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1.  FIBRINOGEN AND PLATELET CONTRIBUTIONS TO CLOT FORMATION: IMPLICATIONS FOR TRAUMA RESUSCITATION AND THROMBOPROPHYLAXIS 
BACKGROUND
Thromboelastography (TEG) is used to diagnose perturbations in clot formation and lysis that are characteristic of acute traumatic coagulopathy (ATC). With novel functional fibrinogen (FF) TEG, fibrin- and platelet-based contributions to clot formation can be elucidated to tailor resuscitation and thromboprophylaxis. We sought to describe the longitudinal contributions of fibrinogen and platelets to clot strength after injury, hypothesizing that low levels of functional fibrinogen and a low contribution of fibrinogen to clot strength on admission would be associated with coagulopathy, increased transfusion requirements, and worse outcomes.
METHODS
603 longitudinal plasma samples were prospectively collected from 251 critically-injured patients at a single Level 1 Trauma Center from 0–120h. TEG maximal amplitude (MA), FF MA, FF levels (FLEV), von Clauss fibrinogen, and standard coagulation measures were performed in parallel. Percentage contributions of FF (%MAFF) and platelets (%MAplatelets) were calculated as each MA divided by overall kaolin TEG MA.
RESULTS
Coagulopathic patients (INR>=1.3) had significantly lower admission %MAFF than non-coagulopathic patients (24.7% vs. 31.2%, p<0.05). Patients requiring plasma transfusion had a significantly lower admission %MAFF (26.6% vs. 30.6%, p<0.05). Higher admission %MAFF was predictive of reduced mortality (HR 0.815, p<0.001). %MAplatelets was higher than %MAFF at all time points, decreased over time, and stabilized at 72 hours (69.4% at 0h, 56.2% at 72h). In contrast, %MAFF increased over time and stabilized at 72 hours (30.6% at 0h, 43.8% at 72).
CONCLUSION
FF TEG affords differentiation of fibrin- versus platelet-based clot dynamics. Coagulopathy and plasma transfusion were associated with a lower %MAFF. Despite this importance of fibrinogen, platelets had a greater contribution to clot strength at all time points after injury. This suggests that attention to these relative contributions should guide resuscitation and thromboprophylaxis, and that antiplatelet therapy may be of under-recognized importance to thromboprophylaxis after trauma.
LEVEL OF EVIDENCE
Level IV; prognostic
doi:10.1097/TA.0000000000000108
PMCID: PMC4238905  PMID: 24458031
Functional fibrinogen; clot strength; thromboprophylaxis
2.  Keratinocyte Growth Factor Promotes Epithelial Survival and Resolution in a Human Model of Lung Injury 
Rationale: Increasing epithelial repair and regeneration may hasten resolution of lung injury in patients with the acute respiratory distress syndrome (ARDS). In animal models of ARDS, keratinocyte growth factor (KGF) reduces injury and increases epithelial proliferation and repair. The effect of KGF in the human alveolus is unknown.
Objectives: To test whether KGF can attenuate alveolar injury in a human model of ARDS.
Methods: Volunteers were randomized to intravenous KGF (60 μg/kg) or placebo for 3 days, before inhaling 50 μg LPS. Six hours later, subjects underwent bronchoalveolar lavage (BAL) to quantify markers of alveolar inflammation and cell-specific injury.
Measurements and Main Results: KGF did not alter leukocyte infiltration or markers of permeability in response to LPS. KGF increased BAL concentrations of surfactant protein D, matrix metalloproteinase (MMP)-9, IL-1Ra, granulocyte-macrophage colony–stimulating factor (GM-CSF), and C-reactive protein. In vitro, BAL fluid from KGF-treated subjects inhibited pulmonary fibroblast proliferation, but increased alveolar epithelial proliferation. Active MMP-9 increased alveolar epithelial wound repair. Finally, BAL from the KGF-pretreated group enhanced macrophage phagocytic uptake of apoptotic epithelial cells and bacteria compared with BAL from the placebo-treated group. This effect was blocked by inhibiting activation of the GM-CSF receptor.
Conclusions: KGF treatment increases BAL surfactant protein D, a marker of type II alveolar epithelial cell proliferation in a human model of acute lung injury. Additionally, KGF increases alveolar concentrations of the antiinflammatory cytokine IL-1Ra, and mediators that drive epithelial repair (MMP-9) and enhance macrophage clearance of dead cells and bacteria (GM-CSF).
Clinical trial registered with ISRCTN 98813895.
doi:10.1164/rccm.201310-1892OC
PMCID: PMC4226011  PMID: 24716610
acute respiratory distress syndrome; acute lung injury; keratinocyte growth factor; lipopolysaccharide; clinical trial
3.  Early acute lung injury: Criteria for identifying lung Injury prior to the need for positive pressure ventilation 
Critical care medicine  2013;41(8):1929-1937.
Objective
Mortality associated with acute lung injury (ALI) remains high. Early identification of ALI prior to onset of respiratory failure may provide a therapeutic window to target in future clinical trials. The recently validated Lung Injury Prediction Score (LIPS) identifies patients at risk for ALI but may be limited for routine clinical use. We sought to empirically derive clinical criteria for a pragmatic definition of Early Acute Lung Injury (EALI) to identify patients with lung injury prior to the need for positive pressure ventilation.
Design
Prospective observational cohort study.
Setting
Stanford University Hospital.
Patients
We prospectively evaluated 256 patients admitted to Stanford University Hospital with bilateral opacities on chest radiograph without isolated left atrial hypertension.
Interventions
None.
Measurements and Main Results
Of the 256 patients enrolled, 62 (25%) progressed to ALI requiring positive pressure ventilation. Clinical variables (through first 72 hours or up to 6 hours prior to ALI) associated with progression to ALI were analyzed by backward regression. Oxygen requirement, maximal respiratory rate, and baseline immune suppression were independent predictors of progression to ALI. A simple 3 component EALI score (1 point for oxygen requirement > 2 to 6 liters/min or 2 points for > 6 liters/min; and 1 point each for a respiratory rate ≥ 30 and immune suppression) accurately identified patients who progressed to ALI requiring positive pressure ventilation (AUC 0.86) and performed similarly to the LIPS. An EALI score ≥ 2 identified patients who progressed to ALI with 89% sensitivity and 75% specificity. Median time of progression from EALI criteria to ALI requiring positive pressure ventilation was 20 hours.
Conclusions
This pragmatic definition of EALI accurately identified patients who progressed to ALI prior to requiring positive pressure ventilation. Pending further validation, these criteria could be useful for future clinical trials targeting early treatment of ALI.
doi:10.1097/CCM.0b013e31828a3d99
PMCID: PMC3748809  PMID: 23782966
acute lung injury; acute respiratory distress syndrome; early diagnosis; cohort study; critical care; emergency medicine
4.  Design and implementation of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of human mesenchymal stem/stromal cells for the treatment of moderate-severe acute respiratory distress syndrome 
Background
Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS.
Methods
This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio).
Results
This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU.
Conclusions
Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses.
Trial registration
Clinical Trials Registration: NCT01775774 and NCT02097641.
doi:10.1186/s13613-014-0022-z
PMCID: PMC4273700  PMID: 25593740
Acute lung injury; Clinical trial; Mesenchymal stem/stromal cell; Pulmonary edema
5.  Plasma Angiopoietin-2 Predicts the Onset of Acute Lung Injury in Critically Ill Patients 
Rationale: Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores.
Objectives: To determine whether plasma angiopoietin-2 (Ang-2), von Willebrand factor (vWF), interleukin-8 (IL-8), and/or receptor for advanced glycation end products (sRAGE) predict ALI in critically ill patients.
Methods: Plasma samples were drawn from critically ill patients (n = 230) identified in the emergency department. Patients who had ALI at baseline or in the subsequent 6 hours were excluded, and the remaining patients were followed for development of ALI.
Measurements and Main Results: Nineteen patients developed ALI at least 6 hours after the sample draw. Higher levels of Ang-2 and IL-8 were significantly associated with increased development of ALI (P = 0.0008, 0.004, respectively). The association between Ang-2 and subsequent development of ALI was robust to adjustment for sepsis and vasopressor use. Ang-2 and the Lung Injury Prediction Score each independently discriminated well between those who developed ALI and those who did not (area under the receiver operating characteristic curve, 0.74 for each), and using the two together improved the area under the curve to 0.84 (vs. 0.74, P = 0.05). In contrast, plasma levels of sRAGE and vWF were not predictive of ALI.
Conclusions: Plasma biomarkers such as Ang-2 can improve clinical prediction scores and identify patients at high risk for ALI. In addition, the early rise of Ang-2 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.
doi:10.1164/rccm.201208-1460OC
PMCID: PMC3678110  PMID: 23328529
acute respiratory distress syndrome; acute lung injury; receptor for advanced glycation end products; angiopoietin-2; Lung Injury Prediction Score
6.  Is there still a role for the lung injury score in the era of the Berlin definition ARDS? 
Background
The Lung Injury Score (LIS) remains a commonly utilized measure of lung injury severity though the additive value of LIS to predict ARDS outcomes over the recent Berlin definition of ARDS, which incorporates severity, is not known.
Methods
We tested the association of LIS (in which scores range from 0 to 4, with higher scores indicating more severe lung injury) and its four components calculated on the day of ARDS diagnosis with ARDS morbidity and mortality in a large, multi-ICU cohort of patients with Berlin-defined ARDS. Receiver Operator Characteristic (ROC) curves were generated to compare the predictive validity of LIS for mortality to Berlin stages of severity (mild, moderate and severe).
Results
In 550 ARDS patients, a one-point increase in LIS was associated with 58% increased odds of in-hospital death (95% CI 14 to 219%, P = 0.006), a 7% reduction in ventilator-free days (95% CI 2 to 13%, P = 0.01), and, among patients surviving hospitalization, a 25% increase in days of mechanical ventilation (95% CI 9 to 43%, P = 0.001) and a 16% increase (95% CI 2 to 31%, P = 0.02) in the number of ICU days. However, the mean LIS was only 0.2 points higher (95% CI 0.1 to 0.3) among those who died compared to those who lived. Berlin stages of severity were highly correlated with LIS (Spearman’s rho 0.72, P < 0.0001) and were also significantly associated with ARDS mortality and similar morbidity measures. The predictive validity of LIS for mortality was similar to Berlin stages of severity with an area under the curve of 0.58 compared to 0.60, respectively (P-value 0.49).
Conclusions
In a large, multi-ICU cohort of patients with ARDS, both LIS and the Berlin definition severity stages were associated with increased in-hospital morbidity and mortality. However, predictive validity of both scores was marginal, and there was no additive value of LIS over Berlin. Although neither LIS nor the Berlin definition were designed to prognosticate outcomes, these findings suggest that the role of LIS in characterizing lung injury severity in the era of the Berlin definition ARDS may be limited.
doi:10.1186/2110-5820-4-4
PMCID: PMC3931496  PMID: 24533450
Acute lung injury; Acute respiratory distress syndrome; Lung injury score; Berlin definition; Clinical outcomes; Critical illness
7.  Biomarkers of lung epithelial injury and inflammation distinguish severe sepsis patients with acute respiratory distress syndrome 
Critical Care  2013;17(5):R253.
Introduction
Despite recent modifications, the clinical definition of the acute respiratory distress syndrome (ARDS) remains non-specific, leading to under-diagnosis and under-treatment. This study was designed to test the hypothesis that a biomarker panel would be useful for biologic confirmation of the clinical diagnosis of ARDS in patients at risk of developing ARDS due to severe sepsis.
Methods
This was a retrospective case control study of 100 patients with severe sepsis and no evidence of ARDS compared to 100 patients with severe sepsis and evidence of ARDS on at least two of their first four ICU days. A panel that included 11 biomarkers of inflammation, fibroblast activation, proteolytic injury, endothelial injury, and lung epithelial injury was measured in plasma from the morning of ICU day two. A backward elimination model building strategy on 1,000 bootstrapped data was used to select the best performing biomarkers for further consideration in a logistic regression model for diagnosis of ARDS.
Results
Using the five best-performing biomarkers (surfactant protein-D (SP-D), receptor for advanced glycation end-products (RAGE), interleukin-8 (IL-8), club cell secretory protein (CC-16), and interleukin-6 (IL-6)) the area under the receiver operator characteristic curve (AUC) was 0.75 (95% CI: 0.7 to 0.84) for the diagnosis of ARDS. The AUC improved to 0.82 (95% CI: 0.77 to 0.90) for diagnosis of severe ARDS, defined as ARDS present on all four of the first four ICU days.
Conclusions
Abnormal levels of five plasma biomarkers including three biomarkers generated by lung epithelium (SP-D, RAGE, CC-16) provided excellent discrimination for diagnosis of ARDS in patients with severe sepsis. Altered levels of plasma biomarkers may be useful biologic confirmation of the diagnosis of ARDS in patients with sepsis, and also potentially for selecting patients for clinical trials that are designed to reduce lung epithelial injury.
doi:10.1186/cc13080
PMCID: PMC4056313  PMID: 24156650
8.  Comparison of Chest Radiograph Scoring to Lung Weight as a Quantitative Index of Pulmonary Edema in Organ Donors 
Clinical transplantation  2012;26(5):665-671.
Quantification of the degree of pulmonary edema in organ donors is useful for assessing the clinical severity of pulmonary edema, determining response to therapy, and as an endpoint for therapeutic trials. Currently, there is no accurate non-invasive method for assessing the degree of pulmonary edema. We tested the performance of a four quadrant chest radiographic scoring system compared to quantification of pulmonary edema by excised lung weight in 84 donors whose lungs were not used for transplantation. Chest radiographs were taken 3.6 ± 3.0 hours prior to organ procurement and were scored by two of the authors. Lungs were excised without perfusion and individually weighed. The chest radiographic scoring system had good performance: correlation between total radiographic score and total lung weight of 0.61, p <0.001. Performance of the scoring system was improved when chest radiographs with atelectasis were excluded (r = 0.79, p < 0.001). The area under the receiver operator characteristic curve for detection of moderate pulmonary edema (total lung weight > 1000g) was 0.80. This chest radiographic scoring system may potentially be used to assess the clinical severity of pulmonary edema and may be useful as part of the evaluation of donors for suitability for lung transplantation.
doi:10.1111/j.1399-0012.2011.01591.x
PMCID: PMC3642873  PMID: 22324977
pulmonary edema; organ donor; lung transplantation; chest radiograph
9.  Comparison of thermodilution measured extravascular lung water with chest radiographic assessment of pulmonary oedema in patients with acute lung injury 
Background
Acute lung injury and the acute respiratory distress syndrome (ALI/ARDS) are characterized by pulmonary oedema, measured as extravascular lung water (EVLW). The chest radiograph (CXR) can potentially estimate the quantity of lung oedema while the transpulmonary thermodilution method measures the amount of EVLW. This study was designed to determine whether EVLW as estimated by a CXR score predicts EVLW measured by the thermodilution method and whether changes in EVLW by either approach predict mortality in ALI/ARDS.
Methods
Clinical data were collected within 48 hours of ALI/ARDS diagnosis and daily up to 14 days on 59 patients with ALI/ARDS. Two clinicians scored each CXR for the degree of pulmonary oedema, using a validated method. EVLW indexed to body weight was measured using the single indicator transpulmonary thermodilution technique.
Results
The CXR score had a modest, positive correlation with the EVLWI measurements (r = 0.35, p < 0.001). There was a 1.6 ml/kg increase in EVLWI per 10-point increase in the CXR score (p < 0.001, 95% confidence interval 0.92-2.35). The sensitivity of a high CXR score for predicting a high EVLWI was 93%; similarly the negative predictive value was high at 94%; the specificity (51%) and positive predictive value (50%) were lower. The CXR scores did not predict mortality but the EVLW thermodilution did predict mortality.
Conclusion
EVLW measured by CXR was modestly correlated with thermodilution measured EVLW. Unlike CXR findings, transpulmonary thermodilution EVLWI measurements over time predicted mortality in patients with ALI/ARDS.
doi:10.1186/2110-5820-3-25
PMCID: PMC3846630  PMID: 23937970
Extravascular lung water; Chest radiograph; Acute lung injury; Acute respiratory distress syndrome
10.  Clinical Evidence of Early Acute Lung Injury Often Precedes the Diagnosis of ALI 
Background
Acute lung injury (ALI) has been primarily defined in patients who require positive pressure ventilation. As a result, the clinical characteristics of patients with early ALI (EALI) prior to the need for mechanical ventilation have not been well characterized. Early identification of patients with ALI and the impending need for positive pressure ventilation could define a study population for trials of novel therapies.
Methods
We analyzed clinical data from 93 patients at 12, 24, and 48 hours prior to the standard diagnosis of ALI. The time of ALI diagnosis was defined when patients were mechanically ventilated and met the 1994 American–European Consensus Conference diagnostic criteria for ALI.
Results
The majority of patients with ALI presented to the hospital more than 24 hours prior to developing ALI. Specifically, 73% presented more than 12 hours prior to diagnosis, and 57% presented more than 24 hours prior to diagnosis. Of patients hospitalized for at least 12 hours prior to ALI diagnosis, 94% had either bilateral infiltrates on chest radiograph, tachypnea, or an oxygen requirement greater than 2 L/min; 79% and 48% had 2 and 3 of these abnormalities, respectively.
Conclusion
The majority of hospitalized patients who are destined to develop ALI demonstrate tachypnea, increased oxygen requirements, and/or bilateral infiltrates on chest radiograph more than 12 hours prior to meeting criteria for diagnosis. Some patients with EALI may be identified prior to meeting diagnostic criteria during a potential therapeutic window.
doi:10.1177/0885066612450850
PMCID: PMC3482421  PMID: 22733725
early acute lung injury; acute respiratory distress syndrome; diagnosis
11.  The Search for Diagnostic Markers in Sepsis 
doi:10.1164/rccm.201205-0854ED
PMCID: PMC3400993  PMID: 22753680
12.  Plasma angiopoietin-2 in clinical acute lung injury: Prognostic and pathogenetic significance* 
Critical care medicine  2012;40(6):1731-1737.
Background
Angiopoietin-2 is a proinflammatory mediator of endothelial injury in animal models, and increased plasma angiopoietin-2 levels are associated with poor outcomes in patients with sepsis-associated acute lung injury. Whether angiopoietin-2 levels are modified by treatment strategies in patients with acute lung injury is unknown.
Objectives
To determine whether plasma angiopoietin-2 levels are associated with clinical outcomes and affected by fluid management strategy in a broad cohort of patients with acute lung injury.
Design, Setting, and Participants
Plasma levels of angiopoietin-2 and von Willebrand factor (a traditional marker of endothelial injury) were measured in 931 subjects with acute lung injury enrolled in a randomized trial of fluid liberal vs. fluid conservative management.
Measurements and Main Results
The presence of infection (sepsis or pneumonia) as the primary acute lung injury risk factor significantly modified the relationship between baseline angiopoietin-2 levels and mortality (p = .01 for interaction). In noninfection-related acute lung injury, higher baseline angiopoietin-2 levels were strongly associated with increased mortality (odds ratio, 2.43 per 1-log increase in angiopoietin-2; 95% confidence interval, 1.57–3.75; p < .001). In infection-related acute lung injury, baseline angiopoietin-2 levels were similarly elevated in survivors and nonsurvivors; however, patients whose plasma angiopoietin-2 levels increased from day 0 to day 3 had more than double the odds of death compared with patients whose angiopoietin-2 levels declined over the same period of time (odds ratio, 2.29; 95% confidence interval, 1.54–3.43; p < .001). Fluid-conservative therapy led to a 15% greater decline in angiopoietin-2 levels from day 0 to day 3 (95% confidence interval, 4.6–24.8%; p = .006) compared with fluid-liberal therapy in patients with infection-related acute lung injury. In contrast, plasma levels of von Willebrand factor were significantly associated with mortality in both infection-related and noninfection-related acute lung injury and were not affected by fluid therapy.
Conclusions
Unlike von Willebrand factor, plasma angiopoietin-2 has differential prognostic value for mortality depending on the presence or absence of infection as an acute lung injury risk factor. Fluid conservative therapy preferentially lowers plasma angiopoietin-2 levels over time and thus may be beneficial in part by decreasing endothelial inflammation.
doi:10.1097/CCM.0b013e3182451c87
PMCID: PMC3601049  PMID: 22610178
acute respiratory distress syndrome; angiopoietin-2; biomarkers; endothelial injury; pulmonary edema; von Willebrand factor
13.  Critical Role of Activated Protein C in Early Coagulopathy and Later Organ Failure, Infection and Death in Trauma Patients 
Annals of surgery  2012;255(2):379-385.
Background
Recent studies have identified an acute traumatic coagulopathy that is present on admission to the hospital and is independent of iatrogenic causes. We have previously reported that this coagulopathy is due to the association of severe injury and shock and is characterized by a decrease in plasma protein C levels. Whether this early coagulopathy and later propensity to infection, MOF and mortality are associated with the activation of protein C pathway has not been demonstrated and constitutes the aim of this study.
Methods and Findings
This was a prospective cohort study of 203 major trauma patients. Serial blood samples were drawn on arrival in the ED, and at 6, 12, and 24 hours after admission to the hospital. PT, PTT, Va, VIIIa, PC aPC t-PA and D-Dimer levels were assayed. Comprehensive injury, resuscitation and outcome data were prospectively collected.
A total of 203 patients were enrolled. Patients with tissue hypoperfusion and severe traumatic injury showed a strong activation of the protein C which was associated with a coagulopathy characterized by inactivation of the coagulation factors V and VIII and a derepression of the fibrinolysis with high plasma levels of plasminogen activator and high D-dimers. Elevated plasma levels of activated protein C were significantly associated with increased mortality, organ injury, increased blood transfusion requirements, and reduced ICU ventilator-free days. Finally early depletion of protein C after trauma is associated with a propensity to post-traumatic ventilator-associated pneumonia.
Conclusions
Acute traumatic coagulopathy occurs in the presence of tissue hypoperfusion and severe traumatic injury and is mediated by activation of the protein C pathway. Higher plasma levels of aPC upon admission are predictive of poor clinical outcomes following major trauma. After activation, patients who fail to recover physiologic plasma values of protein C have an increased propensity to later nosocomial lung infection.
doi:10.1097/SLA.0b013e318235d9e6
PMCID: PMC3549308  PMID: 22133894
14.  Early Release of soluble RAGE After Severe Trauma in Humans 
The Journal of trauma  2010;68(6):1273-1278.
Objective
The receptor for advanced glycation endproducts (RAGE) recognizes a variety of ligands that play an important role in the posttraumatic inflammatory response. However, whether soluble RAGE (sRAGE) is released early after trauma-hemorrhage in humans and whether such a release is associated with the development of an inflammatory response and coagulopathy is not known and therefore constitutes the aim of the present study.
Methods
One hundred sixty eight patients were studied as part of a prospective cohort study of severe trauma patients admitted to a single Level 1 Trauma center. Blood was drawn within 10 minutes of arrival to the Emergency Department (ED) before the administration of any fluid resuscitation. sRAGE, TNF-a, IL-6, von Willebrand Factor (vWF), Angiopoietin-2 (Ang-2), Prothrombin time, (PT), prothrombin fragments 1+2 (PF1+2), soluble thrombomodulin (sTM), protein C (PC), plasminogen activator inhibitor-1 (PAI-1), and D-Dimers (fibrin degradation products) were measured using standard techniques. Base deficit was used as a measure of tissue hypoperfusion. Measurements were compared to outcome measures obtained from the electronic medical record and trauma registry.
Results
Plasma levels of sRAGE were increased within 30 minutes after severe trauma in humans and correlated with the severity of injury, early posttraumatic coagulopathy and hyperfibrinolysis as well as with endothelial cell activation (angiopoietin-1 and complement). Furthermore, we found that there was a significant relationship between plasma levels of sRAGE and the development of acute renal failure. This relationship was not quite significant for patients who developed acute lung injury (p=.11), although patients with less than 26 ventilator-free days had significantly higher plasma levels of sRAGE than those with more than 26 ventilator-free days. Finally, there was no relationship between plasma levels of sRAGE and mortality rate in trauma patients.
Conclusions
The results of this study demonstrate that the release of sRAGE in the bloodstream of trauma patients requires severe injury and is associated with coagulation abnormalities and endothelial cell and complement activation.
doi:10.1097/TA.0b013e3181db323e
PMCID: PMC3531976  PMID: 20539169
sRAGE; Trauma; Coagulopathy; Protein C; Complement
15.  A simple classification model for hospital mortality in patients with acute lung injury managed with lung protective ventilation 
Critical care medicine  2011;39(12):2645-2651.
Objective
Despite improvements in the care of critically-ill patients, hospital mortality for acute lung injury remains high at approximately 40%. We developed a classification rule to stratify mechanically ventilated patients with acute lung injury according to hospital mortality and compared this rule to the APACHE III prediction.
Patients
We used data of 2022 participants in ARDS Network trials to build a classification rule based on 54 variables collected prior to randomization.
Design
We used a classification tree approach to stratify patients according to hospital mortality using a training subset of 1800 participants, and estimated expected prediction errors using tenfold cross validation. We validated our classification tree using a subset of 222 participants not included in model building, and calculated areas under the receiver operating characteristic curves (AUCs).
Measurements and Main Results
We identified combinations of age (>63 years), BUN (>15 mg/dl), shock, respiratory rate (>21 breaths/minute), and minute ventilation (>13.9 L/minute) as important predictors of hospital mortality at 90 days. The classification tree had a similar expected prediction error in the training set (28% versus 26%; p=0.18) and AUC in the validation set (0.71 versus 0.73; p=0.71) as did a model based on APACHE III.
Conclusions
Our tree-based classification rule performed similarly to APACHE III in stratifying patients according to hospital mortality, is simpler to use, contains risk factors that may be specific to acute lung injury, and identified minute ventilation as a potential novel predictor of death in patients with acute lung injury.
doi:10.1097/CCM.0b013e3182266779
PMCID: PMC3227537  PMID: 21725235
16.  Fixing the leak: targeting the vascular endothelium in sepsis 
Critical Care  2012;16(6):177.
Angiopoietin-1 is a Tie-2 receptor agonist that stabilizes vascular endothelium, promoting endothelial maturation and preventing capillary leak. Angiopoietin-2 is largely a competitive partial antagonist that is markedly elevated in humans and animal models of sepsis and other inflammatory states, directly disrupts the endothelial barrier, and has been correlated with end-organ dysfunction and death in sepsis. In the previous issue of Critical Care, Alfieri and colleagues used intravital microscopy to study the microvasculature in a murine model of sepsis. Treatment with a modified angiopoietin-1 molecule led to reversal of albumin vascular leak and improved blood flow to skeletal muscle, as well as a decrease in the levels of several inflammatory cytokines. Importantly, the angiopoietin-1 variant was administered 20 hours after initial lipopolysaccharide challenge. This study adds to the evidence that the angiopoietin/Tie-2 axis represents a modifiable pathway through which targeted therapy may be able to directly reverse part of the pathology of sepsis.
doi:10.1186/cc11829
PMCID: PMC3672578  PMID: 23171759
17.  Active and Passive Cigarette Smoking and Acute Lung Injury after Severe Blunt Trauma 
Rationale: Cigarette smoking has been demonstrated in laboratory studies to have effects on lung epithelial and endothelial function similar to those observed in acute lung injury (ALI). However, the association between active and passive cigarette smoke exposure and susceptibility to ALI has not been prospectively studied.
Objectives: We hypothesized that both active and passive cigarette smoke exposure would be associated with increased susceptibility to ALI after severe blunt trauma.
Methods: We measured levels of cotinine, a metabolite of nicotine and validated biomarker of tobacco use, in plasma samples obtained immediately on arrival at the emergency department from 144 adult subjects after severe blunt trauma. Patients were then followed for the development of ALI.
Measurements and Main Results: Increasing quartiles of plasma cotinine were associated with the development of ALI (odds ratio [OR] for developing ALI in highest cotinine quartile, 3.25; 95% confidence interval [CI], 1.22–8.68; P = 0.017 for trend across quartiles). Moderate to heavy passive smoke exposure was associated with nearly the same odds of developing ALI as active smoking (OR for moderate to heavy passive smoking compared with no exposure or low level exposure, 3.03; 95% CI, 1.15–8.04; OR for active smoking, 2.77; 95% CI, 1.28–5.99). This association persisted after adjusting for other predictors of ALI, including Injury Severity Score and alcohol abuse.
Conclusions: Both moderate to heavy passive smoking and active smoking are independently associated with the development of ALI after severe blunt trauma. This finding has important implications both for public health and for understanding the pathogenesis of ALI.
doi:10.1164/rccm.201011-1802OC
PMCID: PMC3136993  PMID: 21471091
cigarette smoking; acute lung injury; acute respiratory distress syndrome; cotinine; secondhand smoke exposure
18.  ANGPT2 Genetic Variant Is Associated with Trauma-associated Acute Lung Injury and Altered Plasma Angiopoietin-2 Isoform Ratio 
Rationale: Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI.
Objectives: To identify ALI risk variants after major trauma using a large-scale candidate gene approach.
Methods: We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease–centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10−4) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot.
Measurements and Main Results: Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06–1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin-2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038).
Conclusions: An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility.
doi:10.1164/rccm.201005-0701OC
PMCID: PMC3114062  PMID: 21257790
acute lung injury; acute respiratory distress syndrome; functional genetic polymorphism; genetic association study
19.  Acute Lung Injury in Patients with Traumatic Injuries: Utility of a Panel of Biomarkers for Diagnosis and Pathogenesis 
The Journal of Trauma  2010;68(5):1121-1127.
Background
The diagnosis of acute lung injury (ALI) is based on a consensus clinical definition. Despite the simplicity of this definition, ALI remains underdiagnosed and undertreated. Severe trauma is a well-described cause of ALI that represents a relatively homogeneous subset of ALI patients. The goals of this study were to develop a panel of plasma biomarkers to facilitate diagnosis of trauma-induced ALI and to enhance our understanding of the pathogenesis of human ALI.
Methods
A retrospective nested case control of 192 patients admitted to the trauma intensive care unit (ICU) at a university hospital between 2002 and 2006. We compared 107 patients with ALI to 85 patients without ALI. Plasma was collected within 72 h of ICU admission. Twenty-one plasma biomarkers were measured in duplicate in each plasma sample.
Results
Patients with ALI had higher severity of illness scores, more days of mechanical ventilation, longer hospital stays and higher mortality versus controls. Seven biomarkers (RAGE, PCPIII, BNP, ANG2, IL10, TNF-α, and IL8) had a high diagnostic accuracy as reflected by the area under the receiver operating characteristic curve of 0.86 (95% CI 0.82 – 0.92) in differentiating ALI from controls.
Conclusions
A model utilizing seven plasma biomarkers had a high diagnostic accuracy in differentiating patients with trauma-induced ALI from trauma patients without ALI. In addition, use of a panel of biomarkers provides insight into the likely importance of alveolar epithelial injury in the pathogenesis of early acute lung injury.
doi:10.1097/TA.0b013e3181c40728
PMCID: PMC3347639  PMID: 20038857
Acute respiratory distress syndrome; acute pulmonary edema; pulmonary contusion; alveolar epithelium
20.  Plasma IL-8 is not an effective risk stratification tool for adults with vasopressor-dependent septic shock 
Critical Care Medicine  2010;38(6):1436-1441.
Objective
Plasma interleukin-8 (IL-8) levels of < 220 pg/ml have an excellent negative predictive value (94–95%) for death at 28 days in children with septic shock and thus may be useful for risk stratification in clinical trial enrollment in this population. Whether plasma IL-8 would have similar utility in adults with septic shock is unknown.
Design, Setting, and Patients
Analysis of plasma IL-8 levels in 192 adults with vasopressor-dependent septic shock enrolled in clinical trials of acute lung injury conducted by the Acute Respiratory Distress Syndrome Network
Measurements and Main Results
Plasma IL-8 levels ≥ 220 pg/ml were significantly associated with death at 28 days in this cohort (odds ratio 2.92, 95% CI 1.42–5.99; p=0.001). However, in contrast to the findings in pediatric septic shock, a plasma IL-8 cutoff below 220 pg/ml had a negative predictive value for death of only 74% (95% CI 66–81%) in adults with septic shock. Receiver-operating characteristic analysis found an area under the curve of 0.59 for plasma IL-8, indicating that plasma IL-8 is a poor predictor of mortality in this group. In adults under age 40, a plasma IL-8 cutoff < 220 pg/ml had a negative predictive value of 92%.
Conclusions
In contrast to similar pediatric patients, plasma IL-8 levels are not an effective risk stratification tool in older adults with septic shock. Future studies of biomarkers for risk stratification in critically ill subjects will need to be replicated in multiple different populations before being applied in screening for clinical trials.
doi:10.1097/CCM.0b013e3181de42ad
PMCID: PMC3348116  PMID: 20386309
interleukin-8; acute lung injury; sensitivity; specificity; negative predictive value; risk stratification
21.  Use of risk reclassification with multiple biomarkers improves mortality prediction in acute lung injury 
Critical Care Medicine  2011;39(4):711-717.
Objective
Multiple single biomarkers have been associated with poor outcomes in acute lung injury; however, no single biomarker has sufficient discriminating power to clearly indicate prognosis. Using both derivation and replication cohorts, we tested novel risk reclassification methods to determine whether measurement of multiple plasma biomarkers at the time of acute lung injury diagnosis would improve mortality prediction in acute lung injury.
Design
Analysis of plasma biomarker levels and prospectively collected clinical data from patients enrolled in two randomized controlled trials of ventilator therapy for acute lung injury.
Setting
Intensive care units of university hospitals participating in the National Institutes of Health Acute Respiratory Distress Syndrome Network.
Patients
Subjects enrolled in a trial of lower tidal volume ventilation (derivation cohort) and subjects enrolled in a trial of higher vs. lower positive end-expiratory pressure (replication cohort).
Interventions
None.
Measurements and Main Results
The plasma biomarkers were intercellular adhesion molecule-1, von Willebrand factor, interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D. In the derivation cohort (n = 547), adding data on these biomarkers to clinical predictors (Acute Physiology and Chronic Health Evaluation III score) at the time of study enrollment improved the accuracy of risk prediction, as reflected by a net reclassification improvement of 22% (95% confidence interval 13% to 32%; p < .001). In the replication cohort (n = 500), the net reclassification improvement was 17% (95% confidence interval 7% to 26%; p < .001). A reduced set of three biomarkers (interleukin-8, soluble tumor necrosis factor receptor-1, and surfactant protein-D) had nearly equivalent prognostic value in both cohorts.
Conclusions
When combined with clinical data, plasma biomarkers measured at the onset of acute lung injury can improve the accuracy of risk prediction. Combining three or more biomarkers may be useful for selecting a high-risk acute lung injury population for enrollment in clinical trials of novel therapies.
doi:10.1097/CCM.0b013e318207ec3c
PMCID: PMC3260884  PMID: 21283009
acute respiratory distress syndrome; biological marker; pulmonary edema; risk prediction; risk reclassification
22.  Genome Wide Association Identifies PPFIA1 as a Candidate Gene for Acute Lung Injury Risk Following Major Trauma 
PLoS ONE  2012;7(1):e28268.
Acute Lung Injury (ALI) is a syndrome with high associated mortality characterized by severe hypoxemia and pulmonary infiltrates in patients with critical illness. We conducted the first investigation to use the genome wide association (GWA) approach to identify putative risk variants for ALI. Genome wide genotyping was performed using the Illumina Human Quad 610 BeadChip. We performed a two-stage GWA study followed by a third stage of functional characterization. In the discovery phase (Phase 1), we compared 600 European American trauma-associated ALI cases with 2266 European American population-based controls. We carried forward the top 1% of single nucleotide polymorphisms (SNPs) at p<0.01 to a replication phase (Phase 2) comprised of a nested case-control design sample of 212 trauma-associated ALI cases and 283 at-risk trauma non-ALI controls from ongoing cohort studies. SNPs that replicated at the 0.05 level in Phase 2 were subject to functional validation (Phase 3) using expression quantitative trait loci (eQTL) analyses in stimulated B-lymphoblastoid cell lines (B-LCL) in family trios. 159 SNPs from the discovery phase replicated in Phase 2, including loci with prior evidence for a role in ALI pathogenesis. Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (p = 0.0021). PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions. This study supports the feasibility of future multi-center GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research.
doi:10.1371/journal.pone.0028268
PMCID: PMC3266233  PMID: 22295056
23.  Biomarkers increase detection of active smoking and secondhand smoke exposure in critically ill patients 
Critical care medicine  2011;39(1):40-45.
Objectives
The association between tobacco smoke exposure and critical illness is not well studied, largely because obtaining an accurate smoking history from critically ill patients is difficult. Biomarkers can provide quantitative data on active and secondhand cigarette smoke exposure. We sought to compare cigarette smoke exposure as measured by biomarkers to exposure by self-report in a cohort of critically ill patients and to determine how well biomarkers of cigarette smoke exposure correlate with each other in this population.
Design, Setting, and Patients
Serum and urine cotinine and trans-3′-hydroxycotinine, urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and hair and nail nicotine levels were measured in 60 subjects enrolled in an observational cohort of critically ill subjects at a tertiary academic medical center in Tennessee. Smoking history was obtained from patients, their surrogates, or the medical chart. Cigarette smoke exposure as measured by biomarkers was compared to exposure by history.
Measurements and Main Results
By smoking history, 29 subjects were identified as smokers, 28 were identified as nonsmokers, and 3 were identified as unknown. The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified 27 of the 28 nonsmokers by history either as active smokers (n = 6, 21%) or as exposed to secondhand smoke (n = 21, 75%). All biomarker levels were strongly correlated with each other (r = .69–.95, p < .0001).
Conclusions
The combination of serum cotinine and urine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol identified considerably more active smokers than did smoking history and detected a high prevalence of secondhand smoke exposure in a critically ill population. These markers will be important for future studies investigating the relationship between active smoking and secondhand smoke exposure and critical illness.
doi:10.1097/CCM.0b013e3181fa4196
PMCID: PMC3148017  PMID: 20935560
biomarkers; cigarette smoking; cotinine; NNAL; critically ill
24.  FGF-23 and PTH levels in patients with acute kidney injury: A cross-sectional case series study 
Background
Fibroblast growth factor-23 (FGF-23), a novel regulator of mineral metabolism, is markedly elevated in chronic kidney disease and has been associated with poor long-term outcomes. However, whether FGF-23 has an analogous role in acute kidney injury is unknown. The goal of this study was to measure FGF-23 levels in critically ill patients with acute kidney injury to determine whether FGF-23 levels were elevated, as in chronic kidney disease.
Methods
Plasma FGF-23 and intact parathyroid hormone (PTH) levels were measured in 12 patients with acute kidney injury and 8 control subjects.
Results
FGF-23 levels were significantly higher in acute kidney injury cases than in critically ill subjects without acute kidney injury, with a median FGF-23 level of 1948 RU/mL (interquartile range (IQR), 437-4369) in cases compared with 252 RU/mL (IQR, 65-533) in controls (p = 0.01). No correlations were observed between FGF-23 and severity of acute kidney injury (defined by the Acute Kidney Injury Network criteria); among patients with acute kidney injury, FGF-23 levels were higher in nonsurvivors than survivors (median levels of 4446 RU/mL (IQR, 3455-5443) versus 544 RU/mL (IQR, 390-1948; p = 0.02). Severe hyperparathyroidism (defined as intact PTH >250 mg/dL) was present in 3 of 12 (25%) of the acute kidney injury subjects versus none of the subjects without acute kidney injury, although this result did not meet statistical significance.
Conclusions
We provide novel data that demonstrate that FGF-23 levels are elevated in acute kidney injury, suggesting that FGF-23 dysregulation occurs in acute kidney injury as well as chronic kidney disease. Further studies are needed to define the short- and long-term clinical effects of dysregulated mineral metabolism in acute kidney injury patients.
doi:10.1186/2110-5820-1-21
PMCID: PMC3224491  PMID: 21906363
25.  Culprits with evolutionary ties 
Nature  2010;464(7285):41-42.
The cellular organelles we know as mitochondria are thought to have originated as symbiotic bacteria. Indeed, the two use common mechanisms to trigger innate immune responses to injury and infection, respectively.
doi:10.1038/464041a
PMCID: PMC2857339  PMID: 20203598

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