The RALE score can be used to assess both the extent of pulmonary oedema and the severity of ARDS, by utilising information that is already obtained routinely, safely and inexpensively in every patient with ARDS. This novel non-invasive measure should be useful for assessing ARDS severity and monitoring response to therapy.

Background:The alveolar compartment is a procoagulant antifibrinolytic environment in acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). A study was undertaken to test the hypothesis that the alveolar epithelium can initiate intra-alveolar coagulation by expressing active tissue factor (TF). Methods: Using an in vitro cell surface TF assay and TF ELISA, the activity and production of TF in cultured alveolar epithelial (A549) cells following exposure to cytomix (tumour necrosis factor a, interleukin 1b and interferon c) was measured. TF gene transcription was measured by semi-quantitative reverse-transcription PCR. Immunohistochemistry for TF was performed on lung sections from patients with ARDS and controls. TF protein levels were measured by ELISA in undiluted pulmonary oedema fluid from patients with ALI/ARDS and compared with control patients with hydrostatic pulmonary oedema. Results: TF activity, mRNA and protein levels increased in A549 cells after stimulation with cytomix. Increased TF activity was also seen in A549 cells following incubation with pulmonary oedema fluid from patients with ALI/ARDS. Immunohistochemistry for TF in human lung tissue from patients with ARDS showed prominent TF staining in alveolar epithelial cells as well as intra-alveolar macrophages and hyaline membranes. TF antigen levels in oedema fluid (median 37 113 (IQR 14 956-73 525) pg/ml) were significantly higher than in plasma (median 336 (IQR 165-669) pg/ml, p,0.001) in patients with ALI/ARDS, and TF procoagulant activity in oedema fluid was much higher than in plasma of these patients. Higher plasma levels were associated with mortality. Conclusions: The alveolar epithelium is capable of modulating intra-alveolar coagulation through upregulation of TF following exposure to inflammatory stimuli and may contribute to intra-alveolar fibrin deposition in ARDS.

Objective Atrial fibrillation (AF) has been associated with increased mortality in critically-ill patients. We sought to determine whether AF in the intensive care unit (ICU) is an independent risk factor for death. A secondary objective was to determine if patients with new-onset AF have different risk factors or outcomes compared to patients with a previous history of AF. Design Prospective observational cohort study. Setting Medical and general surgical ICUs in a tertiary academic medical center. Patients 1,770 critically-ill patients requiring at least 2 days in the ICU. Interventions None. Measurements Demographics, medical history, development of AF, fluid balance, echocardiographic findings, medication administration, and hospital mortality were collected during the first four days of ICU admission. Main Results AF occurred in 236 (13%) patients (Any AF). Of these, 123 patients (7%) had no prior AF (New-onset AF) while the remaining 113 (6%) had Recurrent AF. Any AF was associated with male gender, Caucasian race, increased age, cardiac disease, organ failures, and disease severity. Patients with Any AF had increased mortality compared to those without AF (31% vs. 17%, p <0.001) and Any AF was independently associated with death (OR 1.62, 95% CI 1.14-2.29, p=0.007) in multivariable analysis controlling for severity of illness and other confounders. The association of AF with death was magnified in patients without sepsis (OR 2.92, 95% CI 1.52-5.60, p=0.001). Treatment for AF had no effect on hospital mortality. New-onset AF and Recurrent AF were each associated with increased mortality. New-onset AF, but not Recurrent AF, was associated with increased diastolic dysfunction and vasopressor use and a greater cumulative positive fluid balance. Conclusions AF in critical illness, whether new-onset or recurrent, is independently associated with increased hospital mortality, especially in patients without sepsis.

LB. Procoagulant alveolar microparticles in the lungs of patients with acute respiratory distress syndrome.

Objective To determine the association of circulating cell-free hemoglobin with poor clinical outcomes in patients with sepsis and to characterize the potential protective effects of acetaminophen, an inhibitor of hemoprotein-mediated oxidation. Design Retrospective observational study. Patients A total of 391 critically ill patients with sepsis in multiple intensive care units in an academic tertiary care hospital. Interventions None. Measurements and Main Results Nonsurvivors had significantly higher plasma cell-free hemoglobin concentrations (median 20 mg/dl, IQR 10–40) measured on enrollment compared to survivors (10 mg/dl, IQR 10–30, p = 0.002). After controlling for potential confounders, patients with higher cell-free hemoglobin concentrations were significantly more likely to die in the hospital (OR 1.078, 95% CI 1.012–1.149, p = 0.02). In addition, receiving acetaminophen in the setting of increased cell-free hemoglobin was independently associated with a protective effect against death (OR 0.48, 95% CI 0.25–0.91, p = 0.026) and lower plasma concentrations of the lipid peroxidation product F2-isoprostanes (18.5 pg/ml IQR 9–22.2) compared to no acetaminophen (42 pg/ml, IQR 29.7–86, p = 0.009). Conclusions In critically ill patients with sepsis, elevated concentrations of circulating cell-free hemoglobin are independently associated with an increased risk of death. Acetaminophen may exert a protective effect by reducing cell-free hemoglobin-induced induced oxidative injury.

BACKGROUND:Oxygen saturation as measured by pulse oximetry/F io 2 (SF) ratio is highly correlated with the Pa o 2 /F io 2 (PF) ratio in patients with ARDS. However, it remains uncertain whether SF ratio can be substituted for PF ratio for diagnosis of ARDS and whether SF ratio might identify patients who are systemically diff erent from patients diagnosed by PF ratio.

Objectives Platelet activation plays an active role in the pathogenesis of acute respiratory distress syndrome (ARDS). In our prior study of 575 patients at high risk for ARDS, concurrent statin and aspirin use was associated with reduced ARDS. However, the largest study (n=3855) to date found no significant benefit of prehospital aspirin in a lower risk population when adjusted for the propensity for aspirin use. We aimed to determine whether prehospital aspirin use is associated with decreased ARDS in patients at high risk for ARDS after adjusting for the propensity to receive aspirin. Design Secondary analysis of patients enrolled prospectively in the Validating Acute Lung Injury Markers for Diagnosis (VALID) study. Patients A total of 1149 critically ill patients (age ≥ 40) admitted to the medical or surgical intensive care units of an academic tertiary care hospital including 575 previously reported patients as well as additional patients who were enrolled after completion of the prior statin and aspirin study. Intervention None Measurements and Results Of 1149 patients, 368 (32%) developed ARDS during the first four ICU days and 287 (25%) patients had prehospital aspirin use. Patients with prehospital aspirin had significantly lower incidence of ARDS (27% vs. 34%, p=0.034). In a multivariable, propensity-adjusted analysis including age, gender, race, sepsis and APACHE II, prehospital aspirin use was associated with a decreased risk of ARDS (OR 0.66, 95% CI 0.46-0.94) in the entire cohort and in a subgroup of 725 patients with sepsis (OR 0.60, 95% CI 0.41-0.90). Conclusions In this selected cohort of critically ill patients, prehospital aspirin use was independently associated with a decreased risk of ARDS even after adjusting for the propensity of pre-hospital aspirin use. These findings support the need for prospective clinical trials to determine whether aspirin may be beneficial for the prevention of clinical ARDS.

Background Influenza A virus (IAV) infection is a common respiratory tract infection that causes considerable morbidity and mortality worldwide. Objective To investigate the effect of a genetic deficiency of tissue factor (TF) in a mouse model of influenza A infection. Methods Wild-type mice, low tissue factor (LTF) mice and mice with the TF gene deleted in different cell types were infected with a mouse-adapted A/Puerto Rico/8/34 H1N1 strain of IAV. TF expression was measured in the lungs, and bronchoalveolar lavage fluid (BALF) was collected to measure extracellular vesicle TF, activation of coagulation, alveolar hemorrhage and inflammation. Results IAV infection of wild-type mice increased lung TF expression, activation of coagulation and inflammation in the BALF, but also led to alveolar hemorrhage. LTF mice and mice with a selective deficiency of TF in lung epithelial cells had low basal levels of TF and failed to increase TF expression after infection; these two strains of mice had more alveolar hemorrhage and death compared with controls. In contrast, deletion of TF in either myeloid cells or endothelial cells and hematopoietic cells did not increase alveolar hemorrhage or death after IAV infection. These results indicate that TF expression in the lung, particularly in epithelial cells, is required to maintain alveolar hemostasis after IAV infection. Conclusion Our study indicates that TF-dependent activation of coagulation is required to limit alveolar hemorrhage and death after influenza A infection.