摘要:

Objectives:The adhesion molecule L-selectin plays an important role in leukocyte-endothelium interactions, thereby contributing to inflammatory reactions. We tested the hypothesis that humanized anti-L-selectin antibodies reduce trauma-associated organ damage and mortality.Design:Prospective, randomized experimental study.Setting:Independent nonprofit research laboratory in a trauma hospital (Ludwig Boltzmann Institute) and a contract research institute (Biocon).Subjects:Twenty-eight male baboons (Papio ursinus), 18 to 29 kg.Interventions:Hemorrhagic-traumatic shock was created by complement activation with cobra venom factor, followed by withdrawal of blood to a mean arterial pressure of 35 to 45 mm Hg. Blood and lactated Ringer's solution were reinfused. Animals were randomized to receive either 2 mg/kg humanized anti-L-selectin antibody (HuDREG-55 [Ab]) or placebo (lactated Ringer's solution [LRS]).Measurements and Main Results:Treatment with humanized anti-L-selectin antibody decreased mortality (Ab 21% vs. LRS 71%;p= .011) and improved survival time (p= .016). A trend toward reduced organ damage, especially in the adrenal glands (score 1.2 ± 0.2 placebo vs. 1.0 ± 0.1 antibody;p= .059) was seen, and at 24 hrs was accompanied by significantly increased mean arterial pressure (Ab 99 ± 6 mm Hg vs. LRS 79 ± 8 mm Hg;p= .023), cardiac output (Ab 3.4 ± 0.2 L/min vs. LRS 2.4 ± 0.3 L/min;p= .007), core temperature (p= .048), and improved perfusion, with less negative base excess (Ab 2.9 ± 1.1 vs. LRS 2.1 ± 1.7;p= .019) and a trend toward less lactate (p= .065). These improvements were accompanied by significantly (p= .006) decreased fluid requirements in the treatment group (Ab 11.7 ± 2.5 mL/kg/hr vs. LRS 23.0 ± 2.3 mL/kg/hr). There were also fewer circulating leukocytes (p= .042) in the treatment group at 24 hrs.Conclusion:Humanized anti-L-selectin antibody has beneficial effects on survival in a long-termin vivomodel of hemorrhagic-traumatic shock.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objectives:Because vasoactive eicosanoids derived from arachidonic acid present in immune cell phospholipids promote lung inflammation in critically ill patients, novel experimental diets containing eicosapentaenoic acid from fish oil and γ-linolenic acid from borage oil have been designed to limit arachidonic acid metabolism. However, excess dietary eicosapentaenoic acid impairs superoxide formation and bacterial killing by immune cells. The present study determined whether short-term enteral feeding with diets enriched with either eicosapentaenoic acid alone or in combination with γ-linolenic acid would modulate alveolar macrophage eicosanoid synthesis without compromising bactericidal function.Design:Prospective, randomized, controlled, blinded study.Setting:University medical center.Subjects:Adult male Sprague-Dawley rats.Interventions:Rats underwent surgical placement of a gastroduodenal feeding catheter and were randomly assigned to receive one of three high-fat (55.2% of total calories), low-carbohydrate diets containing isocaloric amounts of lipids for 4 days. The control diet was enriched with linoleic acid, whereas the two test diets were low in linoleic acid and enriched with either 5 mole % eicosapentaenoic acid alone or in combination with 5 mole % γ-linolenic acid. Alveolar macrophages were then procured to assess phospholipid fatty acid composition, eicosanoid synthesis after stimulation with endotoxin, superoxide formation and phagocytosis by flow cytometry, and killing ofStaphylococcus aureus.Measurements and Main Results:Alveolar macrophage levels of arachidonic acid were significantly (p< .01) lower and levels of eicosapentaenoic and dihomo-γ-linolenic acids were higher after feeding the eicosapentaenoic and γ-linolenic acid diet vs. the linoleic acid diet. Ratios of thromboxane B2,/B3, leukotriene B4/B5, and prostaglandin E2/E1were reduced in the macrophages from rats given either the eicosapentaenoic acid or eicosapentaenoic acid with γ-linolenic acid diet compared with ratios from rats given the linoleic acid diet. Macrophages from rats given the eicosapentaenoic with γ-linolenic acid diet released 35% or 24% more prostaglandin E1than macrophages from rats given either the linoleic acid or the eicosapentaenoic acid diet, respectively. Macrophage superoxide generation, phagocytosis of opsonized zymosan, and killing ofS. aureuswere similar irrespective of dietary treatment.Conclusion:Short-term enteral feeding with an eicosapentaenoic acid-enriched or eicosapentaenoic with γ-linolenic acid-enriched diet rapidly modulated the fatty acid composition of alveolar macrophage phospholipids, promoted a shift toward formation of less inflammatory eicosanoids by stimulated macrophages, but did not impair alveolar macrophage bactericidal function relative to responses observed after feeding a linoleic acid diet.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:To test the hypothesis that perfluorocarbon (PFC) priming before surfactant administration improves gas exchange and lung compliance, and also decreases lung injury, more than surfactant alone.Design:Prospective, randomized animal study.Setting:Animal research laboratory of Children's Hospital of St. Paul.Subjects:Thirty-two newborn piglets, weighing 1.55 ± 0.18 kg.Interventions:We studied four groups of eight animals randomized after anesthesia, paralysis, tracheostomy, and establishment of lung injury using saline washout to receive one of the following treatments: a) surfactant alone (n = 8); b) priming with the PFC perflubron alone (n = 8); c) priming with perflubron followed by surfactant (n = 8); and d) no treatment (control; n = 8). Perflubron priming was achieved by instilling perflubron via the endotracheal tube in an amount estimated to represent the functional residual capacity, ventilating the animal for 30 mins, and then removing perflubron by suctioning. After all treatments were given, animals were mechanically ventilated for 4 hrs.Measurements and Main Results:We evaluated oxygenation, airway pressures, respiratory system compliance, and hemodynamics at baseline, after induction of lung injury, and at 30-min intervals for 4 hrs. Histopathologic evaluation was carried out using a semiquantitative scoring system and by computer-assisted morphometric analysis. After all treatments, animals had decreased oxygenation indices (p< .001) and increased respiratory system compliance (p< .05). Animals in PFC groups had similar physiologic responses to treatments as animals treated with surfactant only; both the PFC-treated groups and the surfactant-treated animals required lower mean airway pressures throughout the experiment (p< .001) and had higher pH levels at 90 and 120 mins (p< .05) compared with the control group. Pathologic analysis demonstrated decreased lung injury in surfactant-treated animals compared with animals treated with PFC or the controls (p< .02).Conclusions:Priming the lung with PFC neither improved the physiologic effects of exogenous surfactant nor improved lung pathology in this animal model.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objectives:a) To determine the relationship of acid-base balance (pH, PCO2) of blood samples from the intraosseous and the mixed venous route during prolonged cardiopulmonary resuscitation; b) to compare the effect of separate infusions of epinephrine, fluid boluses, or sodium bicarbonate through the intraosseous sites on the acid-base status of intraosseous and mixed venous blood during cardiopulmonary resuscitation; and c) to compare pH and PCO2of intraosseous and mixed venous blood samples after sequential infusions of fluid, epinephrine, and sodium bicarbonate through a single intraosseous site.Design:Prospective, randomized study.Setting:Animal laboratory at a university center.Subjects:Thirty-two mixed-breed piglets (mean weight, 30 kg).Interventions:Piglets were anesthetized and prepared for blood sampling and cardiopulmonary resuscitation. After anoxic cardiac arrest, ventilation was resumed and chest compression was resumed. Blood gas samples from the pulmonary artery and both intraosseous sites were obtained simultaneously at baseline, at cardiac arrest, and at 5, 10, 15, 20, and 30 mins of cardiopulmonary resuscitation for group 1 (control group) and after drug (epinephrine and sodium bicarbonate) and saline infusions via one of the intraosseous cannulas in groups 2 through 5.Measurements and Main Results:We found no differences between intraosseous and mixed venous pH and PCO2during periods of <15 mins of cardiopulmonary resuscitation. However, this relationship was not maintained during prolonged cardiopulmonary resuscitation and after bicarbonate infusion. After large volume saline infusion, the pH and PCO2of mixed venous and intraosseous blood were similar. During epinephrine infusion, the relationship between intraosseous and mixed venous pH and PCO2was similar to that found in the control group.Conclusions:The intraosseous blood sample could be used to assess central acid-base balance in the early stage of arrest and cardiopulmonary resuscitation of <15 mins. However, during cardiopulmonary resuscitation of longer duration, drug infusions may render the intraosseous site inappropriate for judging central acidosis.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:To investigate a role of the opiate system during acute hypoxic hypoxia, the effects of naloxone and morphine on hypoxic survival rate were investigated in awake adult mice.Design:Prospective, randomized, animal trial.Setting:University research laboratory.Subjects:Male dd-Y mice (n = 864 in experiment I, n = 144 in experiment II, n = 30 in experiment III).Interventions:The animals were placed in an airtight plastic chamber into which a continuous flow of 8 L/min 5% oxygen-95% nitrogen was passed.Measurements and Main Results:One and 5 mg/kg naloxone had no significant effect on the survival rate of mice subjected to acute hypoxic hypoxia, whereas 10 mg/kg naloxone decreased the survival rate. On the other hand, 2 and 5 mg/kg morphine was shown to have a protective action against acute hypoxic hypoxia. The protective effects of 5 mg/kg morphine against hypoxia was even antagonized by 5 mg/kg naloxone, which did not itself show any significant effect on the survival rate. The oxygen consumption in the morphine-treated (5 mg/kg) mice was significantly (p< .05) lower (87.0% ± 4.6%; mean ± SE) than that in the saline-treated animals.Conclusions:The present study suggests that the endogenous opiate system does not play a significant role on the pathophysiology caused by acute hypoxic hypoxia and that the improved survival of the hypoxic animals by morphine is at least partly attributable to its depressant effect on oxygen consumption.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objectives:To investigate the effects of positive end-expiratory pressure (PEEP) application during partial liquid ventilation (PLV) on gas exchange, lung mechanics, and hemodynamics in acute lung injury.Design:Prospective, randomized, experimental study.Setting:University research laboratory.Subjects:Six piglets weighing 7 to 12 kg.Interventions:After induction of anesthesia, tracheostomy, and controlled mechanical ventilation, animals were instrumented with two central venous catheters, a pulmonary artery catheter and two arterial catheters, and an ultrasonic flow probe around the pulmonary artery. Acute lung injury was induced by the infusion of oleic acid (0.08 mL/kg) and repeated lung lavage procedures with 0.9% sodium chloride (20 mL/kg). The protocol consisted of four different PEEP levels (0, 5, 10, and 15 cm H2O) randomly applied during PLV. The oxygenated and warmed perfluorocarbon liquid (30 mL/kg) was instilled into the trachea over 5 mins without changing the ventilator settings.Measurements and Main Results:Airway pressures, tidal volumes, dynamic and static pulmonary compliance, mean and expiratory airway resistances, and arterial blood gases were measured. In addition, dynamic pressure/volume loops were recorded. Hemodynamic monitoring included right atrial, mean pulmonary artery, pulmonary capillary wedge, and mean systemic arterial pressures and continuous flow recording at the pulmonary artery. The infusion of oleic acid combined with two to five lung lavage procedures induced a significant reduction in PaO2/FIO2from 485 ± 28 torr (64 ± 3.6 kPa) to 68 ± 3.2 torr (9.0 ± 0.4 kPa) (p< .01) and in static pulmonary compliance from 1.3 ± 0.06 to 0.67 ± 0.04 mL/cm H2O/kg (p< .01). During PLV, PaO2/FIO2increased significantly from 68 ± 3.2 torr (8.9 ± 0.4 kPa) to >200 torr (>26 kPa) (p< .01). The highest PaO2values were observed during PLV with PEEP of 15 cm H2O. Deadspace ventilation was lower during PLV when PEEP levels of 10 to 15 cm H2O were applied. There were no differences in hemodynamic data during PLV with PEEP levels up to 10 cm H2O. However, PEEP levels of 15 cm H2O resulted in a significant decrease in cardiac output. Dynamic pressure/volume loops showed early inspiratory pressure spikes during PLV with PEEP levels of 0 and 5 cm H2O.Conclusions:Partial liquid ventilation is a useful technique to improve oxygenation in severe acute lung injury. The application of PEEP during PLV further improves oxygenation and lung mechanics. PEEP levels of 10 cm H2O seem to be optimal to improve oxygenation and lung mechanics.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objectives:Ventilation with positive end-expiratory pressure (PEEP) above the inflection point (Pinf) has been shown to reduce lung injury by recruiting previously closed alveolar regions; however, it carries the risk of hyperinflating the lungs. The present study examined the hypothesis that a new strategy of recruiting the lung with a sustained inflation (SI), followed by ventilation with small tidal volumes, would allow the maintenance of low PEEP levels (<Pinf) without inducing additional lung injury.Design:Prospective, randomized, controlledex vivostudy.Setting:An animal laboratory in a university setting.Subjects:Isolated nonperfused lungs of adult Sprague-Dawley rats.Interventions:We studied the effect on compliance and lung injury in four groups (n = 10 per group) of lavaged rat lungs. One group (group 1) served as a control; their lungs were inflated at PEEP < Pinfbut not ventilated. The other three groups were ventilated with small tidal volumes (5 to 6 mL/kg) for 2 hrs with the following interventions: group 2, PEEP < Pinfwithout SI; group 3, PEEP < Pinfafter a SI to 30 cm H2O for 30 secs; and group 4, PEEP > Pinf.Measurements and Main Results:In groups 2 and 4, static compliance decreased after ventilation (p< .01). Histologically, group 2 (PEEP < Pinfwithout SI) showed significantly greater injury of small airways, but not of terminal respiratory units, compared with group 1. Group 3 (PEEP < Pinfafter a SI), but not group 4, showed significantly less injury of small airways and terminal respiratory units compared with group 2.Conclusions:We conclude that small tidal volume ventilation after a recruitment maneuver allows ventilation on the deflation limb of the pressure/volume curve of the lungs at a PEEP < Pinf. This strategy a) minimizes lung injury as well as, or better than, use of PEEP > Pinf, and b) ensures a lower PEEP, which may minimize the detrimental consequences of high lung volume ventilation.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objectives:To test the hypotheses that during small tidal volume ventilation (5 mL/kg) deliberate volume recruitment maneuvers allow expansion of atelectatic lung units and that a high positive end-expiratory pressure (PEEP) above the lower inflection point of the pressure/volume (PV) curve is not necessarily required to maintain recruited lung volume in acute lung injury.Design:Prospective, randomized, controlled animal study.Setting:An animal laboratory in a university setting.Subjects:Adult New-Zealand rabbits.Interventions:We studied a) the relationship of dynamic loops during intermittent positive pressure ventilation to the quasistatic PV curve, and b) the effect of lung recruitment on oxygenation, end-expiratory lung volume (EELV), and dynamic compliance in two groups (n = 4 per group) of lung-injured animals (lung lavage model): 1) the sustained inflation group, which received ventilation after a recruitment maneuver (sustained inflation); and 2) the control group, which received ventilation without any lung recruitment.Measurements and Main Results:In the presence of PV hysteresis, a single sustained inflation to 30 cm H2O boosted the ventilatory cycle onto the deflation limb of the PV curve. This resulted in a significant increase in EELV, oxygenation, and dynamic compliance despite equal PEEP levels used before and after the recruitment maneuver. Furthermore, after a single sustained inflation, oxygenation remained high over 4 hrs of ventilation when a PEEP above the critical closing pressure of the lungs, defined as "optimal" PEEP, was used and was significantly higher compared with that in the control group ventilated at equal PEEP without preceding lung recruitment.Conclusions:The observation that ventilation occurs on the deflation limb of the tidal cycle-specific PV curve allows placement of the ventilatory cycle, by means of a recruitment maneuver, onto the deflation limb of the PV envelope of the optimally recruited lung. This strategy ensures sufficient lung volume recruitment to maintain the lungs during the tidal cycle while using relatively low airway pressures.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:To evaluate the effects of inhaled nitric oxide (NO) on pulmonary circulation in a porcine endotoxin shock model.Design:Prospective, randomized trial.Setting:Laboratory at a large university medical center.Subjects:Twelve pathogen-free pigs weighing 15 to 31 kg.Interventions:After surgical preparation, all pigs received a 0.5 mg/kg endotoxin infusion over 30 mins. One hour after the start of endotoxin, NO inhalation (40 ppm) was initiated in six pigs, whereas the six remaining pigs served to control the progression of shock in this model. Consecutive changes in systemic and pulmonary hemodynamics, including characteristic resistance, vascular compliance, peripheral vascular resistance, and inductance, were continuously assessed during the experimental protocol using a four-element Windkessel model of the pulmonary circulation.Measurements and Main Results:Endotoxin insult resulted in a biphasic pulmonary artery pressure increase from 14 ± 2 to 32 ± 4 mm Hg. Inhaled NO reversed the resistance to blood flow in small pulmonary arteries from 596 ± 69 to 424 ± 36 dyne·sec/cm5. In contrast, the vascular capacitance of the entire pulmonary circuit, which decreased from 2.4 ± 0.2 to 0.8 ± 0.1 mL/mm Hg throughout endotoxin challenge, remained insensitive to NO administration.Conclusion:In endotoxin-induced pulmonary hypertension, inhaled NO may function as a modulator of distal pulmonary arterial tone but fails to act as a regulator of larger capacitance pulmonary vessels.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

Objective:To investigate whether gabexate mesilate, a synthetic protease inhibitor with anticoagulant properties, prevents hepatic damage by inhibiting leukocyte activation, we examined its effect on ischemia/reperfusion injury of rat liver in which activated leukocytes play a critical role.Design:Prospective, randomized, controlled study.Setting:Research laboratory at a university medical center.Subjects:Male Wistar rats weighing 220 to 280 g.Interventions:Hepatic damage was evaluated by changes in bile flow and serum transaminase concentrations after ischemia/reperfusion. Rats received continuous intravenous infusions of gabexate mesilate (10 mg/kg/hr) or intravenous administration of an inactive derivative of activated factor X (Xa), a selective inhibitor of thrombin generation (3 mg/kg), immediately before the induction of ischemia in the median and left lobes of the liver. To determine whether gabexate mesilate inhibits leukocyte activation, we examined the effects of gabexate mesilate on hepatic concentrations of tumor necrosis factor-α and rat interleukin-8 and on hepatic myeloperoxidase activity after ischemia/reperfusion.Measurements and Main Results:Hepatic dysfunction, observed after 60 mins of ischemia/reperfusion, showed a reduction in bile flow. The ischemia/reperfusion-induced decrease in bile flow was prevented by administration of gabexate mesilate. Serum transaminase concentrations increased after hepatic ischemia/reperfusion, peaking 12 hrs after reperfusion. Gabexate mesilate significantly inhibited the ischemia/reperfusion-induced increase in serum transaminase levels seen 12 hrs after reperfusion. Although an inactive derivative of factor Xa inhibited the increases in serum levels of fibrin and fibrinogen degradation products 6 hrs after reperfusion, it did not prevent ischemia/reperfusion-induced liver injury. Hepatic levels of tumor necrosis factor-α, rat interleukin-8, and myeloperoxidase were significantly increased after ischemia/reperfusion. These increases were significantly inhibited by gabexate mesilate but unaffected by an inactive derivative of factor Xa.Conclusion:Gabexate mesilate reduced ischemia/reperfusion-induced hepatic injury not by inhibiting coagulation, but by inhibiting leukocyte activation.

ISSN:0090-3493    

出版商:OVID    

年代:1999

数据来源: OVID