Circulating microparticle levels are reduced in patients with ARDS.

BACKGROUND: It is unclear how to identify which patients at risk for acute respiratory distress syndrome (ARDS) will develop this condition during critical illness. Elevated microparticle (MP) concentrations in the airspace during ARDS are associated with activation of coagulation and in vitro studies have demonstrated that MPs contribute to acute lung injury, but the significance of MPs in the circulation during ARDS has not been well studied. The goal of the present study was to test the hypothesis that elevated levels of circulating MPs could prospectively identify critically ill patients who will develop ARDS and that elevated circulating MPs are associated with poor clinical outcomes. METHODS: A total of 280 patients with platelet-poor plasma samples from the prospective Validating Acute Lung Injury biomarkers for Diagnosis (VALID) cohort study were selected for this analysis. Demographics and clinical data were obtained by chart review. MP concentrations in plasma were measured at study enrollment on intensive care unit (ICU) day 2 and on ICU day 4 by MP capture assay. Activation of coagulation was measured by plasma recalcification (clot) times. RESULTS: ARDS developed in 90 of 280 patients (32%) in the study. Elevated plasma MP concentrations were associated with reduced risk of developing ARDS (odds ratio (OR) 0.70 per 10 µM increase in MP concentration, 95% CI 0.50-0.98, p = 0.042), but had no significant effect on hospital mortality. MP concentration was greatest in patients with sepsis, pneumonia, or aspiration as compared with those with trauma or receiving multiple blood transfusions. MP levels did not significantly change over time. The inverse association of MP levels with ARDS development was most striking in patients with sepsis. After controlling for age, presence of sepsis, and severity of illness, higher MP concentrations were independently associated with a reduced risk of developing ARDS (OR 0.69, 95% CI 0.49-0.98, p = 0.038). MP concentration was associated with reduced plasma recalcification time. CONCLUSIONS: Elevated levels of circulating MPs are independently associated with a reduced risk of ARDS in critically ill patients. Whether this is due to MP effects on systemic coagulation warrants further investigation.

Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury.

Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF(∆mye), LysM.Cre(+/-)TF(flox/flox)) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI.

Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.

Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI.

A randomized trial comparing didactics, demonstration, and simulation for teaching teamwork to medical residents.

RATIONALE: Effective teamwork is fundamental to the management of medical emergencies, and yet the best method to teach teamwork skills to trainees remains unknown. OBJECTIVES: In a cohort of incoming internal medicine interns, we tested the hypothesis that expert demonstration of teamwork principles and participation in high-fidelity simulation would each result in objectively assessed teamwork behavior superior to traditional didactics. METHODS: This was a randomized, controlled, parallel-group trial comparing three teamwork teaching modalities for incoming internal medicine interns. Participants in a single-day orientation at the Vanderbilt University Center for Experiential Learning and Assessment were randomized 1:1:1 to didactic, demonstration-based, or simulation-based instruction and then evaluated in their management of a simulated crisis by five independent, blinded observers using the Teamwork Behavioral Rater score. Clinical performance was assessed using the American Heart Association Advanced Cardiac Life Support algorithm and a novel "Recognize, Respond, Reassess" score. MEASUREMENTS AND MAIN RESULTS: Participants randomized to didactics (n = 18), demonstration (n = 17), and simulation (n = 17) were similar at baseline. The primary outcome of average overall Teamwork Behavioral Rater score for those who received demonstration-based training was similar to simulation participation (4.40 ± 1.15 vs. 4.10 ± 0.95, P = 0.917) and significantly higher than didactic instruction (4.40 ± 1.15 vs. 3.10 ± 0.51, P = 0.045). Clinical performance scores were similar between the three groups and correlated only weakly with teamwork behavior (coefficient of determination [Rs(2)] = 0.267, P < 0.001). CONCLUSIONS: Among incoming internal medicine interns, teamwork training by expert demonstration resulted in similar teamwork behavior to participation in high-fidelity simulation and was more effective than traditional didactics. Clinical performance was largely independent of teamwork behavior and did not differ between training modalities.

Low levels of tissue factor lead to alveolar haemorrhage, potentiating murine acute lung injury and oxidative stress.

BACKGROUND: Systemic blockade of tissue factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. We used mice with complete knockout of mouse TF and low levels (∼1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury. METHODS: LTF mice were treated with 10 µg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal injection and studied at 24 h. RESULTS: Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4×10(5) wild-type (WT) LPS vs 3.3×10(5) LTF LPS, p=0.947) and protein (493 µg/ml WT LPS vs 1014 µg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS vs LTF LPS) and histology compared with WT mice. LTF mice also had increased haemorrhage and free haemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F(2) isoprostanes and isofurans). CONCLUSIONS: These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar haemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit TF may be deleterious in patients with ALI.