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Objectives To determine the impact of positive end-expiratory pressure during mechanical ventilation with and without spontaneous breathing activity on regional lung inflammation in experimental nonsevere acute respiratory distress syndrome. Design Laboratory investigation. Setting University hospital research facility. Subjects Twenty-four pigs (28.1-58.2 kg). Interventions In anesthetized animals, intrapleural pressure sensors were placed thoracoscopically in ventral, dorsal, and caudal regions of the left hemithorax. Lung injury was induced with saline lung lavage followed by injurious ventilation in supine position. During airway pressure release ventilation with low tidal volumes, positive end-expiratory pressure was set 4 cm H2O above the level to reach a positive transpulmonary pressure in caudal regions at end-expiration (best-positive end-expiratory pressure). Animals were randomly assigned to one of four groups (n = 6/group; 12 hr): 1) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure - 4 cm H2O, 2) no spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure + 4 cm H2O, 3) spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure + 4 cm H2O, 4) spontaneous breathing activity and positive end-expiratory pressure = best-positive end-expiratory pressure - 4 cm H2O. Measurements and main results Global lung inflammation assessed by specific [F]fluorodeoxyglucose uptake rate (median [25-75% percentiles], min) was decreased with higher compared with lower positive end-expiratory pressure both without spontaneous breathing activity (0.029 [0.027-0.030] vs 0.044 [0.041-0.065]; p = 0.004) and with spontaneous breathing activity (0.032 [0.028-0.043] vs 0.057 [0.042-0.075]; p = 0.016). Spontaneous breathing activity did not increase global lung inflammation. Lung inflammation in dorsal regions correlated with transpulmonary driving pressure from spontaneous breathing at lower (r = 0.850; p = 0.032) but not higher positive end-expiratory pressure (r = 0.018; p = 0.972). Higher positive end-expiratory pressure resulted in a more homogeneous distribution of aeration and regional transpulmonary pressures at end-expiration along the ventral-dorsal gradient, as well as a shift of the perfusion center toward dependent zones in the presence of spontaneous breathing activity. Conclusions In experimental mild-to-moderate acute respiratory distress syndrome, positive end-expiratory pressure levels that stabilize dependent lung regions reduce global lung inflammation during mechanical ventilation, independent from spontaneous breathing activity.

To assess the effects of different levels of spontaneous breathing during biphasic positive airway pressure/airway pressure release ventilation on lung function and injury in an experimental model of moderate acute respiratory distress syndrome.Multiple-arm randomized experimental study.University hospital research facility.Thirty-six juvenile pigs.Pigs were anesthetized, intubated, and mechanically ventilated. Moderate acute respiratory distress syndrome was induced by repetitive saline lung lavage. Biphasic positive airway pressure/airway pressure release ventilation was conducted using the airway pressure release ventilation mode with an inspiratory/expiratory ratio of 1:1. Animals were randomly assigned to one of four levels of spontaneous breath in total minute ventilation (n = 9 per group, 6 hr each): 1) biphasic positive airway pressure/airway pressure release ventilation, 0%; 2) biphasic positive airway pressure/airway pressure release ventilation,0-30%; 3) biphasic positive airway pressure/airway pressure release ventilation,30-60%, and 4) biphasic positive airway pressure/airway pressure release ventilation,60%.The inspiratory effort measured by the esophageal pressure time product increased proportionally to the amount of spontaneous breath and was accompanied by improvements in oxygenation and respiratory system elastance. Compared with biphasic positive airway pressure/airway pressure release ventilation of 0%, biphasic positive airway pressure/airway pressure release ventilation more than 60% resulted in lowest venous admixture, as well as peak and mean airway and transpulmonary pressures, redistributed ventilation to dependent lung regions, reduced the cumulative diffuse alveolar damage score across lungs (median [interquartile range], 11 [3-40] vs 18 [2-69]; p0.05), and decreased the level of tumor necrosis factor-α in ventral lung tissue (median [interquartile range], 17.7 pg/mg [8.4-19.8] vs 34.5 pg/mg [29.9-42.7]; p0.05). Biphasic positive airway pressure/airway pressure release ventilation more than 0-30% and more than 30-60% showed a less consistent pattern of improvement in lung function, inflammation, and damage compared with biphasic positive airway pressure/airway pressure release ventilation more than 60%.In this model of moderate acute respiratory distress syndrome in pigs, biphasic positive airway pressure/airway pressure release ventilation with levels of spontaneous breath higher than usually seen in clinical practice, that is, more than 30% of total minute ventilation, reduced lung injury with improved respiratory function, as compared with protective controlled mechanical ventilation.

Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure-related outcome.Prospective, open label, multiple-center trial.A total of 661 patients from 82 German hospitals receiving total parenteral nutrition foror =3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses. The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome.The patients enrolled in this survey were (mean +/- sd) 62.8 +/- 16.5 yrs old, with a body mass index of 25.1 +/- 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 +/- 13.6. Length of hospital stay was 29.1 +/- 18.7 days (12.5 +/- 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11 g.kg(-1).day(-1)), was administered for 8.7 +/- 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4-20.4%) to 12.0% (p.001). The fish oil dose.kg.day did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality). Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 g.kg(-1).day(-1). Lower antibiotic demand by 26% was observed when doses of 0.15-0.2 g.kg(-1).day(-1) were infused as compared with doses of0.05 g.kg(-1).day(-1). After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 g.kg(-1).day(-1) and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery.Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in different diseases. Effects and effect sizes related to fish oil doses are diagnosis dependent. In view of the lack of substantial study literature concerning diagnosis-related nutritional single-substrate intervention in the critically ill, the present data can be used in formulating hypotheses and may serve as reference doses for randomized, controlled studies, which may, for instance, confirm the value of omega-3 fatty acid in the adjunctive therapy of peritonitis and abdominal sepsis.

OBJECTIVE During systemic inflammation, elevated levels of endothelin (ET)-1 have been reported. The aim of this study was to investigate the effects of ET-1 on neutrophil (PMN) respiratory burst, phagocytosis, and elimination of Escherichia coli from blood and tissues. DESIGN Prospective, randomized, controlled trial. SETTING Experimental laboratory in a university hospital. SUBJECTS A total of 18 female chinchilla rabbits. INTERVENTIONS To quantify the clearance process, defined numbers (10(8) colony-forming units) of E. coli were injected intravenously into anesthetized rabbits, 60 mins after onset of continuous 0.2 microg/kg/min ET-1 administration (n = 9) and after saline infusion (control group, n = 9), respectively. To evaluate potential effects of ET-1 on bacterial elimination and killing, blood clearance of E. coli and colonization of different organs were investigated. MEASUREMENTS Variables monitored were neutrophil respiratory burst and phagocytosis activity, rates of bacterial elimination from the blood, arterial blood pressure, blood gases, serum lactate concentrations, and nitrite and nitrate levels. The animals were killed 3 hrs after bacterial injection and tissue samples of liver, kidney, spleen, and lung were collected for bacterial counts. MAIN RESULTS Compared with the control group, ET-1 significantly impaired PMN respiratory burst (p < .05) and prolonged elimination of injected E. coli from the blood (p < .01), whereas phagocytosis functions remained unaltered. The reduced PMN burst activity after ET-1 was associated with a higher bacterial colonization of all organs (lung, p < .01; spleen, p < .05). Endothelin-1 induced increases in mean arterial pressure (p < .01) and serum lactate concentrations, whereas nitrite and nitrate levels remained unaltered. CONCLUSION Endothelin-1 impairs respiratory burst and bacterial clearance from the blood and tissue. Thus, elevated levels of ET-1 during sepsis could induce organ hypoperfusion and cause disturbances in immune functions, increasing the risk of bacterial infections.

To investigate the effects of proportional assist ventilation, variable pressure support, and conventional pressure support ventilation on lung function and damage in experimental acute lung injury.: Randomized experimental study.University hospital research facility.: Twenty-four juvenile pigs.Pigs were anesthetized, intubated, and mechanically ventilated. Acute lung injury was induced by saline lung lavage. After resuming of spontaneous breathing, animals were randomly assigned to 6 hrs of assisted ventilation with pressure support ventilation, proportional assist ventilation, or variable pressure support (n = 8 per group). Mean tidal volume was kept at ≈6 mL/kg in all modes.Lung functional parameters, distribution of ventilation by electrical impedance tomography, and breathing patterns were analyzed. Histological lung damage and pulmonary inflammatory response were determined postmortem. Variable -pressure support and proportional assist ventilation improved oxygenation and venous admixture compared with pressure support ventilation. Proportional assist ventilation led to higher esophageal pressure time product than variable pressure support and pressure support ventilation, and redistributed ventilation from central to dorsal lung regions compared to pressure support ventilation. Variable pressure support and proportional assist ventilation yielded higher tidal volume variability than pressure support ventilation. Such pattern was deterministic (self-organized) during proportional assist ventilation and stochastic (random) during variable pressure support. Subject-ventilator synchrony as well as pulmonary inflammatory response and damage did not differ among groups.In a lung lavage model of acute lung injury, both variable pressure support and proportional assist ventilation increased the variability of tidal volume and improved oxygenation and venous admixture, without influencing subject-ventilator synchrony or affecting lung injury compared with pressure support ventilation. However, variable pressure support yielded less inspiratory effort than proportional assist ventilation at comparable mean tidal volumes of 6 mL/kg.

Objective: The study was designed to investigate the effects of acetylcholine (ACh) on pulmonary circulation with special regard to mediators that could be involved in the mediation of ACh-induced effects. ACh has been reported to induce either vasodilation or vasoconstriction in the pulmonary circulation of different species. Design: Prospective experimental study in rabbits. Setting: Experimental laboratory in a university teaching hospital. Subjects: Sixty-six adult rabbits of either sex. Interventions: The experiments were performed on 66 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. ACh was injected in various concentrations after pulmonary artery preconstriction and in untreated lungs. Measurements and Main Results: Pulmonary arterial pressure (PAP) and lung weight gain were monitored continuously. Perfusate samples were taken intermittently to determine endothelin-1 (ET-1), thromboxane A 2 (TXA 2 ), and prostacyclin (PGI 2 ) concentrations. ACh in final dosages from 10 -5 to 10 -2 M (n = 6 each) was injected into the pulmonary artery of lungs treated with U46619 to induce pulmonary arterial hypertension or was injected into untreated lungs. To analyze the potential mechanisms of action, ACh (10 -5 M) was administered in additional experiments after pretreatment with either ET A receptor antagonist BQ123 (10 -6 M; n = 6) or the cyclooxygenase inhibitor diclofenac (10 μg/mL; n = 6). In preconstricted pulmonary vessels, ACh (10 -3 and 10 -2 M) initially induced a PAP rise for 10 mins followed by a sustained decrease. In untreated lungs, ACh induced an immediate dose-dependent increase in PAP, requiring as long as 30 mins to return to predrug levels. Simultaneously, significantly elevated TXA 2 and PGI 2 levels were observed. Furthermore, ET-1 was detected in the perfusate, which was free from ET-1 before ACh administration. Pretreatment with BQ123 reduced substantially the ACh (10 -5 M)-induced PAP increase and the release of TXA 2 and PGI 2 . At 5 mins, the PAP maximum was reduced from 18.5 ± 3.2 mm Hg to 9.9 ± 0.65 mm Hg by BQ123 pretreatment (p

Objectives: Elevated endothelin-1 (ET-1) levels have been detected during sepsis. The aim of the study was to examine the role of thromboxane A 2 (TXA 2 ) and ET-1 in pulmonary vascular reactions after endotoxin (LPS) challenge. Design: Prospective experimental study in rabbits. Setting: Experimental laboratory in a university teaching hospital. Subjects: Twenty-four adult rabbits of either sex. Interventions: Experiments were performed on 30 isolated and ventilated rabbit lungs, which were perfused with a saline solution containing 10% autologous blood. Measurements and Main Results: Pulmonary arterial pressure and lung weight gain were continuously registered. Perfusate samples were drawn intermittently to determine ET-1, TXA 2 , and prostacyclin (PGI 2 ) concentrations. LPS isolated from Escherichia coli (0.5 mg/mL; n = 6) was added to the perfusate. A marked pulmonary arterial pressure increase followed by massive edema formation after 60 mins was observed after LPS injection. At the same time, elevated TXA 2 and PGI 2 levels in the perfusate were measured. ET-1 was detected 30 mins after LPS infusion (13.4 ± 2.6 fmol/L). Pretreatment with the ET A receptor antagonist LU135252 (10-6 M; n = 6) almost completely suppressed the pressure reaction after endotoxin injection (p

Objective: The aim of this study was to investigate whether the methylxanthine-derivative pentoxifylline (PTX) affects bacterial clearance of the organism in states of hemorrhage and endotoxemia. Design: Prospective, randomized, controlled trial. Setting: Experlmental laboratory in a university hospital. Subjects: Fifty-four female chinchilla rabbits. Interventions: To quantify the clearance process, defined numbers (10 7 CFO) of Escherichia coli bacteria were Injected intravenously Into anesthetized rabbits, 60 mins after induction of hemorrhage (n = 9 + 3) or infusion of endotoxin (lipopolysaccharide [LPS]; 40 μg/kg/hr; n = 9 + 3) and after saline infusion (control; n = 9), respectively. Hemorrhage was induced by bleeding, standardized by defined reduction of mean arterial pressure (30% of baseline value). To evaluate the potential effects of PTX on bacterial elimination and killing, in states of hemorrhage and endotoxemia, blood clearance of E. coll and colonization of different organs were investigated after pretreatment with PTX (30 mg/kg) as a bolus injection followed by continuous infusion of PTX (50 mg/kg/hr) in hemorrhagic (n = 9) and endotoxemic rabbits (n = 9). Three additional experiments were performed to evaluate the effects attributable to PTX itself. Measurements and Main Results: Parameters monitored were rates of bacterial and LPS elimination from the blood, arterial blood pressure, blood gases, and serum lactate concentrations. Additionally, flow cytometric analysis of respiratory burst activity was performed. Three hours after bacterial injection, the animals were killed, and tissue samples of liver, kidney, spleen, and lung were collected for bacteriologic examinations. Compared with the controls, hemorrhage and endotoxemia resulted in a significantly prolonged elimination of injected E. coli from the blood. The delayed blood clearance was associated with a significantly (p

Objective: To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature. Design: Prospective experimental study in rabbits. Setting: Experimental laboratory in a university teaching hospital. Subjects: Thirty adult rabbits. Interventions: The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution. Measurements and Main Results: The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A 2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylaianine (FMLP; 10 -6 M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10 -6 M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A 2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 μg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A 2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p