The bronchoalveolar lavage dilution conundrum: an updated view on a long-standing problem.

Bronchoalveolar lavage (BAL) is used by researchers to study molecular interactions within healthy and diseased human lungs. However, the utility of BAL fluid measurements may be limited by difficulties accounting for dilution of the epithelial lining fluid (ELF) sampled and inconsistent collection techniques. The use of endogenous markers to estimate ELF dilution has been proposed as a potential method to normalize acellular molecule measurements in BAL fluid, but these markers are also imperfect and prone to inaccuracy. The focus of this report is to review factors that affect the interpretation of acellular molecule measurements in lung ELF and present original data comparing the performance of several BAL dilution markers during health and in a human endobronchial endotoxin challenge model of acute inflammation. Our findings suggest that incomplete ELF and lavage fluid mixing, flux of markers across the alveolar barrier, and lung inflammation are all possible factors that can affect marker performance. Accounting for these factors, we show that commonly used markers including urea, total protein, albumin, and immunoglobulin M are likely unreliable BAL dilution markers. In contrast, surfactant protein D appears to be less affected by these factors and may be a more accurate and biologically plausible marker to improve the reproducibility of acellular BAL component measurements across individuals during health and inflammatory states.NEW & NOTEWORTHY In this report, mathematical prediction models and real-world measurements are used to compare the performance of molecular markers of dilution in bronchoalveolar lavage fluid samples. Effects of acute inflammation within individual subjects are highlighted. These findings inform recommendations for normalizing measurements across bronchoalveolar lavage samples and highlight the need for additional markers to improve the rigor of translational studies utilizing bronchoalveolar lavage measurements.

Single-cell RNA sequencing reveals unique monocyte-derived interstitial macrophage subsets during lipopolysaccharide-induced acute lung inflammation.

Interstitial macrophages (IMs) reside in the lung tissue surrounding key structures including airways, vessels, and alveoli. Recent work has described IM heterogeneity during homeostasis, however, there are limited data on IMs during inflammation. We sought to characterize IM origin, subsets, and transcriptomic profiles during homeostasis and lipopolysaccharide (LPS) induced acute lung inflammation. During homeostasis, we used three complementary methods, spectral flow cytometry, single-cell RNA-sequencing, and gene regulatory network enrichment, to demonstrate that IMs can be divided into two core subsets distinguished by surface and transcriptional expression of folate receptor ß (Folr2/FRß). These subsets inhabited distinct niches within the lung interstitium. Within FRß+ IMs we identified a subpopulation marked by coexpression of LYVE1. During acute LPS-induced inflammation, lung IM numbers expand. Lineage tracing revealed IM expansion was due to recruitment of monocyte-derived IMs. At the peak of inflammation, recruited IMs were comprised two unique subsets defined by expression of genes associated with interferon signaling and glycolytic pathways. As recruited IMs matured, they adopted the overall transcriptional state of FRß- resident IMs but retained expression in several origin-specific genes, such as IL-1ß. FRß+ IMs were of near-pure resident origin. Taken together our data show that during LPS-induced inflammation, there are distinct populations of IMs that likely have unique functions. FRΒ+ IMs comprise a stable, resident population, whereas FRß- ΙΜs represent a mixed population of resident and recruited IMs.

Management of Acute Kidney Injury: Core Curriculum 2018.

Acute kidney injury (AKI) is a heterogeneous disorder that is common in hospitalized patients and associated with short- and long-term morbidity and mortality. When AKI is present, prompt workup of the underlying cause should be pursued, with specific attention to reversible causes. Measures to prevent AKI include optimization of volume status and avoidance of nephrotoxic medications. Crystalloids are preferred over colloids for most patients, and hydroxyethyl starches should be avoided. Volume overload in the setting of AKI is associated with adverse outcomes, so attention should be paid to overall fluid balance. Currently there are no targeted pharmacotherapies approved for the treatment of AKI. The optimal timing of renal replacement therapy in critically ill patients with AKI is unclear, but is an area of active investigation. Recent studies suggest that AKI is not a "self-limited" process, but is strongly linked to increased risk for chronic kidney disease, subsequent AKI, and future mortality.

Fibrinolysis Resistance After Injury Is a Risk Factor for a Hospital-Acquired Pneumonia-Like Disease Pattern.

Background: Pneumonia is associated with increased morbidity and costs in the intensive care unit (ICU). Its early identification is key for optimal outcomes, but early biomarkers are lacking. Studies suggest that fibrinolysis resistance (FR) after major abdominal surgery is linked to an increased risk of infection. Patients and Methods: Patients in a randomized controlled trial for hemorrhagic shock were evaluated for FR. Fibrinolysis resistance was quantified by thrombelastography with exogenous tissue plasminogen activator (tPA-TEG) at 24- and 48-hours post-injury and measuring LY30 (%). A receiver-operating characteristics (ROC) curve analysis was used to identify a cutoff for increased risk of pneumonia, which was then validated in ICU patients at risk for venous thromboembolism (VTE). Multivariable logistic regression was used to control for confounders. Results: Forty-nine patients in the hemorrhagic shock cohort had tPA-TEGs at 24- and 48-hours (median ISS, 27; 7% pneumonia). A composite tPA-TEG LY30 of less than 4% at 24 and 48 hours was found to be the optimal cutoff for increased risk of pneumonia. This cohort had a seven-fold increased rate of pneumonia (4% vs. 28%; p = 0.048). Eighty-eight patients in the VTE cohort had tPA-TEGs at 24 and 48 hours post-ICU admission (median ISS, 28; 6% pneumonia). The tPA-TEG LY30 of less than 4% was associated with a 10-fold increased rate of pneumonia (19% vs. 1.5%; p = 0.002). In patients with traumatic brain injury, the same association was found (33% vs. 3.2%; p = 0.006). Adjusting for confounders, the tPA-TEG persisted as a substantial risk factor for pneumonia (adjusted odds ratio [OR], 35.7; 95% confidence interval [CI], 1.9-682; p = 0.018). Conclusions: Fibrinolysis resistance quantified by tPA-TEG within 48 hours of ICU admission is associated with an increased risk of pneumonia in patients in hemorrhagic shock and those at risk for VTE. Prospective validation of the tPA-TEG LY30 optimal cutoff for pneumonia and further investigation into whether endogenous FR is a cause of an altered immunity is warranted.

Neutrophil-mediated Inflammatory Plasminogen Degradation, Rather Than High Plasminogen-Activator Inhibitor-1, May Underly Failures and Inefficiencies of Intrapleural Fibrinolysis.

BACKGROUND: Complex pleural space infections often require treatment with multiple doses of intrapleural tissue plasminogen activator (tPA) and deoxyribonuclease, with treatment failure frequently necessitating surgery. Pleural infections are rich in neutrophils, and neutrophil elastase degrades plasminogen, the target substrate of tPA, that is required to generate fibrinolysis. We hypothesized that pleural fluid from patients with pleural space infection would show high elastase activity, evidence of inflammatory plasminogen degradation, and low fibrinolytic potential in response to tPA that could be rescued with plasminogen supplementation. RESEARCH QUESTION: Does neutrophil elastase degradation of plasminogen contribute to intrapleural fibrinolytic failure? STUDY DESIGN AND METHODS: We obtained infected pleural fluid and circulating plasma from hospitalized adults (n = 10) with institutional review board approval from a randomized trial evaluating intrapleural fibrinolytics vs surgery for initial management of pleural space infection. Samples were collected before the intervention and on days 1, 2, and 3 after the intervention. Activity assays, enzyme-linked immunosorbent assays, and Western blot analysis were performed, and turbidimetric measurements of fibrinolysis were obtained from pleural fluid with and without exogenous plasminogen supplementation. Results are reported as median (interquartile range) or number (percentage) as appropriate, with an α value of .05. RESULTS: Pleural fluid elastase activity was more than fourfold higher (P = .02) and plasminogen antigen levels were more than threefold lower (P = .04) than their corresponding plasma values. Pleural fluid Western blot analysis demonstrated abundant plasminogen degradation fragments consistent with elastase degradation patterns. We found that plasminogen activator inhibitor 1 (PAI-1), the native tPA inhibitor, showed high antigen levels before the intervention, but the overwhelming majority of this PAI-1 (82%) was not active (P = .003), and all PAI-1 activity was lost by day 2 after the intervention in patients receiving intrapleural tPA and deoxyribonuclease. Finally, using turbidity clot lysis assays, we found that the pleural fluid of 9 of 10 patients was unable to generate a significant fibrinolytic response when challenged with tPA and that plasminogen supplementation rescued fibrinolysis in all patients. INTERPRETATION: Our findings suggest that inflammatory plasminogen deficiency, not high PAI-1 activity, is a significant contributor to intrapleural fibrinolytic failure. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03583931; URL: www. CLINICALTRIALS: gov.

MUlticenter STudy of tissue plasminogen activator (alteplase) use in COVID-19 severe respiratory failure (MUST COVID): A retrospective cohort study.

Background: Few therapies exist to treat severe COVID-19 respiratory failure once it develops. Given known diffuse pulmonary microthrombi on autopsy studies of COVID-19 patients, we hypothesized that tissue plasminogen activator (tPA) may improve pulmonary function in COVID-19 respiratory failure. Methods: A multicenter, retrospective, observational study of patients with confirmed COVID-19 and severe respiratory failure who received systemic tPA (alteplase) was performed. Seventy-nine adults from seven medical centers were included in the final analysis after institutional review boards' approval; 23 were excluded from analysis because tPA was administered for pulmonary macroembolism or deep venous thrombosis. The primary outcome was improvement in the PaO2/FiO2 ratio from baseline to 48 h after tPA. Linear mixed modeling was used for analysis. Results: tPA was associated with significant PaO2/FiO2 improvement at 48 h (estimated paired difference = 23.1 ± 6.7), which was sustained at 72 h (interaction term p < 0.00). tPA administration was also associated with improved National Early Warning Score 2 scores at 24, 48, and 72 h after receiving tPA (interaction term p = 0.00). D-dimer was significantly elevated immediately after tPA, consistent with lysis of formed clot. Patients with declining respiratory status preceding tPA administration had more marked improvement in PaO2/FiO2 ratios than those who had poor but stable (not declining) respiratory status. There was one intracranial hemorrhage, which occurred within 24 h following tPA administration. Conclusions: These data suggest tPA is associated with significant improvement in pulmonary function in severe COVID-19 respiratory failure, especially in patients whose pulmonary function is in decline, and has an acceptable safety profile in this patient population.

Study of Alteplase for Respiratory Failure in SARS-CoV-2 COVID-19: A Vanguard Multicenter, Rapidly Adaptive, Pragmatic, Randomized Controlled Trial.

BACKGROUND: Pulmonary vascular microthrombi are a proposed mechanism of COVID-19 respiratory failure. We hypothesized that early administration of tissue plasminogen activator (tPA) followed by therapeutic heparin would improve pulmonary function in these patients. RESEARCH QUESTION: Does tPA improve pulmonary function in severe COVID-19 respiratory failure, and is it safe? STUDY DESIGN AND METHODS: Adults with COVID-19-induced respiratory failure were randomized from May14, 2020 through March 3, 2021, in two phases. Phase 1 (n = 36) comprised a control group (standard-of-care treatment) vs a tPA bolus (50-mg tPA IV bolus followed by 7 days of heparin; goal activated partial thromboplastin time [aPTT], 60-80 s) group. Phase 2 (n = 14) comprised a control group vs a tPA drip (50-mg tPA IV bolus, followed by tPA drip 2 mg/h plus heparin 500 units/h over 24 h, then heparin to maintain aPTT of 60-80 s for 7 days) group. Patients were excluded from enrollment if they had not undergone a neurologic examination or cross-sectional brain imaging within the previous 4.5 h to rule out stroke and potential for hemorrhagic conversion. The primary outcome was Pao2 to Fio2 ratio improvement from baseline at 48 h after randomization. Secondary outcomes included Pao2 to Fio2 ratio improvement of > 50% or Pao2 to Fio2 ratio of ≥ 200 at 48 h (composite outcome), ventilator-free days (VFD), and mortality. RESULTS: Fifty patients were randomized: 17 in the control group and 19 in the tPA bolus group in phase 1 and eight in the control group and six in the tPA drip group in phase 2. No severe bleeding events occurred. In the tPA bolus group, the Pao2 to Fio2 ratio values were significantly (P < .017) higher than baseline at 6 through 168 h after randomization; the control group showed no significant improvements. Among patients receiving a tPA bolus, the percent change of Pao2 to Fio2 ratio at 48 h (16.9% control [interquartile range (IQR), -8.3% to 36.8%] vs 29.8% tPA bolus [IQR, 4.5%-88.7%]; P = .11), the composite outcome (11.8% vs 47.4%; P = .03), VFD (0.0 [IQR, 0.0-9.0] vs 12.0 [IQR, 0.0-19.0]; P = .11), and in-hospital mortality (41.2% vs 21.1%; P = .19) did not reach statistically significant differences when compared with those of control participants. The patients who received a tPA drip did not experience benefit. INTERPRETATION: The combination of tPA bolus plus heparin is safe in severe COVID-19 respiratory failure. A phase 3 study is warranted given the improvements in oxygenation and promising observations in VFD and mortality. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT04357730; URL: www. CLINICALTRIALS: gov.

The plasma fraction of stored erythrocytes augments pancreatic cancer metastasis in male versus female mice.

BACKGROUND: Males with pancreatic cancer have decreased survival compared with females. Interestingly, perioperative blood transfusions have been shown to reduce survival in patients with pancreatic adenocarcinoma. Recent evidence incriminates blood transfusions from female donors as a causative factor in acute lung injury. We therefore hypothesize that male mice with pancreatic cancer will have greater tumor progression than female mice in response to transfusion. METHODS: Mice previously inoculated with pancreatic cancer cells received an intravenous injection of acellular plasma collected from single donor erythrocytes from either male or female donors. Control mice received an equal volume of intravenous saline. Necropsy to determine metastasis was performed in female mice at 4 wk status post-transfusion. The male group necessitated sacrifice at 3 wk post-transfusion due to clinical deterioration. RESULTS: Male mice developed more metastatic events than female mice, and this was accentuated when receiving blood from female donors. Male mice experienced weight loss within 2 wk of tail vein injection, and three mice in the male transfused groups died secondary to malignancy. Female mice did not manifest substantial weight loss, and did not die in the study time period. CONCLUSION: Male mice, compared with female, had significantly more metastatic events following transfusion of plasma from stored erythrocytes in an immunocompetent murine model of pancreatic adenocarcinoma. Moreover, the adverse effect of transfusion was augmented with female donor blood. These data are consistent with clinical outcomes from centers of excellence in treating pancreatic cancer and warrant further investigation.

Study of alteplase for respiratory failure in severe acute respiratory syndrome coronavirus 2/COVID-19: Study design of the phase IIa STARS trial.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused a large surge of acute respiratory distress syndrome (ARDS). Prior phase I trials (non-COVID-19) demonstrated improvement in pulmonary function in patients ARDS using fibrinolytic therapy. A follow-up trial using the widely available tissue-type plasminogen activator (t-PA) alteplase is now needed to assess optimal dosing and safety in this critically ill patient population. Objective: To describe the design and rationale of a phase IIa trial to evaluate the safety and efficacy of alteplase treatment for moderate/severe COVID-19-induced ARDS. Patients/Methods: A rapidly adaptive, pragmatic, open-label, randomized, controlled, phase IIa clinical trial will be conducted with 3 groups: intravenous alteplase 50 mg, intravenous alteplase 100 mg, and control (standard-of-care). Inclusion criteria are known/suspected COVID-19 infection with PaO2/FiO2 ratio <150 mm Hg for > 4 hours despite maximal mechanical ventilation management. Alteplase will be delivered through an initial bolus of 50 mg or 100 mg followed by heparin infusion for systemic anticoagulation, with alteplase redosing if there is a >20% PaO2/FiO2 improvement not sustained by 24 hours. Results: The primary outcome is improvement in PaO2/FiO2 at 48 hours after randomization. Other outcomes include ventilator- and intensive care unit-free days, successful extubation (no reintubation ≤3 days after initial extubation), and mortality. Fifty eligible patients will be enrolled in a rapidly adaptive, modified stepped-wedge design with 4 looks at the data. Conclusion: Findings will provide timely information on the safety, efficacy, and optimal dosing of t-PA to treat moderate/severe COVID-19-induced ARDS, which can be rapidly adapted to a phase III trial (NCT04357730; FDA IND 149634).

Fibrinolysis Shutdown Correlation with Thromboembolic Events in Severe COVID-19 Infection.

BACKGROUND: COVID-19 predisposes patients to a prothrombotic state with demonstrated microvascular involvement. The degree of hypercoagulability appears to correlate with outcomes; however, optimal criteria to assess for the highest-risk patients for thrombotic events remain unclear; we hypothesized that deranged thromboelastography measurements of coagulation would correlate with thromboembolic events. STUDY DESIGN: Patients admitted to an ICU with COVID-19 diagnoses who had thromboelastography analyses performed were studied. Conventional coagulation assays, d-dimer levels, and viscoelastic measurements were analyzed using a receiver operating characteristic curve to predict thromboembolic outcomes and new-onset renal failure. RESULTS: Forty-four patients with COVID-19 were included in the analysis. Derangements in coagulation laboratory values, including elevated d-dimer, fibrinogen, prothrombin time, and partial thromboplastin time, were confirmed; viscoelastic measurements showed an elevated maximum amplitude and low lysis of clot at 30 minutes. A complete lack of lysis of clot at 30 minutes was seen in 57% of patients and predicted venous thromboembolic events with an area under the receiver operating characteristic curve of 0.742 (p = 0.021). A d-dimer cutoff of 2,600 ng/mL predicted need for dialysis with an area under the receiver operating characteristic curve of 0.779 (p = 0.005). Overall, patients with no lysis of clot at 30 minutes and a d-dimer > 2,600 ng/mL had a venous thromboembolic event rate of 50% compared with 0% for patients with neither risk factor (p = 0.008), and had a hemodialysis rate of 80% compared with 14% (p = 0.004). CONCLUSIONS: Fibrinolysis shutdown, as evidenced by elevated d-dimer and complete failure of clot lysis at 30 minutes on thromboelastography predicts thromboembolic events and need for hemodialysis in critically ill patients with COVID-19. Additional clinical trials are required to ascertain the need for early therapeutic anticoagulation or fibrinolytic therapy to address this state of fibrinolysis shutdown.

Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov decision analysis.

BACKGROUND: COVID-19 threatens to quickly overwhelm our existing critical care infrastructure in the USA. Systemic tissue plasminogen activator (tPA) has been previously demonstrated to improve PaO2/FiO2 (mmHg) when given to critically ill patients with acute respiratory distress syndrome (ARDS). It is unclear to what extent tPA may impact population-based survival during the current US COVID-19 pandemic. METHODS: A decision analytic Markov state transition model was created to simulate the life critically ill COVID-19 patients as they transitioned to either recovery or death. Two patient groups were simulated (50,000 patients in each group); (1) Patients received tPA immediately upon diagnosis of ARDS and (2) patients received standard therapy for ARDS. Base case critically ill COVID-19 patients were defined as having a refractory PaO2/FiO2 of < 60 mmHg (salvage use criteria). Transition from severe to moderate to mild ARDS, recovery, and death were estimated. Markov model parameters were extracted from existing ARDS/COVID-19 literature. RESULTS: The use of tPA was associated with reduced mortality (47.6% [tTPA] vs. 71.0% [no tPA]) for base case patients. When extrapolated to the projected COVID-19 eligible for salvage use tPA in the USA, peak mortality (deaths/100,000 patients) was reduced for both optimal social distancing (70.5 [tPA] vs. 75.0 [no tPA]) and no social distancing (158.7 [tPA] vs. 168.8 [no tPA]) scenarios. CONCLUSIONS: Salvage use of tPA may improve recovery of ARDS patients, thereby reducing COVID-19-related mortality and ensuring sufficient resources to manage this pandemic.

Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series.

A prothrombotic coagulopathy is commonly found in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). A unique feature of COVID-19 respiratory failure is a relatively preserved lung compliance and high Alveolar-arterial oxygen gradient, with pathology reports consistently demonstrating diffuse pulmonary microthrombi on autopsy, all consistent with a vascular occlusive etiology of respiratory failure rather than the more classic findings of low-compliance in ARDS. The COVID-19 pandemic is overwhelming the world's medical care capacity with unprecedented needs for mechanical ventilators and high rates of mortality once patients progress to needing mechanical ventilation, and in many environments including in parts of the United States the medical capacity is being exhausted. Fibrinolytic therapy has previously been used in a Phase 1 clinical trial that led to reduced mortality and marked improvements in oxygenation. Here we report a series of three patients with severe COVID-19 respiratory failure who were treated with tissue plasminogen activator. All three patients had a temporally related improvement in their respiratory status, with one of them being a durable response.

Fibrinolytic therapy for refractory COVID-19 acute respiratory distress syndrome: Scientific rationale and review.

The coronavirus disease 2019 (COVID-19) pandemic has caused respiratory failure and associated mortality in numbers that have overwhelmed global health systems. Thrombotic coagulopathy is present in nearly three quarters of patients with COVID-19 admitted to the intensive care unit, and both the clinical picture and pathologic findings are consistent with microvascular occlusive phenomena being a major contributor to their unique form of respiratory failure. Numerous studies are ongoing focusing on anticytokine therapies, antibiotics, and antiviral agents, but none to date have focused on treating the underlying thrombotic coagulopathy in an effort to improve respiratory failure in COVID-19. There are animal data and a previous human trial demonstrating a survival advantage with fibrinolytic therapy to treat acute respiratory distress syndrome. Here, we review the extant and emerging literature on the relationship between thrombotic coagulopathy and pulmonary failure in the context of COVID-19 and present the scientific rationale for consideration of targeting the coagulation and fibrinolytic systems to improve pulmonary function in these patients.

Three-dimensional patterns in the Lengyel-Rabai-Epstein model of the chlorine dioxide-iodine-malonic acid reaction.

We present computational solutions to the Lengyel-Rabai-Epstein model in three space dimensions. The results show that three-dimensional patterns exist and that they differ significantly from the two-dimensional patterns. Patterns occur at three locations in the reactor corresponding to peaks in the one-dimensional concentration of the starch tri-iodide concentration. Each pattern possesses its own intrinsic wavelength and is neither striped nor hexagonal, the two types that have been shown to exist in two dimensions. Computations suggest a bifurcation exists as a function of the reactor thickness. Solutions are computed using a high-order adaptive finite element method coupled with a multistep integrator in time. Linear systems generated in the multistep solver are solved using the iterative method GMRES with a Jacobi preconditioner. Matrix storage is reduced by incomplete assembly via thresholding. Preconditioner factorization and matrix-vector multiplication efficiency are enhanced by the use of OPENMP.

A Man in His 50s With Hemoptysis, Dyspnea, and Bilateral Patchy Ground-Glass Opacities.

CASE PRESENTATION: A man in his 50s presented to the ED with a 3-day history of small-volume hemoptysis and new-onset dyspnea. The patient did not have fevers, chills, chest pain, abdominal pain, or changes in urination. His medical history included hypertension, a 35-pack-year active smoking history, and occupational hydrocarbon exposure as a mechanic in the foresting industry. He reported no recent travels, and he denied sick contacts. His medications included amlodipine, hydrochlorothiazide, lisinopril, omeprazole, and nicotine replacement therapy.

Higher prevalence of detectable troponin I among cocaine-users without known cardiovascular disease.

BACKGROUND: While cocaine use is an established risk factor for acute cardiovascular complications, associations between cocaine use and markers of cardiac injury outside of acute hospital presentation remain poorly characterized. We leveraged advances in cardiac troponin (cTnI) testing to assess low but clinically meaningful levels of cardiac injury among cocaine users and non-users. METHODS: We conducted a case control study comparing cTnI levels by the presence of cocaine among patients presenting for non-cardiac care in an urban safety net hospital. Samples were chosen sequentially among those for which urine drug screens were ordered by providers hospital-wide. RESULTS: During 2015, 14% of all hospital drug screens ordered were cocaine-positive. Among unique persons providing cocaine-positive (N=100) and cocaine-negative (N=100) samples, 37% were female, 45% were African-American and the median age was 51. Detectable cTnI (> 0.02ng/mL) was observed in 21 samples (11%). It was more common in subjects using cocaine (Adjusted OR=2.81; 95% CI=1.03-7.65), but not other drugs. Moreover, there was a significant correlation between concentrations of cTnI and the cocaine metabolite, benzoylecgonine (Spearman Correlation=0.34, p<0.01). CONCLUSIONS: Among urban safety net hospital patients, 11% had detectable cTnI, and cTnI concentration was significantly correlated with benzoylecgonine concentration. While these preliminary results require additional confirmation, they suggest the potential utility of considering cocaine use as more than just an episodic exposure leading to acute cardiac events. The consideration of cocaine use as an ongoing chronic exposure leading to subclinical cardiac injury may improve risk-stratification and patient outcomes in populations where cocaine use is high.

Prehospital hemoglobin-based oxygen carrier resuscitation attenuates postinjury acute lung injury.

BACKGROUND: Crystalloid infusion has been the standard prehospital fluid resuscitation in the United States for the past 35 years, but the emergence of a safe and effective hemoglobin-based oxygen carrier (HBOC) may change that practice. The purpose of this in vivo study is to simulate an existing multicenter prehospital trial of HBOC versus crystalloid to determine the effects in a controlled 2-event construct of postinjury multiple organ failure. METHODS: Rats underwent hemorrhagic shock (30 mm Hg x 45 min) and were resuscitated over 2 hours in a clinically relevant design: 2 x volume of shed blood (SB) using normal saline (NS) in the first 30 minutes; 1/2 volume of SB in the next 30 minutes; another 2 x SB volume with NS over the remaining 60 minutes. Study groups represented alternative fluid strategies during the first hour of resuscitation: (1) Inhospital SB (standard resuscitation), (2) Inhospital HBOC, (3) Prehospital SB, and (4) Prehospital HBOC. Global physiologic response was assessed via tissue oxygenation (near infrared spectroscopy) and arterial base deficit, and pulmonary response, via lung polymorphonuclear neutrophil accumulation and vascular permeability. RESULTS: Prehospital HBOC resuscitation provided the most efficient recovery of tissue oxygenation and correction of base deficit, had the greatest reduction in pulmonary polymorphonuclear neutrophil accumulation, and abrogated acute lung injury. Prehospital SB and Inhospital HBOC regimens afforded intermediate lung protection, compared with standard resuscitation. CONCLUSIONS: The findings in this controlled in vivo study suggest prehospital HBOC resuscitation improves the recovery from postshock oxygen debt and reduces postinjury organ dysfunction.

Polymerized hemoglobin induces heme oxygenase-1 protein expression and inhibits intercellular adhesion molecule-1 protein expression in human lung microvascular endothelial cells.

BACKGROUND: Our clinical trials using a polymerized hemoglobin solution (PolyHb) as a red cell substitute in severely injured patients suggested that this hemoglobin-based oxygen carrier has a systemic antiinflammatory effect. Heme oxygenase-1 (HO-1) has recently been shown to be cytoprotective, and is known to be induced by heme moieties. We investigated the effects of this hemoglobin-based oxygen carrier on HO-1 induction and proinflammatory activation of pulmonary endothelium. STUDY DESIGN: Human lung microvascular endothelial cells were grown to confluence and preincubated with either cell media (control) or with an equal volume mixture of polymerized hemoglobin/cell media (experimental). The cell cultures were subsequently stimulated with lipopolysaccharide. HO-1 expression was detected by protein immunoblot and further quantified by ELISA; intercellular adhesion molecule-1 protein expression was measured by flow cytometry. RESULTS: Polymerized hemoglobin induced synthesis of HO-1 protein in human lung microvascular endothelial cells and, concurrently, inhibited lipopolysaccharide-induced intercellular adhesion molecule-1 protein cell surface expression. CONCLUSIONS: Polymerized hemoglobin attenuates lipopolysaccharide-stimulated expression of intercellular adhesion molecule-1 protein, which is associated with upregulation of the cytoprotective protein HO-1 in human pulmonary endothelial cells. This antiinflammatory effect offers a novel mechanism by which hemoglobin-based oxygen carrier solutions may be exploited therapeutically as resuscitative fluids.

The abdominal compartment syndrome as a second insult during systemic neutrophil priming provokes multiple organ injury.

In our recent clinical study of damage control laparotomy, the abdominal compartment syndrome (ACS) emerged as an independent risk factor for postinjury multiple organ failure (MOF). We and others have shown previously that the ACS promotes the systemic production of proinflammatory cytokines. Our study objective was to develop a clinically relevant two-event animal model of postinjury MOF using the ACS as a second insult during systemic neutrophil priming to provoke organ dysfunction. Male adult rats underwent hemorrhagic shock (30 mmHg x 45 min) and were resuscitated with crystalloids and shed blood. The timing of postshock systemic neutrophil (PMN) priming was determined by the surface expression of CD11b via flow cytometry. Finding maximal PMN priming at 8 h, but no priming at 2 h (early) and 18 h (late), the ACS (25 mmHg x 60 min) was introduced at these time points. At 24 h postshock, lung injury was assessed by lung elastase concentration and Evans blue dye extravasation in bronchoalveolar lavage. Liver and renal injuries were determined by serum alanine aminotransferase, serum creatinine, and blood urea nitrogen. The ACS during the time of maximal systemic PMN priming (8 h) provoked lung and liver injury, but did not if introduced at 2 or 18 h postshock when there was no evidence of systemic PMN priming. The 24-h mortality of this two-event model was 33%. These findings corroborate the potential for the ACS to promote multiple organ injury when occurring at the time of systemic PMN priming. This clinically relevant two-event animal model of PMN organ injury may be useful in elucidating therapy strategies to prevent postinjury MOF.