Julie A. Bastarache

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

Coagulation and fibrinolysis abnormalities are observed in acute lung injury (ALI) in both human disease and animal models and may contribute to ongoing inflammation in the lung. Tissue factor (TF), the main initiator of the coagulation cascade, is upregulated in the lungs of patients with ALI/acute respiratory distress syndrome (ARDS) and likely contributes to fibrin deposition in the air space. The mechanisms that govern TF upregulation and activation in the lung are not well understood. In the vascular space, TF-bearing microparticles (MPs) are central to clot formation and propagation. We hypothesized that TF-bearing MPs in the lungs of patients with ARDS contribute to the procoagulant phenotype in the air space during acute injury and that the alveolar epithelium is one potential source of TF MPs. We studied pulmonary edema fluid collected from patients with ARDS compared with a control group of patients with hydrostatic pulmonary edema. Patients with ARDS have higher concentrations of MPs in the lung compared with patients with hydrostatic edema (25.5 IQR 21.3-46.9 vs. 7.8 IQR 2.3-27.5 micromol/l, P = 0.009 by Mann-Whitney U-test). These MPs are enriched for TF, have procoagulant activity, and likely originate from the alveolar epithelium [as measured by elevated levels of RAGE (receptor for advanced glycation end products) in ARDS MPs compared with hydrostatic MPs]. Furthermore, alveolar epithelial cells in culture release procoagulant TF MPs in response to a proinflammatory stimulus. These findings suggest that alveolar epithelial-derived MPs are one potential source of TF procoagulant activity in the air space in ARDS and that epithelial MP formation and release may represent a unique therapeutic target in ARDS.

Acute lung injury edema fluid decreases net fluid transport across human alveolar epithelial type II cells

Most patients with acute lung injury (ALI) have reduced alveolar fluid clearance that has been associated with higher mortality. Several mechanisms may contribute to the decrease in alveolar fluid clearance. In this study, we tested the hypothesis that pulmonary edema fluid from patients with ALI might reduce the expression of ion transport genes responsible for vectorial fluid transport in primary cultures of human alveolar epithelial type II cells. Following exposure to ALI pulmonary edema fluid, the gene copy number for the major sodium and chloride transport genes decreased. By Western blot analyses, protein levels of αENaC, α1Na,K-ATPase, and cystic fibrosis transmembrane conductance regulator decreased as well. In contrast, the gene copy number for several inflammatory cytokines increased markedly. Functional studies demonstrated that net vectorial fluid transport was reduced for human alveolar type II cells exposed to ALI pulmonary edema fluid compared with plasma (0.02 ± 0.05 versus 1.31 ± 0.56 μl/cm2/h, p < 0.02). An inhibitor of p38 MAPK phosphorylation (SB202190) partially reversed the effects of the edema fluid on net fluid transport as well as gene and protein expression of the main ion transporters. In summary, alveolar edema fluid from patients with ALI induced a significant reduction in sodium and chloride transport genes and proteins in human alveolar epithelial type II cells, effects that were associated with a decrease in net vectorial fluid transport across human alveolar type II cell monolayers.

Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: an observational study.

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 ICUs in an academic tertiary care hospital. Interventions:None. Measurements and Main Results:Nonsurvivors had significantly higher plasma cell-free hemoglobin concentrations (median 20mg/dL, interquartile range 10–40) measured on enrollment compared to survivors (10mg/dL, interquartile range 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 (odds ratio 1.078, 95% confidence interval 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 (odds ratio 0.48, 95% confidence interval 0.25–0.91, p = 0.026) and lower plasma concentrations of the lipid peroxidation product F2-isoprostanes (18.5 pg/mL, interquartile range 9–22.2) compared to no acetaminophen (42 pg/mL, interquartile range 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 oxidative injury.

Development of animal models for the acute respiratory distress syndrome.

Injury to the lung parenchyma results in the acute respiratory distress syndrome (ARDS), which is a common and life-threatening cause of respiratory failure and mortality that develops after a variety of insults, including sepsis, multiple trauma, pneumonia, aspiration of gastric contents and severe burns. The pathogenesis of ARDS is complex with loss of the alveolar-capillary barrier and flooding of the airspaces with protein-rich fluid; injury to the alveolar epithelium; an influx of neutrophils and macrophages; and fibrin deposition as a result of activation of coagulation and inhibition of fibrinolysis. These changes develop over hours to a few days after the initiating event and often take days or weeks to resolve. Despite decades of research, there is only one therapy (low tidal volume ventilation) that has been shown to reduce mortality in ARDS. Further research into the pathogenesis of this devastating condition is crucial for the development of novel and specific therapies that target specific disease mechanisms. Unfortunately, no single animal model of ARDS replicates the complex pathophysiological changes seen in patients. This is a severe limitation in the study of ARDS and has impaired scientific and therapeutic progress in this field. Here, we discuss the primary features of this syndrome, highlight limitations of current animal models and suggest new approaches to investigate key components of pathogenesis. Hopefully, as new technologies and approaches emerge, barriers to scientific progress in ARDS will be overcome.

Atrial Fibrillation Is an Independent Predictor of Mortality in Critically Ill Patients.

Objectives:Atrial fibrillation has been associated with increased mortality in critically ill patients. We sought to determine whether atrial fibrillation in the ICU is an independent risk factor for death. A secondary objective was to determine if patients with new-onset atrial fibrillation have different risk factors or outcomes compared with patients with a previous history of atrial fibrillation. Design:Prospective observational cohort study. Setting:Medical and general surgical ICUs in a tertiary academic medical center. Patients:One thousand seven hundred seventy critically ill patients requiring at least 2 days in the ICU. Interventions:None. Measurements and Main Results:Demographics, medical history, development of atrial fibrillation, fluid balance, echocardiographic findings, medication administration, and hospital mortality were collected during the first 4 days of ICU admission. Atrial fibrillation occurred in 236 patients (13%) (Any AF). Of these, 123 patients (7%) had no prior atrial fibrillation (New-onset AF) while the remaining 113 (6%) had recurrent atrial fibrillation (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 with those without atrial fibrillation (31% vs 17%; p < 0.001), and Any AF was independently associated with death (odds ratio, 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 atrial fibrillation with death was magnified in patients without sepsis (odds ratio, 2.92; 95% CI, 1.52–5.60; p = 0.001). Treatment for atrial fibrillation 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:Atrial fibrillation in critical illness, whether new-onset or recurrent, is independently associated with increased hospital mortality, especially in patients without sepsis.

Determining the aetiology of pulmonary oedema by the oedema fluid-to-plasma protein ratio.

We hypothesised that the oedema fluid-to-plasma protein (EF/PL) ratio, a noninvasive measure of alveolar capillary membrane permeability, can accurately determine the aetiology of acute pulmonary oedema. 390 mechanically ventilated patients with acute pulmonary oedema were enrolled. A clinical diagnosis of acute lung injury (ALI), cardiogenic pulmonary oedema or a mixed aetiology was based on expert medical record review at the end of hospitalisation. The EF/PL ratio was measured from pulmonary oedema fluid and plasma samples collected at intubation. 209 patients had a clinical diagnosis of ALI, 147 had a diagnosis of cardiogenic pulmonary oedema and 34 had a mixed aetiology. The EF/PL ratio had an area under the receiver-operating curve of 0.84 for differentiating ALI from cardiogenic pulmonary oedema. Using a predefined cut-off of 0.65, the EF/PL ratio had a sensitivity of 81% and a specificity of 81% for the diagnosis of ALI. An EF/PL ratio ≥0.65 was also associated with significantly higher mortality and fewer ventilator-free days. Noninvasive measurement of the EF/PL ratio is a safe and reliable bedside method for rapidly determining the aetiology of acute pulmonary oedema that can be used at the bedside in both developed and developing countries.

Prehospital aspirin use is associated with reduced risk of acute respiratory distress syndrome in critically ill patients: a propensity-adjusted analysis.

Objectives:Platelet activation plays an active role in the pathogenesis of acute respiratory distress syndrome. In our prior study of 575 patients at high risk for acute respiratory distress syndrome, concurrent statin and aspirin use was associated with reduced acute respiratory distress syndrome. However, the largest study (n = 3,855) 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 acute respiratory distress syndrome in patients at high risk for acute respiratory distress syndrome after adjusting for the propensity to receive aspirin. Design:Secondary analysis of patients enrolled prospectively in the Validating Acute Lung Injury Markers for Diagnosis study. Patients:A total of 1,149 critically ill patients (≥ 40 years old) admitted to the medical or surgical ICUs 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 1,149 patients, 368 (32%) developed acute respiratory distress syndrome during the first 4 ICU days and 287 (25%) patients had prehospital aspirin use. Patients with prehospital aspirin had significantly lower prevalence of acute respiratory distress syndrome (27% vs 34%; p = 0.034). In a multivariable, propensity-adjusted analysis including age, gender, race, sepsis, and Acute Physiology and Chronic Health Evaluation score II, prehospital aspirin use was associated with a decreased risk of acute respiratory distress syndrome (odds ratio, 0.66; 95% CI, 0.46–0.94) in the entire cohort and in a subgroup of 725 patients with sepsis (odds ratio, 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 acute respiratory distress syndrome even after adjusting for the propensity of prehospital aspirin use. These findings support the need for prospective clinical trials to determine whether aspirin may be beneficial for the prevention of clinical acute respiratory distress syndrome.

The coagulation cascade in sepsis.

Intravascular and extravascular fibrin formation are characteristic findings in patients with sepsis, suggesting that the activation of coagulation and the inhibiton of fibrinolysis are important in the pathogenesis of sepsis. Activation of coagulation during sepsis is primarily driven by the tissue factor (TF) pathway, while inhibition of fibrinolysis is primarily due to increases in plasminogen activator inhibitor -1(PAI-1). Downregulation of the anticoagulant Protein C pathway also plays an important role in the modulation of coagulation and inflammation in sepsis. Recent advances in the understanding of pathogenetic mechanisms of coagulation and fibrinolysis in sepsis may have therapeutic implications. Recombinant human activated protein C (rhAPC) is currently the only pharmacologic therapy that has been shown to reduce mortality in adults with severe sepsis, highlighting the importance of coagulation and fibrinolysis as a therapeutic target in sepsis. This review summarizes recent basic and clinical findings with regard to the role of the coagulation cascade in sepsis and explores potential therapeutic targets in the coagulation and fibrinolytic pathways in the management of sepsis.

Randomized, placebo-controlled trial of acetaminophen for the reduction of oxidative injury in severe sepsis: the Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis trial.

Objectives:This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free hemoglobin. Design:Single-center, randomized, double-blind, placebo-controlled phase II trial. Setting:Medical ICU in a tertiary, academic medical center. Patients:Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin. Interventions:Patients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration. Measurements and Main Results:F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24–41) and placebo (36 pg/mL; interquartile range, 25–80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19–36) when compared with placebo (36 pg/mL; interquartile range, 23–55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6–1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83–2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599). Conclusions:In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.

Longer storage duration of red blood cells is associated with an increased risk of acute lung injury in patients with sepsis

BackgroundThe storage duration of red blood cells transfused to critically ill patients is associated with increased morbidity and mortality. Whether the association exists between storage duration of red blood cells transfused to patients with sepsis and the risk of developing ALI/ARDS is unknown. We aimed to determine the association of the storage duration of red blood cells transfused to patients with sepsis and risk of developing acute lung injury in the subsequent 96 hours, with comparator trauma and nonsepsis/nontrauma groups.MethodsWe conducted a retrospective observational study of 96 transfused, critically ill patients with sepsis, 176 transfused, critically ill patients with traumatic injury, and 125 transfused, critically ill nontrauma, nonsepsis patients. The primary outcome was the development of ALI/ARDS up to 96 hours after transfusion.ResultsIn 96 patients with sepsis, 49 (51%) patients developed ALI/ARDS. The median storage duration of transfused blood in the ALI/ARDS group was greater (24.5 days, interquartile range (IQR) 20–31) compared with the patients who did not develop ALI/ARDS (21 days, IQR 15–27, p = 0.018). Longer median storage duration was independently associated with an increased risk of developing ALI/ARDS in the subsequent 4 days (odds ratio 1.8, p = 0.028). The same association was not seen in the trauma or nonsepsis, nontrauma patients.ConclusionsTransfusion of blood with longer median storage duration to patients with sepsis is associated with a higher risk of developing ALI up to 4 days after transfusion. This same association is not seen in other critically ill patient populations.