosing strategies and clinical trial design.

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveIn this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase.DesignA prospective, controlled,in vivoanimal laboratory study.SettingResearch laboratory at a university.SubjectsMale, Wistar rats (8–9 wks old; n = 83).InterventionsIn pentobarbital-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived fromKlebsiella pneumoniaeor physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer.Measurements and Main ResultsLPS administration immediately induced progressive hypotension. The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 ± 2 to 56 ± 3 mm Hg (p< .001). LV end-diastolic internal dimensions decreased from 6.4 ± 0.1 to 3.1 ± 0.1 mm (p< .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 ± 0.2 to 0.5 ± 0.1 mm (p< .001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 ± 1% to 84 ± 2% (p< .001) at 30 mins after LPS and remained elevated compared with control rats. LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine. There was no elevation of concentrations of nitrite and nitrate. Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration.ConclusionsThe hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thickness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectivesAlthough studies have indicated that adrenal insufficiency occurs after severe trauma and hemorrhagic shock, it remains controversial whether adrenal function is depressed during the late stage of polymicrobial sepsis.DesignProspective, controlled animal study.SettingA university research laboratory.SubjectsMale rats (275–325 g) were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) or sham operation followed by the administration of normal saline solution.Measurements and Main ResultsSystemic blood samples were taken at 20 hrs after CLP (i.e., a late stage of sepsis) or sham operation to measure plasma levels of corticosterone and corticotropin as well as adrenal contents of corticosterone. Additional groups of animals were utilized to examine corticotropin-stimulated plasma corticosterone release as well as adrenal levels of cyclic adenosine monophosphate (cAMP, the second messenger of corticotropin action). The results indicate that despite a 75% (p< .05) higher concentration in plasma corticotropin at 20 hrs after the onset of sepsis, plasma corticosterone levels were similar to those in sham-operated animals. In addition, adrenal contents of corticosterone were reduced by 42% (p< .05) in septic animals. Moreover, the plasma corticosterone and adrenal cAMP responses to corticotropin were reduced by 53% and 27% (p< .05), respectively, at 20 hrs after CLP.ConclusionsThese findings suggest that, despite high plasma levels of endogenous corticotropin, adrenal dysfunction, as indicated by the reduction of corticotropin-induced plasma corticosterone release and adrenal contents of cAMP as well as the decreased adrenal levels of corticosterone, occurs during the late stage of polymicrobial sepsis. Therefore, the recognition of adrenal insufficiency and interventions to improve adrenal responsiveness may be beneficial in improving the outcome during late sepsis.

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveTo investigate the effects of naloxone and morphine during acute hypoxia.DesignProspective, randomized animal study.SettingUniversity laboratory.SubjectsTwenty-eight adult male Sprague Dawley rats, weighing 300–350 g.InterventionsThe rats were implanted with a femoral catheter and subcutaneous electrodes for electrocardiogram recording and were randomly assigned to receive morphine (5 mg/kg), naloxone (5 mg and 10 mg/kg), or normal saline (control) (n = 7 in each). Fifteen minutes after intraperitoneal injection of the drug, each rat was exposed to hypoxic gas (5% oxygen, 95% N2) for 70 mins. Hypoxic survival time was measured. Mean arterial pressure (MAP), arterial pH, Paco2, Pao2, and base excess were measured before injection (baseline), 14 mins after injection (H0), and 6 mins (H1), 33 mins (H2), and 48 mins (H3) after exposure to hypoxia.Measurements and Main ResultsHypoxic survival was similar between the naloxone 5 mg/kg and control groups (p= .183), significantly lower in the naloxone 10 mg/kg group (p< .01), and significantly higher in the morphine 5 mg/kg group (p< .05) compared with controls. MAP significantly decreased in all groups. However, at H2–H3, MAP was better preserved in both naloxone groups and was lower in the morphine group compared with controls. Paco2was maintained higher at H0–H3 in the morphine group and lower at H2–H3 in both naloxone groups compared with controls.ConclusionDuring acute hypoxia, naloxone preserves arterial blood pressure and attenuates hypoxic ventilatory depression by antagonizing endogenous opiates, but it does not improve hypoxic survival. In contrast, morphine, which enhances the action of endogenous opiates, does improve hypoxic survival. The acute hypoxic tolerance of morphine may be partly attributable to a depression of oxygen consumption, increased cerebral blood flow secondary to high Paco2, and protective actions mediated by &dgr;-opioid receptors.

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

摘要:

ObjectiveSepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-&agr; and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653.DesignProspective, randomized study.SettingAnimal research facility in a university.SubjectsMale Sprague-Dawley rats weighing 200–270 g.InterventionsAll the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg·kg−1·hr−1, commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs.Measurements and Main ResultsLPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-&agr; and IL-1&bgr; and plasma concentrations of thromboxane B2were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues.ConclusionsFR167653 administration decreased serum TNF-&agr; and IL-1&bgr; concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-&agr; and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID

ISSN:0090-3493    

出版商:OVID    

年代:2001

数据来源: OVID