***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Objective To examine the effect of intratracheal heparin instillation on Legionella pneumophila-related acute lung injury ( ALI ) and systemic dissemination . Design Prospect i ve , controlled experimental study . Setting University research laboratory . Interventions A/J mice received 5 μg of sulfated heparin intratracheally co-instilled with 106 or 108 colony-forming units ( CFU ) of a virulent isolate of L. pneumophila . Measurements and results ALI was assessed in control groups ( PBS and PBS-heparin ) and on days 1 , 2 and 3 post-infection , in terms of the lung wet-to-dry ( W/D ) weight ratios and of lung endothelial permeability to radio-labeled albumin ( Perm-I125 ) . Lung bacterial loads were measured and systemic spread was assessed by blood and target organ culture . The alveolar inflammatory response was evaluated by measuring the cytokine levels ( TNF-α , IFN-γ , IL-6 and IL-12p70 ) in bronchoalveolar lavage fluids ( BALF ) . Co-instilled heparin  improved mouse survival after the 108 CFU challenge ( p < 0.01 ) . On day 2 , heparin co-instillation significantly reduced the W/D ratio and Perm-I125 ( p < 0.01 and p < 0.001 respectively ) , improved lung bacterial clearance ( p < 0.001 ) , prevented systemic dissemination ( blood , liver , spleen , kidneys and brain cultures , all p < 0.05 ) and significantly increased IFN-γ and IL-12p70 levels in BALF ( p < 0.05 ) . Conclusions Heparin co-instillation during intratracheal L. pneumophila challenge has a protective effect on the alveolar – capillary barrier and prevents bacterial dissemination . These results tend to confirm the competitive inhibition by heparin of L. pneumophila attachment to lung epithelium in vivo , and point to the possible involvement of a heparan-sulfate adhesin in L. pneumophila binding to pneumocytes RATIONALE Microvascular injury , inflammation , and coagulation play critical roles in the pathogenesis of acute lung injury ( ALI ) . Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days . OBJECTIVES To test the efficacy of activated protein C ( APC ) as a therapy for patients with ALI . METHODS Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI . Patients with severe sepsis and an APACHE II score of 25 or more were excluded . Participants were r and omized to receive APC ( 24 microg/kg/h for 96 h ) or placebo in a double-blind fashion within 72 hours of the onset of ALI . The primary endpoint was ventilator-free days . MEASUREMENTS AND MAIN RESULTS APC increased plasma protein C levels ( P = 0.002 ) and decreased pulmonary dead space fraction ( P = 0.02 ) . However , there was no statistically significant difference between patients receiving placebo ( n = 38 ) or APC ( n = 37 ) in the number of ventilator-free days ( median [ 25 - 75 % interquartile range ] : 19 [ 0 - 24 ] vs. 19 [ 14 - 22 ] , respectively ; P = 0.78 ) or in 60-day mortality ( 5/38 vs. 5/37 patients , respectively ; P = 1.0 ) . There were no differences in the number of bleeding events between the two groups . CONCLUSIONS APC did not improve outcomes from ALI . The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity Introduction Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition . Heparin may reduce pulmonary inflammation and fibrin deposition . We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation . Methods Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind r and omized placebo-controlled trial of nebulized heparin ( 25,000 U ) or placebo ( normal saline ) 4 or 6 hourly , depending on patient height . The study drug was continued while the patient remained ventilated to a maximum of 14 days from r and omization . Results Nebulized heparin was not associated with a significant improvement in the primary end-point , the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated , but was associated with improvement in the secondary end-point , ventilator-free days amongst survivors at day 28 ( 22.6 ± 4.0 versus 18.0 ± 7.1 , treatment difference 4.6 days , 95 % CI 0.9 to 8.3 , P = 0.02 ) . Heparin administration was not associated with any increase in adverse events . Conclusions Nebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation . Further trials are required to confirm these findings .Trial registration The Australian Clinical Trials Registry ( ACTR-12608000121369 ) Introduction We recently demonstrated that intravenously infused recombinant human activated protein C ( APC ) attenuates ovine lipopolysaccharide (LPS)-induced lung injury . In this study , our aim was to find out whether treatment with inhaled aerosolised APC ( inhAPC ) prevents formation of increased lung densities and oedema and derangement of oxygenation during exposure to LPS . Methods Sheep were anaesthetised during placement of intravascular introducers . After one to four days of recovery from instrumentation , the animals were re-anaesthetised , endotracheally intubated and mechanically ventilated throughout a six-hour experiment where the sheep underwent quantitative lung computed tomography . Sheep were r and omly assigned to one of three groups : a sham-operated group ( n = 8) receiving inhaled aerosolised saline from two hours after the start of the experiment ; a LPS group ( n = 8) receiving an intravenous infusion of LPS 20 ng/kg per hour and , after two hours , inhaled aerosolised saline over the next four hours ; a LPS+inhAPC group ( n = 8) receiving an intravenous infusion of LPS 20 ng/kg per hour and , after two hours , aerosolised APC 48 μg/kg per hour inhaled throughout the experiment . Data were analysed with analysis of variance ; P less than 0.05 was regarded as significant . Results An infusion of LPS was associated with a reduction of well-aerated lung volume and a rapid fall in arterial oxygenation that were both significantly antagonised by inhaled APC . Pulmonary vascular pressures and extravascular lung water index increased significantly during exposure to LPS , but inhaled APC had no effect on these changes . Conclusions Inhalation of aerosolised APC  attenuates LPS-induced lung injury in sheep by preventing a decline in the volume of aerated lung tissue and improving oxygenation OBJECTIVE This study evaluates the effects of heparin alone and in combination with lisofylline , 1-(5-R-hydroxyhexyl)3,7-dimethylxanthine , on severe smoke injury . DESIGN Prospect i ve animal study with concurrent controls . SETTING An animal laboratory . SUBJECTS Eighteen 1-yr-old female sheep , weighing 24 - 32 kg . INTERVENTIONS After smoke exposure and tracheostomy , animals were divided into three groups . Group S ( n = 6 ) received nebulized saline through an endotracheal tube every 4 hrs for 48 hrs . Group H ( n = 6 ) received 10,000 units of nebulized heparin every 4 hrs . Group LH ( n = 6 ) was treated with nebulized heparin and intravenous infusion of lisofylline ( 10 mg x kg(-1 ) x hr(-1 ) ) for 48 hrs after a bolus injection ( 20 mg/kg ) . Animals initially breathed room air spontaneously . If PaO2 was < 50 torr and PaCO2 > 60 torr , animals were mechanically ventilated . Sheep were killed 48 hrs postinjury . MEASUREMENTS AND MAIN RESULTS Blood gases were measured serially . At 48 hrs , ventilation perfusion distribution mismatching was analyzed by using the multiple inert gas elimination technique . Lung malondialdehyde was determined . The postinjury increase in alveolar-arterial oxygen tension gradient ( LH , 36.7 + /- 3.5 vs. S , 89.0 + /- 24.6 torr at 48 hrs ) was significantly attenuated in those animals receiving LH . The percentage of pulmonary shunt , Qs/Qt ( LH , 20.8 + /- 4.9 vs. S , 36.6 + /- 4.6 % ) , and the percentage of animals that required ventilation ( LH , 0 vs. S , 67 % ) were significantly reduced in LH . Multiple inert gas elimination technique study showed that the true shunt fraction was decreased in LH . Lung malondialdehyde was significantly less in LH ( LH , 0.33 + /- 0.06 vs. S , 0.56 + /- 0.09 nmol/mg protein ) . There was no significant difference in any of these variables between H and S. CONCLUSION Treatment with heparin alone did not attenuate pulmonary dysfunction after severe smoke injury . Combined treatment with nebulized heparin and systemic lisofylline had beneficial effects on pulmonary function in association with a decrease in blood flow to poorly ventilated areas and less lipid peroxidation BACKGROUND In November 2001 , the Food and Drug Administration ( FDA ) approved drotrecogin alfa ( activated ) ( DrotAA ) for adults who had severe sepsis and a high risk of death . The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death . METHODS We r and omly assigned adult patients with severe sepsis and a low risk of death ( defined by an Acute Physiology and Chronic Health Evaluation [ APACHE II ] score < 25 or single-organ failure ) to receive an intravenous infusion of placebo or DrotAA ( 24 microg per kilogram of body weight per hour ) for 96 hours in a double-blind , placebo-controlled , multicenter trial . The prospect ively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion . In-hospital mortality within 90 days after the start of the infusion was measured , and safety information was collected . RESULTS Enrollment in the trial was terminated early because of a low likelihood of meeting the prospect ively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA .  The study enrolled 2640 patients and collected data on 2613 ( 1297 in the placebo group and 1316 in the DrotAA group ) at the 28-day follow-up . There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality ( 17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group ; P=0.34 ; relative risk , 1.08 ; 95 percent confidence interval , 0.92 to 1.28 ) or in in-hospital mortality ( 20.5 percent vs. 20.6 percent ; P=0.98 ; relative risk , 1.00 ; 95 percent confidence interval , 0.86 to 1.16 ) . The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion ( 2.4 percent vs. 1.2 percent , P=0.02 ) and the 28-day study period ( 3.9 percent vs. 2.2 percent , P=0.01 ) . CONCLUSIONS The absence of a beneficial treatment effect , coupled with an increased incidence of serious bleeding complications , indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death , such as those with single-organ failure or an APACHE II score less than 25 Introduction Animal studies of acute lung injury ( ALI ) suggest nebulised heparin may limit damage from fibrin deposition in the alveolar space and microcirculation . No human studies have been undertaken to date . We assessed the feasibility , safety and potential anticoagulant effects of administration of nebulised heparin to patients with ALI . Methods An open label phase 1 trial of four escalating doses of nebulised heparin was performed . A total of 16 ventilated patients with ALI were studied . The first group was administered a total of 50,000 U/day , the second group 100,000 U/day , the third group 200,000 U/day and the fourth group 400,000 U/day . Assessment s of lung function included the PaO2/FiO2 ratio , lung compliance and the alveolar dead space fraction . Monitoring of anticoagulation included the activated partial thromboplastin time ( APTT ) and the thrombin clotting time . Broncho 
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Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation .
Notably , nebulized danaparoid and heparin but not activated protein C and antithrombin , were found to have an effect on systemic coagulation .
Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI .
In a trial of critically ill patients who needed mechanical ventilation for longer than two days , nebulized heparin was associated with a higher number of ventilator-free days .
In line with results from pre clinical studies , nebulization of heparin was found to have an effect on systemic coagulation , but without causing systemic bleedings .
Conclusion Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in pre clinical studies of lung injury .