Early Acute Lung Injury Research Articles

Nebulised heparin: a new approach to the treatment of acute lung injury?

The administration of heparin by nebulisation has been proposed for the 'local' treatment of pulmonary coagulation disturbances in acute lung injury (ALI). Alveolar and lung micro-vascular fibrin accumulation and breakdown inhibition indeed play a central role in the development and clinical course of this disease. Preclinical studies provide some evidence of the beneficial effects of heparin inhalation in several animal models of ALI. Clinical investigations are sparse, and trials such as the one presented by Dixon and colleagues in a recent issue of Critical Care are welcome as they provide insight into the possible clinical use of nebulised heparin in this situation. This phase 1 trial involved 16 patients with early ALI, and showed the feasibility of the approach. In addition, non-significant changes in respiratory functions and systemic anticoagulant effects were documented with the four doses tested. The study of Dixon and colleagues adds to data that helps pave the way towards a possible clinical use of heparin by nebulisation in ALI. It remains to be clarified in which clinical situations, at what time points and with which dosages the best chances exist for a beneficial effect on the prognosis of these patients.

Assessment of Early Acute Lung Injury in Rats Exposed to Aerosols of Consumer Products: Attempt to Disentangle the “Magic Nano” Conundrum

In Germany in 2006 a series of rapidly developing and sometimes severe cases of pulmonary health impairment were observed after normal use of the “Magic Nano Glass & Ceramic” spray and “Magic Nano Bath” spray. In contrast, the previously marketed “Magic Nano” pump spray product (handheld trigger device without propellants) was unobtrusive. Analysis of particles discharged from these products did not reveal stable (solid) nano-sized particles. The precipitous increase of pulmonary health impairment in humans caused by “Magic Nano Sprays” triggered a comparative assessment of the acute inhalation toxicity of “Magic Nano Glass & Ceramic” spray, “Magic Nano Bath” spray, and “Magic Nano” pump spray in rats. The first two test specimens were examined as spray-can aerosols using an intermittent generation principle, whereas the undiluted liquid content of the pump spray was continuously aerosolized. Groups of Wistar rats were nose-only exposed for 4 h. However, due to mortality occurring already during exposure following exposure to Glass & Ceramic spray, the exposure duration was reduced to ∼ 2 h in some groups. In addition to endpoints called for by contemporary testing guidelines, respiratory tract injury was also probed by respiratory function measurements during exposure supplemented by analyses in bronchoalveolar lavage (BAL) fluid on the first postexposure day, including lung histopathology in rats exposed to Glass & Ceramic spray. The Glass & Ceramic spray caused mortality at 2269 mg/m3 and above, the pump spray was in the beginning lethal range at 81222 mg/m3, while the bath spray was tolerated without mortality up to the maximum tested nominal concentrations of 28100 mg/m3. The time-adjusted 4-h LC50 of Glass & Ceramic spray was 5098 mg/m3. The analysis of respiratory patterns revealed changes indicative of both upper and lower respiratory tract sensory irritation. In addition to clinical signs suggestive of marked lung irritation, especially in the rats exposed to the Glass & Ceramic spray, histopathology revealed lung inflammation, hemorrhages, edema, and focal septal thickening. Lung weights and BAL endpoints (lactate dehydrogenase [LDH], protein, γ -glutamyltransaminase, and neutrophilic granulocytes) were markedly increased. In summary, this comparative study demonstrates that the conventional OECD 403 protocol is suitable to comparatively assess the potential and potency of these types of consumer products in their end-use configuration. Measurements in BAL were most suitable for the identification of acute lung injury. By contrast, lung function measurements during exposure did not demonstrate any conclusive association with lung injury. It does not appear that the particle size per se is a key determinant in the toxicity of “Magic Nano Glass & Ceramic” spray (approximately 100% mortality occurred at a MMAD of ∼ 7 μ m; GSD ≈ 3). This might suggest that more volatile substances or substances contained in the test articles that co-evaporate with solvents or water may be causative for the findings observed. Hence, the findings of this study support the notion that the assessment of the acute inhalation toxicity of complex end-use products is methodologically challenging and cannot be readily anticipated based on compositional or physical (particle size) data. Accordingly, in the absence of predictive and validated in vitro assays, in vivo inhalation testing of potentially toxic commercialized spray products appears to be indispensable for consumer safety. In order to prevent indiscriminant testing of such products in bioassays, the development of standardized in vitro alternatives should be considered with high priority.

Pulmonary Dead Space Fraction and Pulmonary Artery Systolic Pressure as Early Predictors of Clinical Outcome in Acute Lung Injury

The primary objective of this study was to test whether an elevated systolic pulmonary artery (PA) pressure or an elevated pulmonary dead space fraction (Vd/Vt) in early acute lung injury (ALI) is associated with poor clinical outcomes in the era of lung-protective ventilation. Prospective observational cohort study. ICUs of a university hospital. Forty-two patients with ALI receiving mechanical ventilation. PA pressure was measured noninvasively using transthoracic echocardiography. Vd/Vt was measured by volumetric capnography (NICO Cardiopulmonary Management System; Novametrix; Wallingford, CT). There was no difference in the mean systolic PA pressure in patients who died compared to those who survived (43 +/- 9 mm Hg vs 41 +/- 9 mm Hg, p = 0.54) [mean +/- SD]. In contrast to the PA systolic pressure, Vd/Vt was significantly higher in patients who died compared to those who survived (0.61 +/- 0.09 vs 0.53 +/- 0.10, p = 0.02). Similarly, Vd/Vt was higher in patients with < 7 ventilator-free days during the first 28 days after enrollment compared to those with > 7 ventilator-free days (0.61 +/- 0.08 vs 0.52 +/- 0.11, p = 0.008). In the era of lung-protective ventilation, systolic PA pressure early in the course of ALI is elevated but not predictive of outcome. However, elevated Vd/Vt in early ALI is associated with increased mortality and with fewer ventilator-free days.

Effects of recruitment maneuver in combination with lung protective ventilation strategy on gas exchange in early acute lung injury after liver transplantation

目的 探讨肺复张结合肺保护通气策略对肝移植术后ALI或ARDS早期换气功能、血流动力学的影响.方法 肝移植术后合并ALI者18例,其中6例发展为ARDS,给予25 cm H2O气道压力及PEEP 17 cmH2O通气2 min,扩张已萎陷实变的肺泡,并用适当的PEEP预防肺泡闭塞,保持肺泡复张.结果 18例病人肺复张后氧分压、氧饱和度及吸氧分数均有明显改善,除1例肺部严重感染病人肺复张后吸氧分数仅上升40%,余17例均对肺复张反应良好.复张后平均氧分压上升68 mm Hg,平均氧饱和度上升9.5%,平均吸氧分数上升104.66%,改善的氧合可维持2～24 h.肺复张结合肺保护通气策略纠正低氧血症的有效率为94.4%.病人对肺复张的耐受性佳,无明显并发症.结论 肺复张结合肺保护通气策略是治疗肝移植术后ALI或ARDS的安全有效措施。

The treatment strategy of early ALI after liver transplantation

To investigate the treatment strategy of early acute lung injury (ALI) after liver transplantation. 18 patients complicated with ALI after liver transplantation were given comprehensive therapies and two minutes of recruitment maneuver (RM) to open previously collapsed lung units and then lung protective ventilatory strategy within 3 hours of hypoxemia. The inspiratory pressure was 25 cm H2O and PEEP 17 cm H2O. Optimal PEEP were maintained after RM to stabilize lung volume. The PaO(2), SaO(2) and PaO(2)/FiO(2) of all 18 patients were improved greatly. RM was effective in 17 patients except one case of severe pulmonary infection, whose PaO(2)/FiO(2) was only improved by 40%. PaO(2), SaO(2) and PaO(2)/FiO(2) were increased by 68 mm Hg, 9.5%, and 104.7% respectively. And the improved oxygenation can be maintained 2 - 24 hours. The effective rate of RM was 94.4%. All 18 patients were weaned and extubated successfully with the survival rate of 100%. RM was well tolerated without complications. ALI post liver transplantation should be diagnosed and treated in early stage. RM combined with lung protective ventilatory strategy is a safe and effective treatment for early ALI after liver transplantation.

Dexamethasone treatment attenuates early seawater instillation-induced acute lung injury in rabbits

There is very little evidence on the value of giving corticoids in cases of seawater drowning induced acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate whether dexamethasone treatment can attenuate seawater instillation-induced acute lung injury in rabbits. Seawater (4 ml/kg body weight) was instilled into the lower trachea of ventilated, anesthetized rabbits. Then these rabbits were assigned randomly 20 min later to receive intravenous injection of 1 mg/kg body weight of dexamethasone (dissolving in 2 ml of normal saline) or 2 ml of normal saline. All animals demonstrated immediate drops in arterial oxygen tension (PaO 2) and the total thoracic compliance, which were significantly improved after 2 h of dexamethasone treatment. Histopathological study also indicated that dexamethasone treatment markedly attenuated lung histopathological changes, alveolar hemorrhage and inflammatory cells infiltration with evidence of decreasing of myeloperoxidase (MPO) activity and tumor necrosis factor-α (TNF-α) concentration in lung tissue. In addition, dexamethasone treatment reduced extravascular lung water and lung epithelial–endothelial barrier permeability, up-regulated the expression of surfactant protein-A (SP-A) and α-epithelial Na + channel, and increased Na +/K +-adenosine triphosphatase (Na +/K +-ATPase) activity and Na +/K +-ATPase-α1 protein abundance. Thus, these data indicate that dexamethasone treatment might be of benefit in patients with seawater aspiration-induced ALI.

Assisted spontaneous breathing during early acute lung injury

In the early phase of their disease process, patients with acute lung injury are often ventilated with strategies that control the tidal volume or airway pressure, while modes employing spontaneous breathing are applied later to wean the patient from the ventilator. Spontaneous breathing modes may integrate intrinsic feedback mechanisms that should help prevent ventilator-induced lung injury, and should improve synchrony between the ventilator and the patient's demand. Airway pressure release ventilation with spontaneous breathing was shown to decrease cyclic collapse/recruitment of dependent, juxtadiaphragmatic lung areas compared with airway pressure release ventilation without spontaneous breathing. Combined with previous data demonstrating improved cardiorespiratory variables, airway pressure release ventilation with spontaneous breathing may turn out to be a less injurious ventilatory strategy.

β-Catenin in the Fibroproliferative Response to Acute Lung Injury

Resolution of alveolar epithelial/capillary membrane damage after acute lung injury requires coordinated and effective tissue repair to reestablish a functional alveolar epithelial/capillary membrane barrier. We hypothesized that signaling pathways important in lung alveolar bud ontogeny are activated in the recovery and remodeling phases after profound oxidant stress lung injury in a murine model. To test this, we characterized the expression of noncanonical beta-catenin pathway proteins E-cadherin, integrin-linked kinase-1, and beta-catenin in mice undergoing normoxic recovery after exposure to butylated hydroxytoluene (BHT, ionol) and concomitant sublethal (75% O2) hyperoxia. Mice developed early acute lung injury with subsequent inflammation, collagen deposition, interstitial cellular proliferation, and lung architectural distortion. Reduced E-cadherin expression after 6 d of BHT and hyperoxia was accompanied by enhanced expression and nuclear localization of beta-catenin and increased integrin-linked kinase-1 expression during subsequent normoxic recovery. This resulted in increased expression of the cotranscriptional regulators TCF-1 and -3 and cyclin D1. Proliferation of murine lung epithelial-12 cells in vitro after 8 h of treatment with BHT quinone-methide and hyperoxia and 48 h of normoxic recovery was enhanced 2.7-fold compared with vehicle-treated control mice at the same time point. BHT/hyperoxia-exposed mice treated with the pan-caspase inhibitor z-ASP had increased acute lung injury and reduced survival despite the presence of TUNEL-positive cells, suggesting enhanced lung cell necrosis. Beta-catenin expression was reduced in z-ASP-co-treated lungs after BHT/hyperoxia. The noncanonical cadherin-beta-catenin axis is associated with fibroproliferative repair after BHT/hyperoxia exposure and may regulate epithelial proliferation and lung matrix remodeling and repair in response to lung injury.

Inspiratory vs. expiratory pressure-volume curves to set end-expiratory pressure in acute lung injury

To study the effects of two levels of positive end-expiratory pressure (PEEP), 2 cm H(2)O above the lower inflection point of the inspiratory limb and equal to the point of maximum curvature on the expiratory limb of the pressure-volume curve, in gas exchange, respiratory mechanics, and lung aeration. Prospective clinical study in the intensive care unit and computed tomography ward of a university hospital. Eight patients with early acute lung injury. Both limbs of the static pressure-volume curve were traced and inflection points calculated using a sigmoid model. During ventilation with a tidal volume of 6 ml/kg we sequentially applied a PEEP 2 cm H(2)O above the inspiratory lower inflection point (15.5+/-3.1 cm H(2)O) and a PEEP equal to the expiratory point of maximum curvature (23.5+/-4.1 cmH(2)O). Arterial blood gases, respiratory system compliance and resistance and changes in lung aeration (measured on three computed tomography slices during end-expiratory and end-inspiratory pauses) were measured at each PEEP level. PEEP according to the expiratory point of maximum curvature was related to an improvement in oxygenation, increase in normally aerated, decrease in nonaerated lung volumes, and greater alveolar stability. There was also an increase in PaCO(2), airway pressures, and hyperaerated lung volume. High PEEP levels according to the point of maximum curvature of the deflation limb of the pressure-volume curve have both benefits and drawbacks.

Increased Circulating Endothelial Progenitor Cells Are Associated with Survival in Acute Lung Injury

Repair of damaged endothelium is important in recovery from acute lung injury. In animal models, bone marrow-derived endothelial progenitor cells differentiate into mature endothelium and assist in repairing damaged vasculature. The quantity of endothelial progenitor cells in patients with acute lung injury is unknown. We hypothesize that increased numbers of circulating endothelial progenitor cells will be associated with an improved outcome in acute lung injury and the acute respiratory distress syndrome. Peripheral blood mononuclear cells from the buffy coat of patients with early acute lung injury (n=45), intubated control subjects (n=10), and healthy volunteers (n=7) were isolated using Ficoll density gradient centrifugation, and plated on fibronectin-coated cellware. After 24 hours, nonadherent cells were removed and replated on fibronectin-coated cellware at a concentration of 1x10(6) cells/well. Colony-forming units were counted after 7 days' incubation. Endothelial progenitor cell colony numbers were significantly higher in patients with acute lung injury compared with healthy control subjects (p<0.05), but did not differ between patients with acute lung injury and intubated control subjects. However, in the 45 patients with acute lung injury, improved survival correlated with a higher colony count (p<0.04). Patients with acute lung injury with a colony count of >or= 35 had a mortality of 30%, compared with 61% in those with colony counts <35 (p<0.03), results that persisted in a multivariable analysis correcting for age, sex, and severity of illness. An increased number of circulating endothelial progenitor cells in acute lung injury is associated with improved survival.

Interleukin-1 (IL-1) is prominent in early acute lung injury caused by hepatic cryoablation

Interleukin-1 (IL-1) is prominent in early acute lung injury caused by hepatic cryoablation

Selective inducible nitric oxide synthase (iNOS) inhibition attenuates remote acute lung injury in a model of ruptured abdominal aortic aneurysm 1

Objective Abdominal aortic aneurysm rupture is associated with a systemic inflammatory response syndrome and acute lung injury. Using a selective inducible nitric oxide synthase (iNOS) inhibitor, N 6-(iminoethyl)-lysine (L-NIL), we explored the role of iNOS in the early pro-inflammatory signaling and acute lung injury in experimental abdominal aortic aneurysm rupture. Materials and methods Anesthetized rats were randomized to sham control or shock and clamp (s + c) groups, which underwent one hour of hemorrhagic shock, followed by 45 minutes of supramesenteric aortic clamping, and then two hours resuscitated reperfusion. Animals in s + c were randomized to receive intravenous L-NIL at 50 μg/kg/h or saline at the start of reperfusion. Pulmonary permeability to 125I-labeled albumin, myeloperoxidase (MPO) activity, cytokine levels, and semi-quantitative RT-PCR for mRNA were indicators of microvascular permeability, leuco-sequestration, and pro-inflammatory signaling, respectively. Results Lung permeability index were significantly increased in s + c compared to sham (4.43 ± 0.96 versus 1.30 ± 0.17, P < 0.01), and attenuated by L-NIL treatment (2.14 ± 0.70, P < 0.05). Lung tissue MPO activity was significantly increased in s + c compared to sham (2.80 ± 0.32 versus 1.03 ± 0.29, P < 0.002), and attenuated by L-NIL treatment (1.50 ± 0.20, P < 0.007). Lung tissue iNOS activity was significantly increased in s + c compared to sham animals ( P < 0.05), and attenuated by L-NIL treatment ( P < 0.05). Lung tissue iNOS mRNA was upregulated 8-fold in s + c compared to sham ( P < 0.05). Data represents mean ± standard error mean, comparisons with ANOVA. Conclusions These data suggest that in our model of ruptured abdominal aortic aneurysm iNOS plays a crucial role in reperfusion lung injury. Selective inhibition of iNOS during early reperfusion prevents neutrophil mediated acute lung injury.

Pulmonary net release of tissue-type plasminogen activator during porcine primary and secondary acute lung injury.

Tissue-type plasminogen activator (tPA) is a key mediator of fibrinolysis. Matching of pulmonary perfusion and ventilation is a critical denominator of oxygenation in acute lung injury (ALI). This study investigates pulmonary venoarterial plasma tPA gradients in association with acute ALI induced by bronchoalveolar lavage (BAL) and endotoxinemia (ETX). Twenty-one anaesthetized, ventilated pigs were allocated to control (CTRL, n=5), bronchoalveolar saline lavage (BAL, n=8) or infusion of Escherichia coli endotoxin (ETX, n=8). Total tPA was analyzed in plasma (ELISA calibrated for porcine tPA). The inflammatory response was assessed by TNFa levels (ELISA). All variables were assessed at baseline and 2 h following ALI. Bronchoalveolar lavage and ETX induced similar increases in pulmonary shunt whereas pulmonary vascular resistance was significantly more increased in ETX animals. Cardiac output remained stable in BAL animals but decreased in ETX animals. The pulmonary venoarterial tPA plasma gradient increased in ETX animals, yielding a positive pulmonary net flux of tPA, which was absent in BAL animals. TNFalpha levels increased in ETX, but not in BAL, animals. A significant correlation was observed between TNFalpha and tPA plasma levels in ETX animals. All variables remained unchanged in CTRL animals. Plasma changes of tPA levels support a pulmonary release of tPA in early experimental ALI induced by acute ETX but not lavage, and are related to the inflammatory response. Despite increased vascular fibrinolytic capacity in ETX animals, pulmonary dysfunction was not different from BAL animals. The results demonstrate the close relation between inflammation and coagulation in early ALI.

Colloidal gold particles as a new in vivo marker of early acute lung injury.

Permeability of the endothelial barrier to large molecules plays a pivotal role in the manifestation of early acute lung injury. We present a novel and sensitive technique that brings microanatomical visualization and quantification of microvascular permeability in line. White New Zealand rabbits were anesthetized and ventilated mechanically. Rabbit serum albumin (RSA) was labeled with colloidal gold particles. We quantified macromolecular leakage of gold-labeled RSA and thickening of the gas exchange distance by electron microscopy, taking into account morphology of microvessels. The control group receiving a saline solution represented a normal gas exchange barrier without extravasation of gold-labeled albumin. Infusion of lipopolysaccharide (LPS) resulted in a significant displacement of gold-labeled albumin into pulmonary cells, the lung interstitium, and even the alveolar space. Correspondingly, intravital fluorescence microscopy and digital image analysis indicated thickening of width of alveolar septa. The findings were accompanied by a deterioration of alveolo-arterial oxygen difference, whereas wet/dry ratio and albumin concentration in the bronchoalveolar lavage fluid failed to detect that early stage of pulmonary edema. Inhibition of the nuclear enzyme poly(ADP-ribose) synthetase by 3-aminobenzamide prevented LPS-induced microvascular injury. To summarize: colloidal gold particles visualized by standard electron microscopy are a new and very sensitive in vivo marker of microvascular permeability in early acute lung injury. This technique enabling detailed microanatomical and quantitative pathophysiological characterization of edema formation can form the basis for evaluating novel treatment strategies against acute lung injury.

Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury.

The alveolar fibrinolytic system is altered in acute lung injury (ALI). Levels of the fibrinolytic protease inhibitor, plasminogen activator inhibitor-1 (PAI-1), are too low in bronchoalveolar lavage to address its prognostic significance. This study was performed to assess whether PAI-1 antigen in undiluted pulmonary edema fluid levels can identify patients with ALI and predict their outcome. PAI-1 antigen levels in both plasma and edema fluid were higher in ALI compared with hydrostatic edema, and edema fluid PAI-1 values identified those with ALI with high sensitivity and specificity. Both the high plasma and edema fluid PAI-1 antigen values were associated with a higher mortality rate and fewer days of unassisted ventilation in patients with ALI. Differences in PAI-1 activity were concordant with levels of PAI-1 antigen. Although the fibrin-derived alveolar D-dimer levels were strikingly similar in both groups, ALI patients had a higher relative proportion of D-monomer. In conclusion, PAI-1 levels in edema fluid and plasma identify those with ALI that have a poor prognosis. The data indicate that fibrin turnover in early ALI is a consequence of a rapid fibrinogen influx and fractional fibrinolytic inhibition.

Anticoagulant therapy in acute lung injury.

To review the rationale for evaluating anticoagulant therapies in acute lung injury (ALI) and to review selected data regarding the effectiveness of anticoagulants in animals and human patients with ALI and acute respiratory distress syndrome. Published literature on coagulation alterations and anticoagulant strategies in ALI during the past 25 yrs. In the lung, alveolar and interstitial fibrin deposition are the hallmarks of early phase ALI. Local procoagulant activity and reduced fibrinolysis constitute the rationale for anticoagulant use in the treatment of ALI. An activated complex of tissue factor and factor VIIa triggers procoagulant activity in the lung, with subsequent thrombin formation and fibrin deposition. Increased pulmonary vascular permeability and leukocyte accumulation have been successfully prevented in animals treated with tissue factor/activated factor VII pathway inhibitor. In humans, a phase II study evaluating tissue factor pathway inhibitor in the treatment of severe sepsis suggested that lung function in acute respiratory distress syndrome patients was improved. However, the phase III trial failed to demonstrate a survival benefit; data regarding respiratory dysfunction have not yet been published. Heparin, despite effectively inhibiting thrombin formation, has not shown consistent benefits in reducing lung injury, and its efficacy has not yet been evaluated in a controlled study. Antithrombin administration in animals has shown consistent benefits with ALI, but clinical studies have failed to demonstrate reductions in mortality and lung injury. Activated protein C administration has been shown to improve survival and lung function in both animal and clinical studies. Soluble thrombomodulin has been shown to improve ALI in animals, and it is currently being evaluated in humans with sepsis. Finally, plasminogen activators may improve gas exchange in ALI, but studies in humans are limited.

Angiogenic growth factors in the pathophysiology of a murine model of acute lung injury.

Capillary leakage and alveolar edema are hallmarks of acute lung injury (ALI). Neutrophils and serum macromolecules enter alveoli, promoting inflammation. Vascular endothelial growth factor (VEGF) causes plasma leakage in extrapulmonary vessels. Angiopoietin (Ang)-1 and -4 stabilize vessels, attenuating capillary leakage. We hypothesized that VEGF and Ang-1 and -4 modulate vessel leakage in the lung, contributing to the pathogenesis of ALI. We examined a murine model of lipopolysaccharide (LPS)-induced ALI. C57BL/6 and 129/J mice were studied at baseline and 24, 48, and 96 h after single or multiple doses of aerosolized LPS. Both strains exhibited time- and dose-dependent increases in inflammation and a deterioration of lung mechanics. Bronchoalveolar lavage (BAL) protein levels increased significantly, suggesting capillary leakage. Increased BAL neutrophil and total protein content correlated with time-dependent increased tissue VEGF and decreased Ang-1 and -4 levels, with peak VEGF and minimum Ang-1 and -4 expression after 96 h of LPS challenge. These data suggest that changes in the balance between VEGF and Ang-1 and -4 after LPS exposure may modulate neutrophil influx, protein leakage, and alveolar flooding during early ALI.

Von Willebrand factor antigen is an independent marker of poor outcome in patients with early acute lung injury.

The primary objective of this study was to test the hypothesis that the degree of systemic endothelial activation, as measured by the release of von Willebrand factor antigen into the circulation and pulmonary edema fluid, is an important determinant of outcome from acute lung injury and acute respiratory distress syndrome. Observational study. Intensive care unit patients in a tertiary university hospital and a university-affiliated city hospital. Fifty-one intubated, mechanically ventilated intensive care unit patients with acute lung injury or acute respiratory distress syndrome as defined by the North American European Consensus Conference definitions. Undiluted pulmonary edema fluid and plasma were collected within 1 hr of endotracheal intubation in all patients. von Willebrand factor antigen concentrations and protein concentration were measured in pulmonary edema fluid and in plasma. At the time of intubation, median plasma von Willebrand factor antigen was 251%, two-fold higher than the median pulmonary edema fluid von Willebrand factor antigen of 130%. Median edema fluid and plasma von Willebrand factor antigen concentrations were significantly higher in patients who did not survive hospitalization. Plasma von Willebrand factor antigen was also higher in those patients who had a longer duration of mechanical ventilation (as measured by ventilator-free days). Plasma von Willebrand factor antigen was also significantly higher in patients with sepsis and two or more organ system failures. According to stepwise logistic regression analysis, plasma von Willebrand factor antigen was independently associated with in hospital death. The positive predictive value for death if the plasma von Willebrand factor antigen concentration was >450% was 83%. A plasma von Willebrand factor antigen concentration of >450% previously has been shown to predict the development of acute respiratory distress syndrome. These findings suggest that the degree of systemic endothelial activation and injury at the onset of acute lung injury is an important determinant of the outcome from acute lung injury.

Early post-traumatic acute respiratory distress syndrome and albumin excretion rate: a prospective evaluation of a ‘point-of care’ predictive test

All patients sustaining major trauma exhibit increased capillary permeability, manifested as micro-albuminuria. Urinary albumin excretion rate (AER) measured on intensive care units (ICU) can predict early post-traumatic acute respiratory distress syndrome (ARDS). This prospective study sought to evaluate AER as a practical predictive test for early ARDS. Staff at the participating centres were trained in the use of the Behring Turbitimer and the concept of AER as a predictor of early post-traumatic ARDS. AER was measured every 2 h for the first 24 h, on 54 adult blunt trauma admissions (ISS≥18). A diagnosis of early acute lung injury (ALI) or ARDS was made using the American–European Consensus Conference criteria. Eleven patients developed ARDS, ten developed ALI, and 23 had no pulmonary dysfunction. The AER was significantly greater in those who developed ARDS 8 and 18 h after admission. The positive predictive value of the test was 64% at 8 h, the negative predictive power 73%. The test was performed most consistently in the middle 10 h of the study period. If intervention had been based on the 8 h data point result, 75% patients who had the test performed and later developed ARDS would have had intervention appropriately. In principle, testing for AER as a predictor of post-traumatic ARDS on ICU is feasible, however, this study has underlined the challenges of introducing new concepts into the ICU environment.

Increased levels of nitrate and surfactant protein a nitration in the pulmonary edema fluid of patients with acute lung injury.

Levels of nitrite (NO2-) and nitrate (NO3-) were measured in pulmonary edema fluid and plasma from 34 patients with early acute lung injury (ALI) and 20 patients with hydrostatic pulmonary edema. Pulmonary edema fluid from patients with ALI had significantly higher levels of NO2- + NO3- compared with pulmonary edema fluid from patients with hydrostatic pulmonary edema (108 +/- 13 microM versus 66 +/- 9 microM; means +/- SEM; p < 0.05). In addition, patients with shock had higher plasma NO2- + NO3- levels than those without shock (79 +/- 11 microM versus 53 +/- 12 microM, p < 0.05). Acidemia and increased anion gap, markers of systemic hypoperfusion, were also associated with twofold higher plasma NO2- + NO3- levels (p < 0.01). Increased levels of NO2- + NO3- in edema fluid samples were associated with slower rates of alveolar fluid clearance. Nitrated pulmonary surfactant protein A (SP-A) was also detected in the edema fluid of patients with ALI after immunoprecipitation with a specific antibody against this protein. Previously, we have shown that nitration of SP-A impairs its host- defense properties. In aggregate, the results of this study indicate that reactive oxygen-nitrogen species may play a role in the pathogenesis of human ALI.