摘要:

ObjectiveWe examined the hypothesis that mechanical ventilation with a potentially injurious strategy would predispose animals to the detrimental effects of subsequent instillation of bacteria.DesignInterventional animal study.SettingA university hospital research laboratory.SubjectsFifty Sprague-Dawley male rats.InterventionsRats were anesthetized and randomized to receive a protective (tidal volume 7 mL/kg, positive end-expiratory pressure 5 cm H2O, n = 25) or an injurious ventilatory strategy (tidal volume 21 mL/kg, zero positive end-expiratory pressure, n = 25). Hemodynamics were similar during the 1-hr ventilation period in the two groups. Animals were then disconnected from the ventilator andPseudomonas aeruginosawas instilled intratracheally before extubation. Thereafter, animals breathed spontaneously; mortality rate was assessed up to 48 hrs, at which time the animals were killed.Measurements and Main ResultsThe 48-hr mortality rate was 28% in the protective group and 40% in the injurious group (p= not significant). A positive bacterial culture from the lung was obtained in 56% of the surviving rats in the low tidal volume group and 67% in the high tidal volume group (p= .059). A positive blood bacterial culture was found in 11% of the low tidal volume group and 33% in the high tidal volume group (p< .05). The absolute bacterial count in the blood was lower in the low tidal volume group compared with the high tidal volume group (p< .05). Concentrations of blood tumor necrosis factor-&agr; and macrophage inflammatory protein-2, and lung macrophage inflammatory protein-2 at 48 hrs were significantly higher in the low tidal volume group than in the high tidal volume group.ConclusionsAn injurious ventilatory strategy predisposes animals to subsequent bacteremia associated with an impaired host defense reflected by cytokine response.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveTo compare the changes in respiratory mechanics within the breathing cycle in healthy lungs between gas ventilation and partial liquid ventilation using a special forced-oscillation technique.DesignProspective animal trial.SettingsAnimal laboratory in a university setting.SubjectsA total of 12 newborn piglets (age, <12 hrs; mean weight, 725 g)InterventionsAfter intubation and instrumentation, lung mechanics of the anesthetized piglets were measured by forced-oscillation technique at the end of inspiration and the end of expiration. The measurements were performed during gas ventilation and 80 mins after instillation of 30 mL/kg perfluorocarbon PF 5080.Measurements and Main ResultsBrief flow pulses (width, 10 msec; peak flow, 16 L/min) were generated by a jet generator to measure the end-inspiratory and the end-expiratory respiratory input impedance in the frequency range of 4–32 Hz. The mechanical variables resistance, inertance, and compliance were determined by model fitting, using the method of least squares. At least in the lower frequency range, respiratory mechanics could be described adequately by an RIC single-compartment model in all piglets. During gas ventilation, the respiratory variables resistance and inertance did not differ significantly between end-inspiratory and end-expiratory measurements (mean [sd]: 4.2 [0.7] vs. 4.1 [0.6] kPa·L−1·sec, 30.0 [3.2] vs. 30.7 [3.1] Pa·L−1·sec2, respectively), whereas compliance decreased during inspiration from 14.8 (2.0) to 10.2 (2.4) mL·kPa−1·kg−1due to a slight lung overdistension. During partial liquid ventilation, the end-inspiratory respiratory mechanics was not different from the end-inspiratory respiratory mechanics measured during gas ventilation. However, in contrast to gas ventilation during partial liquid ventilation, compliance rose from 8.2 (1.0) to 13.0 (3.0) mL·kPa−1·kg−1during inspiration. During expiration, when perfluorocarbon came into the upper airways, both resistance and inertance increased considerably (mean with 95% confidence interval) by 34.3% (23.1%–45.8%) and 104.1% (96.0%–112.1%), respectively.ConclusionsThe changes in the respiratory mechanics within the breathing cycle are considerably higher during partial liquid ventilation compared with gas ventilation. This dependence of lung mechanics from the pulmonary gas volume hampers the comparability of dynamic measurements during partial liquid ventilation, and the magnitude of these changes cannot be detected by conventional respiratory-mechanical analysis using time-averaged variables.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectivePotentially fatal pulmonary toxicity is a dreaded complication of bleomycin. Increased use of granulocyte colony-stimulating factor in patients receiving chemotherapy has been paralleled by an increased incidence of bleomycin-induced pulmonary toxicity. We investigated whether granulocyte colony-stimulating factor (25 &mgr;g·kg−1·day−1, 4 days) enhanced endotracheal bleomycin-induced (5 mg/kg) acute lung injury and fibrosis in rats.SettingUniversity laboratory.SubjectsSprague-Dawley rats.InterventionsWe compared the effects of alveolar instillation of bleomycin in rats treated with either granulocyte colony-stimulating factor or saline.Measurements and Main ResultsMortality was 25% with bleomycin only and 50% with bleomycin + granulocyte colony-stimulating factor. Granulocyte colony-stimulating factor increased alveolar neutrophil recruitment, pulmonary edema, and lung myeloperoxidase activity on day 4. Lung static compliance on day 15 was severely decreased with bleomycin alone and showed a further significant decrease when granulocyte colony-stimulating factor was added (controls, 3.85 ± 0.14 mL/kPa; bleomycin, 1.44 ± 0.06 mL/kPa; and bleomycin + granulocyte colony-stimulating factor, 0.65 ± 0.09 mL/kPa; control vs. bleomycin,p< .0001; and bleomycin vs. bleomycin + granulocyte colony-stimulating factor,p= .0003). Lung morphology with bleomycin + granulocyte colony-stimulating factor showed, in addition to the changes observed with bleomycin alone, four patterns indicating more severe disease: honeycomb foci, pleural thickening with hyaline fibrosis, interstitial granuloma with increased number of macrophages but not neutrophils, and established interstitial fibrosis. Lidocaine, which prevents neutrophil adhesion to endothelial cells, inhibited granulocyte colony-stimulating factor-related exacerbation of acute lung injury (bronchoalveolar lavage fluid cells and pulmonary edema) and pulmonary fibrosis (lung static compliance and morphologic changes).ConclusionsGranulocyte colony-stimulating factor enhances bleomycin-induced lung toxicity by a mechanism that probably involves neutrophils.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveTo investigate the possible role of tumor necrosis factor in mediating cardiotoxicity following venom injection in a rat.DesignA randomized controlled experimental study using a Langendorff isolated heart model.SettingAnimal laboratory.SubjectsAdult male Wistar rats.InterventionsThe control group (n = 10) was injected with saline only. Each animal in the experimental groups 1–3 (n = 10 each) was injected withVipera aspisvenom 500 &mgr;g/kg intramuscularly. Group 1 animals received no additional substance beforehand, group 2 animals were injected intramuscularly with 250 &mgr;g of soluble tumor necrosis factor receptor (sTNF-R p55) 15 mins before the venom injection, and group 3 animals were injected intraperitoneally with 40 &mgr;g of anti-tumor necrosis factor 60 mins before the venom injection.Measurements and Main ResultsCardiac performances were investigated following envenomation. Cardiac histology and myocardial tumor necrosis factor-RNA concentrations were assessed. Serum tumor necrosis factor concentrations rose and peaked 2 hrs following envenomation. A reduction in peak systolic pressures, maximum and minimum change in pressure over time, time-pressure integral, and coronary flow occurred in the venom-only-injected rats compared with controls, whereas blocking tumor necrosis factor activity prevented the deleterious cardiac effects of the envenomation. No histologic changes or increases in myocardial tumor necrosis factor-RNA concentrations were detected.ConclusionThese results strongly suggest that systemic release of tumor necrosis factor mediates cardiac toxicity followingVipera aspisenvenomation.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveTo test the hypothesis that intravascular acid infusion promotes intrapulmonary nitric oxide formation by promoting inducible nitric oxide synthase (iNOS) and inhibiting endothelial nitric oxide synthase (eNOS) expression in rats.DesignProspective, placebo controlled, randomized laboratory study.SettingUniversity laboratory.SubjectsTwelve male Sprague-Dawley rats weighing 317 ± 30 g served as study subjects. All animals were anesthetized, paralyzed, and mechanically ventilated throughout the experiment.InterventionsThe animals were randomized to receive either 0.1 N hydrochloric acid or 0.9% saline intravenously. The infusions were initially given at a rate of 11 mL/kg/hr for 15 mins and then at a rate of 0.95 mL/kg/hr for the remainder of the experiment. Exhaled nitric oxide concentrations and hemodynamic measurements were monitored throughout the experiment. Lung tissues were harvested for Western blot analysis and immunostaining 4 hrs after starting the intravascular infusion.Measurement and Main ResultsAt the end of the experiment, we found more than a four-fold higher concentration of exhaled nitric oxide in the acid-treated animals than in the saline-treated animals (p< .001). Western blot analysis revealed that the acid infusion increased intrapulmonary iNOS concentrations (p< .001), yet it decreased intrapulmonary eNOS concentrations (p= .009). Acid-related lung injury manifested as a decrease in blood oxygen tensions (p= .045) and as an increase in lung homogenate interleukin-6 concentrations (p= .003).ConclusionsOur results reveal that hydrochloric acid infusion stimulates intrapulmonary nitric oxide formation at least in part by promoting the expression of iNOS. Our findings suggest that correcting acidosis should attenuate iNOS formation. Our data also support the idea that metabolic acidosis itself can lead to impaired intrapulmonary gas exchange and increased expression of pro-inflammatory cytokines such as interleukin-6. Whether the induction of intrapulmonary nitric oxide formation mediates or simply indicates lung injury warrants further investigation.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

We investigated a new method of pulmonary ventilation that included a minitracheostomy, a reverse thrust catheter to deliver continuous flow of gas to the carina, and a threshold valve to avoid lung overinflation. In six lightly sedated healthy sheep, at a continuous flow of 5, 10, or 15 L/min and a threshold valve of 5, 10, 15, or 20 cm H2O, we observed a novel respiratory pattern that was characterized either by active lung inflation followed by passive and prolonged inspiratory hold (mixed pattern) or by an absence of all active inspiratory effort and only passive inflation of the lungs (passive pattern). We correlated airway pressure changes with direct visualization of the glottic opening through a fiberoptic bronchoscope. We measured airway pressures at the level of the carina, the subglottic level, and in the pleural space, and respiratory events were monitored through inductive plethysmography. An increase in continuous flow, threshold valve, or both resulted in 1) an increase in glottic breathing; 2) a decrease in respiratory rate, with a decrease in inspiratory pleural pressure excursion; or 3) an increased inspiratory/expiratory ratio and mean airway pressure. During transtracheal gas insufflation, as in this study, a novel respiratory pattern evolved that was modulated by the glottis, accompanied by a decreased effort of breathing; coughing and swallowing remained, and vocalization remained unimpaired.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveTo investigate the mechanism by which methylprednisolone protects the liver from hypoxia-induced injury.DesignProspective control study using the isolated rat liver.SettingAnimal research facility.SubjectsMale, fasted, pathogen-free Sprague-Dawley rats.InterventionsLow-flow hypoxia was produced by reducing afferent perfusate pressure from 10 to 2.5 cm H2O; isolated livers were portally perfused for 2 hrs.Measurements and Main ResultsWe measured mitochondrial membrane potential and hydrogen peroxide production by imaging rhodamine 123 and 2′-7′-dichlorofluorescein fluorescence, respectively. Leakage of mitochondrial enzymes was also monitored by assaying mitochondrial aspartate aminotransferase activity in the outflow perfusate, and the radical-scavenging effect of methylprednisolone was assessed by measuring luminol-dependent hydrogen peroxide chemiluminescence. Apoptosis in liver cells was determined by using terminal deoxynucleotidyl transferase–mediated dUTP-digoxigenin nick-end labeling. Rhodamine 123 fluorescence was significantly diminished in the hypoxic liver, especially in the region of the terminal hepatic venules, which is indicative of membrane depolarization in the mitochondria in those areas. Hypoxia-induced mitochondrial dysfunction was indicated by leakage of aspartate aminotransferase into the outflow perfusate, and increased 2′-7′-dichlorofluorescein fluorescence indicated increased hydrogen peroxide levels, particularly in the midzone. Pretreatment with 30, 10, or 3 mg/kg of methylprednisolone inhibited the hypoxia-induced mitochondrial membrane depolarization and enzyme leakage, although hydrogen peroxide levels and apoptosis in sinusoidal endothelial cells were unaffected.ConclusionsMethylprednisolone does not protect the liver from hypoxia-induced injury by suppressing hydrogen peroxide production. Instead, the beneficial effect of methylprednisolone seems to be related to its ability to protect against mitochondrial membrane depolarization under hypoxic conditions.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveWe sought to determine the potential usefulness of 2′-deoxycoformycin (pentostatin), an inhibitor of adenosine deaminase, as a postinsult, or prophylactic treatment for systemic inflammatory response syndrome resulting from fecal peritonitis.DesignProspective, randomized, controlled experiment.SettingSmall animal basic science laboratory.SubjectsMale Spague-Dawley rats, weighing 300 to 350 g.InterventionsRats with fecal peritonitis (intraperitoneal cecal slurry) were treated with 1 mg/kg pentostatin intraperitoneally 24 hrs before, or intravenously when signs of illness presented (2 hrs after induction of peritonitis). Signs of illness included tachycardia, tachypnea, and leukopenia. All rats received 50 mL/kg 0.9% saline resuscitative fluid at 2 hrs.Measurements and Main ResultsSurvival to day 6 was 100% in nonseptic sham rats, but 33% in untreated septic rats. In rats given pentostatin either 2 hrs after the insult, or 24 hrs before the insult, 6-day survival improved to 81% and 78%, respectively. Histology revealed diffuse peritonitis, and evidence of systemic inflammatory response syndrome, including local and distant site vascular damage and leukocyte activation. These responses to the septic challenge were abrogated by pentostatin treatment. Return of significant amount of tissue adenosine deaminase activity by 24 hrs and later recovery of white blood cell counts argue against any potential for inappropriate immunosuppression by pentostatin.ConclusionsThese data indicate that the novel use of pentostatin to prevent systemic inflammatory response syndrome secondary to fecal peritonitis shows uncommon promise as a therapeutic tool. All indices of systemic inflammatory response syndrome were abrogated and survival improved when pentostatin was not given until after signs of the illness became manifest. Because protection was afforded with treatment 24 hrs in advance of the inciting insult, pentostatin also has the unique potential for use as a true prophylactic agent.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveTo determine whether extracellular concentrations of glutamate and other amino acids are significantly elevated after intracerebral hemorrhage and, if so, the temporal characteristics of these changes. Although the role of excitotoxic amino acids, particularly that of glutamate, has been described in ischemic stroke and head trauma, no information exists regarding their possible contribution to the pathogenesis of neuronal injury in intracerebral hemorrhage.DesignProspective, controlled, laboratory trial.SettingsAnimal research laboratory.SubjectsSixteen anesthetized New Zealand rabbits.InterventionWe introduced intracerebral hemorrhage in each of eight anesthetized New Zealand rabbits by injecting 0.4 mL of autologous blood under arterial pressure into the deep gray matter of the cerebrum.Measurements and Main ResultsExtracellular fluid samples were collected from the perihematoma region and contralateral (right) hemisphere byin vivomicrodialysis at 30-min intervals for 6 hrs. Corresponding samples were similarly collected from both hemispheres in each of eight control animals that underwent needle placement without introduction of a hematoma. Concentrations of amino acids (glutamate, aspartate, asparagine, glycine, taurine, and &ggr;-aminobutyric acid) in the samples were measured by use of high-pressure liquid chromatography with fluorescence detection. Glutamate concentrations (mean ± sem) were significantly higher in the hemisphere ipsilateral to the hematoma than in the contralateral hemisphere (92 ± 22 pg/&mgr;L vs. 22 ± 6 pg/&mgr;L) at 30 mins after hematoma creation. A significant increase was observed at 30 mins posthematoma creation in the hemisphere ipsilateral to the hematoma compared with the baseline value. A nonsignificant increase in glutamate concentration persisted in the hemisphere ipsilateral to the hematoma, ranging from 134% to 187% of baseline value between 1 and 5 hrs after hematoma creation. In the hemisphere ipsilateral to the hematoma, a three-fold increase in the concentration of glycine was observed at 30 mins after hematoma creation compared with the baseline level (890 ± 251 pg/&mgr;L vs. 291 ± 73 pg/&mgr;L). There was a significant difference between the hemisphere ipsilateral to the hematoma compared with the ipsilateral (corresponding) hemisphere of the control group at 30 mins posthematoma (890 ± 251 pg/&mgr;L vs. 248 ± 66 pg/&mgr;L). A similar transient increase was observed in taurine and asparagine concentrations at 30 mins after hematoma creation, compared with baseline measurements. Taurine concentrations in the hemisphere ipsilateral to the hematoma were significantly higher than the ipsilateral hemisphere of the control group (622 ± 180 pg/&mgr;L vs. 202 ± 64 pg/&mgr;L) at 30 mins after hematoma creation.ConclusionsThe present study suggests that glutamate and other amino acids accumulate transiently in extracellular fluids in the perihematoma region during the early period of intracerebral hemorrhage. The exact role of these amino acids in the pathogenesis of neuronal injury observed in intracerebral hemorrhage needs to be defined.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

ObjectiveTo establish a representative model for the evaluation of interleukin (IL)-6 and IL-6 receptor for pathogenicity and lethality in the postburn period.DesignTen-week-old C 57 BL/6J mice received a 20% body surface area contact burn and/or lipopolysaccharide (LPS) 48 hrs later. Standardized burns were created with a metal stamp of 150°C of defined pressure and surface area (2.4525 Newton/0.00166 m2) over a period of 11 secs. The depth of dermal injury was verified histologically. The following groups were formed: I: no burn, no LPS (n = 35); II: burn, no LPS (n = 140); III, no burn, LPS (n = 56); and IV, burn, LPS (n = 80), to study the effect of burn alone, sepsis alone, or the combination. Lethal LPS dose (LD100) was determined by application of LPS in increasing doses (200, 300, 400, and 500 &mgr;g, n = 32) after burns.MeasurementsConcentrations of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-&agr;) and interferon-gamma (IFN-&ggr;), and leukocytes, platelets and organ pathology were evaluated.SettingResearch laboratory.ResultsBurn and LPS showed an additive effect on the release of IL-6 but not of TNF-&agr; and IFN-&ggr;. Leukocyte and platelet numbers decreased significantly (group IV) compared with the other groups (I–III). The maximal levels of IL-6 in group IV were reached earlier than those of TNF-&agr;. The contact burn model has a mortality rate of 30%, which is close to clinical outcome. We found the model of contact burn superior to scald or flame burn models. A dose of 400-&mgr;g LPS was found to be the lethal LPS dose (LD100).ConclusionsOur data suggest that preexisting burn injury increases the response to endotoxin. TNF-&agr; is not involved in priming. IL-6 on the other hand is a very representative parameter for priming. Because TNF-&agr; was obviously not the causative factor, it was concluded that the application of anti-IL-6-mAb should be of great value. Therefore, a therapeutic application was designed, see part II.

ISSN:0090-3493    

出版商:OVID    

年代:2003

数据来源: OVID