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Plasma gelsolin (pGSN) is the secreted isoform of an intracellular actin remodeling protein found in high concentrations in human plasma. Clinical studies demonstrate reduced pGSN concentrations in several disease states, including severe trauma, burns, and sepsis. Markedly decreased pGSN concentrations in these conditions precede and predict adverse clinical outcomes. In this study, we measured pGSN in patients with chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and dysregulated inflammation. pGSN was quantified using a sandwich ELISA in plasma from healthy volunteers, clinically stable CGD patients, and X-linked CGD carriers and in sera from 12 CGD patients undergoing bone marrow transplantation. pGSN was also quantified in healthy volunteers challenged with intravenous endotoxin. pGSN concentrations were lower in CGD patients without active infection or systemic inflammation compared with healthy control subjects. In CGD patients undergoing bone marrow transplantation, pGSN concentrations increased significantly following successful transplant. X-linked carriers of CGD had normal pGSN. Despite reduction of pGSN in CGD patients, we did not detect significant changes in pGSN over 24 h following challenge of healthy volunteers with intravenous endotoxin (4 ng/kg) that elicited a febrile response. We describe, for the first time, significantly lower pGSN in clinically stable patients with CGD compared with age- and sex-matched healthy volunteers. Low pGSN levels in CGD patients significantly increased following bone marrow transplantation. X-linked carriers of CGD had normal pGSN. In healthy volunteers challenged with intravenous endotoxin, pGSN is not an acute phase reactant.

PURPOSE: To develop an isotropic high-resolution stack-of-spirals UTE sequence for pulmonary imaging at 0.55 Tesla by leveraging a combination of robust respiratory-binning, trajectory correction, and concomitant-field corrections. METHODS: A stack-of-spirals golden-angle UTE sequence was used to continuously acquire data for 15.5 minutes. The data was binned to a stable respiratory phase based on superoinferior readout self-navigator signals. Corrections for trajectory errors and concomitant field artifacts, along with image reconstruction with conjugate gradient SENSE, were performed inline within the Gadgetron framework. Finally, data were retrospectively reconstructed to simulate scan times of 5, 8.5, and 12 minutes. Image quality was assessed using signal-to-noise, image sharpness, and qualitative reader scores. The technique was evaluated in healthy volunteers, patients with coronavirus disease 2019 infection, and patients with lung nodules. RESULTS: The technique provided diagnostic quality images with parenchymal lung SNR of 3.18 ± 0.0.60, 4.57 ± 0.87, 5.45 ± 1.02, and 5.89 ± 1.28 for scan times of 5, 8.5, 12, and 15.5 minutes, respectively. The respiratory binning technique resulted in significantly sharper images (p < 0.001) as measured with relative maximum derivative at the diaphragm. Concomitant field corrections visibly improved sharpness of anatomical structures away from iso-center. The image quality was maintained with a slight loss in SNR for simulated scan times down to 8.5 minutes. Inline image reconstruction and artifact correction were achieved in

Observational studies suggest obesity is associated with sepsis survival, but these studies are small, fail to adjust for key confounders, measure body mass index at inconsistent time points, and/or use administrative data to define sepsis. To estimate the relationship between body mass index and sepsis mortality using detailed clinical data for case detection and risk adjustment.Retrospective cohort analysis of a large clinical data repository.One-hundred thirty-nine hospitals in the United States.Adult inpatients with sepsis meeting Sepsis-3 criteria.Body mass index in six categories: underweight (body mass index18.5 kg/m), normal weight (body mass index = 18.5-24.9 kg/m), overweight (body mass index = 25.0-29.9 kg/m), obese class I (body mass index = 30.0-34.9 kg/m), obese class II (body mass index = 35.0-39.9 kg/m), and obese class III (body mass index ≥ 40 kg/m).Multivariate logistic regression with generalized estimating equations to estimate the effect of body mass index category on short-term mortality (in-hospital death or discharge to hospice) adjusting for patient, infection, and hospital-level factors. Sensitivity analyses were conducted in subgroups of age, gender, Elixhauser comorbidity index, Sequential Organ Failure Assessment quartiles, bacteremic sepsis, and ICU admission.From 2009 to 2015, we identified 55,038 adults with sepsis and assessable body mass index measurements: 6% underweight, 33% normal weight, 28% overweight, and 33% obese. Crude mortality was inversely proportional to body mass index category: underweight (31%), normal weight (24%), overweight (19%), obese class I (16%), obese class II (16%), and obese class III (14%). Compared with normal weight, the adjusted odds ratio (95% CI) of mortality was 1.62 (1.50-1.74) for underweight, 0.73 (0.70-0.77) for overweight, 0.61 (0.57-0.66) for obese class I, 0.61 (0.55-0.67) for obese class II, and 0.65 (0.59-0.71) for obese class III. Results were consistent in sensitivity analyses.In adults with clinically defined sepsis, we demonstrate lower short-term mortality in patients with higher body mass indices compared with those with normal body mass indices (both unadjusted and adjusted analyses) and higher short-term mortality in those with low body mass indices. Understanding how obesity improves survival in sepsis would inform prognostic and therapeutic strategies.

Background Coronavirus disease 2019 (COVID-19) requiring hospitalization is characterized by robust antibody production, dysregulated immune response, and immunothrombosis. Fostamatinib is a novel spleen tyrosine kinase inhibitor that we hypothesize will ameliorate Fc activation and attenuate harmful effects of the anti-COVID-19 immune response. Methods We conducted a double-blind, randomized, placebo-controlled trial in hospitalized adults requiring oxygen with COVID-19 where patients receiving standard of care were randomized to receive fostamatinib or placebo. The primary outcome was serious adverse events by day 29. Results A total of 59 patients underwent randomization (30 to fostamatinib and 29 to placebo). Serious adverse events occurred in 10.5% of patients in the fostamatinib group compared with 22% in placebo (P = .2). Three deaths occurred by day 29, all receiving placebo. The mean change in ordinal score at day 15 was greater in the fostamatinib group (-3.6 ± 0.3 vs -2.6 ± 0.4, P = .035) and the median length in the intensive care unit was 3 days in the fostamatinib group vs 7 days in placebo (P = .07). Differences in clinical improvement were most evident in patients with severe or critical disease (median days on oxygen, 10 vs 28, P = .027). There were trends toward more rapid reductions in C-reactive protein, D-dimer, fibrinogen, and ferritin levels in the fostamatinib group. Conclusion For COVID-19 requiring hospitalization, the addition of fostamatinib to standard of care was safe and patients were observed to have improved clinical outcomes compared with placebo. These results warrant further validation in larger confirmatory trials. Clinical Trials Registration Clinicaltrials.gov, NCT04579393.

Bacterial products including endotoxin have been administered to humans over the past century as therapeutic, diagnostic, and experimental agents. The acute phase response is the early immediate host response to infection or tissue injury and results in fever, leukocytosis, changes in vascular permeability, and altered metabolic responses in various organs. Humoral defense mechanisms are rapidly activated after endotoxin administration. The contact system composed of Factors XII, XI, prekallikrein, and high molecular weight kininogen amplifies several host inflammatory responses including the initiation of coagulation via the intrinsic pathway, activation of plasminogen and neutrophils, as well as the generation of bradykinin, a potent vasodilator. Cytokines serve as important links to amplify the inflammatory response initiated by endotoxin. Hepatic synthetic function is rapidly upregulated in response to endotoxin. Endotoxin has been implicated in the pathogenesis of gram-negative bacterial pneumonia as well as the development of acute and chronic lung inflammation due to occupational dust exposure.

Guidelines-recommend thrombolytic therapy for pulmonary embolism in patients with severe hemodynamic compromise and low risk of bleeding. Thrombolytics in submassive pulmonary embolism have an unfavorable risk/benefit ratio and remain controversial. Based on our experience with extensive, lower extremity thrombi, nine patients with symptomatic, submassive pulmonary embolisms (five medical, four surgical) were treated with low-dose alteplase (

MicroRNA (miRNA) control gene transcription by binding to and repressing the translation of messenger RNA (mRNA). Their role in the acute respiratory distress syndrome (ARDS) is undefined.Blood leukocytes from 51 patients enrolled in a prior randomized trial of corticosteroids for ARDS were analyzed. After screening eight patients with microarrays for altered miRNA expression, 25 miRNAs were selected for further analysis using RT-PCR in all 51 patients.On day 0, the 51 patients had APACHE III score of 60.4 ± 17.7 and PaO2/FiO2 of 117 ± 49. 21 miRNA were expressed at increased levels in blood leukocytes at the onset of ARDS compared with healthy controls. These miRNA remained elevated at day 3 and increased further by day 7 (log2 fold change from 0.66 to 5.7 fold, P 0.05 compared to day 0). In a subgroup analysis (37 patients treated with corticosteroids and 14 treated with placebo), the interaction of miRNA expression over time and steroid administration was not significant suggesting that systemic corticosteroids had no effect on the miRNA detected in our study. In contrast, corticosteroids but not placebo decreased IL-6 and C-reactive protein at day 3 (P 0.001) demonstrating an early systemic anti-inflammatory response whereas both treatment arms had decreased values by day 7 (P 0.001).Expression of miRNA is increased in blood leukocytes of patients with ARDS at day 0 and day 3 and rises further by day 7, when systemic inflammation is subsiding. These effects appear independent of the administration of steroids, suggesting different inflammatory modifying roles for each in the resolving phases of ARDS.

Background Mortality after smoke inhalation–associated acute lung injury (SI-ALI) remains substantial. Age and burn surface area are risk factors of mortality, whereas the impact of patient- and center-level variables and treatments on survival are unknown. Methods We performed a retrospective cohort study of burn and non-burn centers at 68 US academic medical centers between 2011 and 2014. Adult inpatients with SI-ALI were identified using an algorithm based on a billing code for respiratory conditions from smoke inhalation who were mechanically ventilated by hospital day 4, with either a length-of-stay ≥ 5 days or death within 4 days of hospitalization. Predictors of in-hospital mortality were identified using logistic regression. The primary outcome was the odds ratio for in-hospital mortality. Results A total of 769 patients (52.9 ± 18.1 years) with SI-ALI were analyzed. In-hospital mortality was 26% in the SI-ALI cohort and 50% in patients with ≥ 20% surface burns. In addition to age > 60 years (OR 5.1, 95% CI 2.53-10.26) and ≥ 20% burns (OR 8.7, 95% CI 4.55-16.75), additional risk factors of in-hospital mortality included initial vasopressor use (OR 5.0, 95% CI 3.16-7.91), higher diagnostic-related group–based risk-of-mortality assignment and lower hospital bed capacity (OR 2.3, 95% CI 1.23-4.15). Initial empiric antibiotics (OR 0.93, 95% CI 0.58-1.49) did not impact survival. These new risk factors improved mortality prediction by 9.9% (P Conclusions In addition to older age and major surface burns, mortality in SI-ALI is predicted by initial vasopressor use, higher diagnostic-related group–based risk-of-mortality assignment, and care at centers with

From September 2014 to April 2015, 6 persons who had occupational exposures to Zaire ebolavirus in West Africa received investigational agent rVSV-ZEBOV or TKM-100802 for postexposure prophylaxis and were monitored in the United States. All patients experienced self-limited symptoms after postexposure prophylaxis; none developed Ebola virus disease.

Racial disparities in sepsis outcomes have been previously reported. However, recently, there have been inconsistencies in identifying which socioeconomic variables, such as race, account for these disparities. The objective of this study was to perform a systematic review in order to examine the impact of race on sepsis-attributable mortality. Systematic searches for English-language articles identified through MEDLINE, EBSCOhost, PubMed, ERIC, and Cochrane Library databases from 1960 to 1 February 2017. Included studies examined sepsis outcomes in the context of sepsis incidence and/or mortality. Two investigators independently extracted data and assessed study quality. The meta-analysis was performed in accordance with the Cochrane Collaboration guidelines. Twenty-one studies adhered to the predefined selection criteria and were included in the review. Of the 21 studies, we pooled data from 6 studies comparing African American/Black race as a risk factor for sepsis-related mortality disparities (reference group being Caucasian/White). From the meta-analysis on these six studies, African American/Black race was found to have no statistical significant relationship with sepsis-related mortality (odds ratio 1.20, 95% CI, 0.81 to 1.77). Similar results were found for other races (Native Americans, Asians) and ethnicities (Hispanic/Latinos). On the basis of available evidence from a limited number of observation retrospective studies, race alone cannot fully explain sepsis-related disparities, especially sepsis-attributable mortality.

BACKGROUND: Resistance to all first-line antibiotics necessitates the use of less effective or more toxic “reserve” agents. Gram-negative bloodstream infections (GNBSIs) harboring such difficult-to-treat resistance (DTR) may have higher mortality than phenotypes that allow for ≥1 active first-line antibiotic. METHODS: The Premier Database was analyzed for inpatients with select GNBSIs. DTR was defined as intermediate/resistant in vitro to all ß-lactam categories, including carbapenems and fluoroquinolones. Prevalence and aminoglycoside resistance of DTR episodes were compared with carbapenem-resistant, extended-spectrum cephalosporin-resistant, and fluoroquinolone-resistant episodes using CDC definitions. Predictors of DTR were identified. The adjusted relative risk (aRR) of mortality was examined for DTR, CDC-defined phenotypes susceptible to ≥1 first-line agent, and graded loss of active categories. RESULTS: Between 2009–2013, 471 (1%) of 45011 GNBSI episodes at 92 (53.2%) of 173 hospitals exhibited DTR, ranging from 0.04% for Escherichia coli to 18.4% for Acinetobacter baumannii. Among patients with DTR, 79% received parenteral aminoglycosides, tigecycline, or colistin/polymyxin-B; resistance to all aminoglycosides occurred in 33%. Predictors of DTR included urban healthcare and higher baseline illness. Crude mortality for GNBSIs with DTR was 43%; aRR was higher for DTR than for carbapenem-resistant (1.2; 95% confidence interval, 1.0–1.4; P = .02), extended-spectrum cephalosporin-resistant (1.2; 1.1–1.4; P = .001), or fluoroquinolone-resistant (1.2; 1.0–1.4; P = .008) infections. The mortality aRR increased 20% per graded loss of active first-line categories, from 3–5 to 1–2 to 0. CONCLUSION: Nonsusceptibility to first-line antibiotics is associated with decreased survival in GNBSIs. DTR is a simple bedside prognostic measure of treatment-limiting coresistance.

The mortality rate of alveolar hemorrhage (AH) after allogeneic hematopoietic stem cell transplantation is greater than 60% with supportive care and high-dose steroid therapy. We performed a retrospective cohort analysis to assess the benefits and risks of recombinant human factor VIIa (rFVIIa) as a therapeutic adjunct for AH. Between 2005 and 2012, 57 episodes of AH occurred in 37 patients. Fourteen episodes (in 14 patients) were treated with steroids alone, and 43 episodes (in 23 patients) were treated with steroids and rFVIIa. The median steroid dose was 1.9 mg/kg/d (interquartile range [IQR], 0.8 to 3.5 mg/kg/d; methylprednisolone equivalents) and did not differ statistically between the 2 groups. The median rFVIIa dose was 41 μg/kg (IQR, 39 to 62 μg/kg), and a median of 3 doses (IQR, 2 to 17) was administered per episode. Concurrent infection was diagnosed in 65% of the episodes. Patients had moderately severe hypoxia (median PaO2/FiO2, 193 [IQR, 141 to 262]); 72% required mechanical ventilation, and 42% survived to extubation. The addition of rFVIIa did not alter time to resolution of AH (P = .50), duration of mechanical ventilation (P = .89), duration of oxygen supplementation (P = .55), or hospital mortality (P = .27). Four possible thrombotic events (9% of 43 episodes) occurred with rFVIIa. rFVIIa in combination with corticosteroids did not confer clear clinical advantages compared with corticosteroids alone. In patients with AH following hematopoietic stem cell transplantation, clinical factors (ie, worsening infection, multiple organ failure, or recrudescence of primary disease) may be more important than the benefit of enhanced hemostasis from rFVIIa.

Objective The incidence of thoracic injuries resulting from cardiopulmonary resuscitation (CPR) is not well characterized. We describe a case in which a CPR-associated atrial rupture was identified with ultrasound and successfully managed in the intensive care unit with a bedside thoracotomy and atrial repair. We then describe a systematic review with pooled data analysis of CPR-associated cardiovascular, pulmonary, pleural, and thoracic wall injuries. Data sources PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, Current Controlled Trials, and Google. Study selection Inclusion criteria for the pooled analysis were any clinical or autopsy study in which (a) patients underwent cardiopulmonary resuscitation, (b) chest compressions were administered either manually or with the assistance of active compression–decompression devices, and (c) autopsy or dedicated imaging assessments were conducted to identify complications. Exclusion criteria for the pooled analysis were pre-clinical studies, case reports and abstracts. Data extraction Nine-hundred twenty-eight potentially relevant references were identified. Twenty-seven references met inclusion criteria. Data synthesis A systematic review of the literature is provided with pooled data analysis. Conclusions The incidence of reported CPR-associated cardiovascular and thoracic wall injuries varies widely. CPR with active compression–decompression devices has a higher reported incidence of cardiopulmonary injuries. Bedside ultrasound may be a useful adjunct to assess and risk-stratify patients to identify serious or life-threatening CPR-associated injuries.

Objective Inhaled anticoagulation regimens are increasingly being used to manage smoke inhalation-associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruction, ventilation, oxygenation, pulmonary infections, bleeding complications, and survival. Data sources PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Relevant unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library, ClinicalTrials.gov, MINDCULL.com, Current Controlled Trials, and Google. Study selection Inclusion criteria were any preclinical or clinical study in which 1) animals or subjects experienced smoke inhalation exposure, 2) they were treated with nebulized or aerosolized anticoagulation regimens, including heparin, heparinoids, antithrombins, or fibrinolytics (e.g., tissue plasminogen activator), 3) a control and/or sham group was described for preclinical studies, and 4) a concurrent or historical control group described for clinical studies. Exclusion criteria were 1) the absence of a group treated with a nebulized or aerosolized anticoagulation regimen, 2) the absence of a control or sham group, and 3) case reports. Data extraction Ninety-nine potentially relevant references were identified. Twenty-seven references met inclusion criteria including 19 preclinical references reporting 18 studies and eight clinical references reporting five clinical studies. Data synthesis A systematic review of the literature is provided. Both clinical and methodological diversity precluded combining these studies in a meta-analysis. Conclusions The high mortality associated with smoke inhalation-associated acute lung injury results from airway damage, mucosal dysfunction, neutrophil infiltration, airway coagulopathy with cast formation, ventilation-perfusion mismatching with shunt, and barotrauma. Inhaled anticoagulation regimens in both preclinical and clinical studies improve survival and decrease morbidity without altering systemic markers of clotting and anticoagulation. In some preclinical and clinical studies, inhaled anticoagulants were associated with a favorable effect on survival. This approach appears sufficiently promising to merit a well-designed prospective study to validate its use in patients with severe smoke inhalation-associated acute lung injury requiring mechanical ventilation.

One of the first double-blind, multicenter trials of hydrocortisone in the management of severe infections involved 194 patients and was reported in 1963.1 The authors noted that “the role of adren...

Background: Chronic graft versus host disease of the lungs may result in bronchiolitis obliterans syndrome (BOS), an inflammatory injury to medium size airways leading to fibrosis. BOS is often treated with an increase in immunosuppression which can be associated with systemic complications (e.g. organ dysfunction, increased susceptibility to infection and blunting of graft versus leukemia effect). In order to provide enhanced local delivery of an immunosuppressant, cyclosporine, we studied the effects of cyclosporine inhalation solution (CIS) in allogeneic hematopoietic stem cell transplant (HSCT) patients with BOS with a short-term assessment of lung function and inflammatory markers in blood and bronchoalveolar lavage (BAL). Methods: Patients who underwent an allogeneic HSCT meeting the NIH consensus clinical definition of BOS were eligible for inclusion, and were treated with CIS and monitored for treatment response with serial pulmonary function tests (PFTs). At baseline, patients were classified as having stable or progressive disease (i.e. > 10% decline in forced expiratory volume in one second (FEV1) in the preceding 18 weeks). Response was defined as either improvement or stabilization at week 18. Improvement was defined as an increase in FEV1 (regardless of baseline categorization) > 10%. Stabilization was defined as FEV1 increase or decrease < 10% in patients with progressive disease at baseline, and with a reduction in systemic immunosuppression by 25% in those with stable disease at baseline. Patients with declining FEV1 > 10% were classified as non-responders, and patients with FEV1 decline > 20% or with worsening clinical status were taken off protocol. BALs were performed at study entry and week 18 of treatment. BAL and serum samples were analyzed via a custom Luminex® panel. The 37 analytes studied included the following categories: 1) chemokines (CCL2, 3, 5, 18; CXCL5, 9, 10, 13), 2) cytokines (IL-1β, -1ra, -2, -2rα, -6, -7, -8, -10, -12p70, -15, -17a, -23, -17E/25, TNFα, IFNγ), 3) matrix metalloproteinases (MMP1-3, 7-9, 12-13), 4) growth-factors (VEGF-α, G-CSF), and 5) others (PD-L1, surfactant protein D, osteopontin, myeloperoxidase). Results: In total, 20 HSCT patients with BOS were enrolled (median age 45.5 yrs: range 14-71; 13 men and 7 women), and 11 patients completed the study through week 18. The average time from transplant was 4.6 yrs (range 1-28, median 3 yrs). Baseline FEV1 was 1.18 liters (range 0.5-2.02), and with an average FEV1 of 36% predicted (range 18-56%). At the time of enrollment, 12 patients had stable disease, and 8 had progressive disease. Nine patients discontinued treatment due to either worsening FEV1 by 25% (n=1), relapse of primary disease (n=1), or side effects (n=7; cough and bronchospasm). Sixteen patients were included in the evaluable patient population (patients who received treatment for at least the first two weeks) with 9 responders (4 with improvement, 5 with stabilization) and 7 non-responders. Among those completing the study (n=11), 4 had improvement in FEV1, 5 had stable disease, and 2 were non-responders. Seven patients were continued on CIS through an extended use protocol. The baseline BAL cell differentials demonstrated a neutrophil predominance (66 + 29 %) that persisted at week 18 (56 + 35%). In the BAL, MMP-7 increased from baseline (150 + 215 pg/mL) to week 18 (1956 + 2624 pg/mL; p value 0.049), while soluble PD-L1 levels fell (97 + 55 pg/mL to 55 + 43 pg/mL; p value 0.04). The other categories of biomarkers in BAL were either undetectable (n = 12) or demonstrated no significant difference (n = 23) in patients with or without a clinical response to CIS. Similarly, concomitant serum biomarkers showed no difference in treatment after CIS, even when classified amongst responders and non-responders. Conclusion: In HSCT-BOS, CIS led to an improvement or stabilization of PFTs and/or a decrease in systemic immunosuppression in 9 of the 11 patients that completed the study. Due to cough and bronchospasm, only 11 of 20 patients were able to complete treatment through week 18. Inflammatory markers in the serum and BAL were not elevated at baseline or at the end of study. These data suggest that later stages of BOS may represent progression from a state of inflammatory injury to a fibrotic process. Based on our findings, we believe patients with later stage BOS may benefit from investigational therapeutics targeting lung remodeling. Figure Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Not really. This drug is not commercially available or FDA approved. An IND was obtained for the use of an inhaled formulation of cyclosporine. Aerosolized cyclosporine has been used previously in other patients (lung transplant associated BOS)

Background At least 25 % of adults admitted to intensive care units (ICU) in the United States have an overweight, obese or morbidly obese body mass index (BMI). The effect of BMI on adjusted mortality in adults requiring ICU treatment for sepsis is unclear. We performed a systematic review of adjusted all-cause mortality for underweight, overweight, obese and morbidly obese BMIs relative to normal BMI for adults admitted to the ICU with sepsis, severe sepsis, and septic shock. Method PubMed, the Cochrane Library, and EMBASE electronic databases were searched through November 18, 2015, without language restrictions. We included studies that reported multivariate regression analyses for all-cause mortality using standard BMI categories for adults admitted to the ICU for sepsis, severe sepsis, and septic shock. Articles were selected by consensus among multiple reviewers. Electronic database searches yielded 10,312 articles, of which six were eligible. Data were extracted by one reviewer and then reviewed by three independent reviewers. For the meta-analyses performed, the adjusted odds ratios (aOR) of mortality were combined using a random-effects model. Risk of bias was assessed using the Newcastle-Ottawa quality assessment scale for cohort studies. Results Four retrospective (n = 6609 patients) and two prospective (n = 556) studies met inclusion criteria. Compared to normal BMI, across five studies each, overweight or obese BMIs reduced the adjusted odds ratio (95 % CI) of mortality [aOR] [0.83 (0.75, 0.91) p

Reports that septic shock incidence is rising and mortality rates declining may be confounded by improving recognition of sepsis and changing coding practices. We compared trends in septic shock incidence and mortality in academic hospitals using clinical vs claims data.We identified all patients with concurrent blood cultures, antibiotics, and vasopressors for ≥ two consecutive days, and all patients with International Classification of Diseases, 9th edition (ICD-9) codes for septic shock, at 27 academic hospitals from 2005 to 2014. We compared annual incidence and mortality trends. We reviewed 967 records from three hospitals to estimate the accuracy of each method.Of 6.5 million adult hospitalizations, 99,312 (1.5%) were flagged by clinical criteria, 82,350 (1.3%) by ICD-9 codes, and 44,651 (0.7%) by both. Sensitivity for clinical criteria was higher than claims (74.8% vs 48.3%; P .01), whereas positive predictive value was comparable (83% vs 89%; P = .23). Septic shock incidence, based on clinical criteria, rose from 12.8 to 18.6 cases per 1,000 hospitalizations (average, 4.9% increase/y; 95% CI, 4.0%-5.9%), while mortality declined from 54.9% to 50.7% (average, 0.6% decline/y; 95% CI, 0.4%-0.8%). In contrast, septic shock incidence, based on ICD-9 codes, increased from 6.7 to 19.3 per 1,000 hospitalizations (19.8% increase/y; 95% CI, 16.6%-20.9%), while mortality decreased from 48.3% to 39.3% (1.2% decline/y; 95% CI, 0.9%-1.6%).A clinical surveillance definition based on concurrent vasopressors, blood cultures, and antibiotics accurately identifies septic shock hospitalizations and suggests that the incidence of patients receiving treatment for septic shock has risen and mortality rates have fallen, but less dramatically than estimated on the basis of ICD-9 codes.

Background Sepsis is the focus of national quality improvement programs and a recent public reporting measure from the Centers for Medicare and Medicaid Services. However, diagnosing sepsis requires interpreting nonspecific signs and can therefore be subjective. We sought to quantify interobserver variability in diagnosing sepsis. Methods We distributed five case vignettes of patients with suspected or confirmed infection and organ dysfunction to a sample of practicing intensivists. Respondents classified cases as systemic inflammatory response syndrome, sepsis, severe sepsis, septic shock, or none of the above. Interobserver variability was calculated using Fleiss’ κ for the five-level classification, and for answers dichotomized as severe sepsis/septic shock versus not-severe sepsis/septic shock and any sepsis category (sepsis, severe sepsis, or septic shock) versus not-sepsis. Results Ninety-four physicians completed the survey. Most respondents (88 %) identified as critical care specialists; other specialties included pulmonology (39 %), anesthesia (19 %), surgery (9 %), and emergency medicine (9 %). Respondents had been in practice for a median of 8 years, and 90 % practiced at academic hospitals. Almost all respondents (83 %) felt strongly or somewhat confident in their ability to apply the traditional consensus sepsis definitions. However, overall interrater agreement in sepsis diagnoses was poor (Fleiss’ κ 0.29). When responses were dichotomized into severe sepsis/septic shock versus not-severe sepsis/septic shock or any sepsis category versus not-sepsis, agreement was still poor (Fleiss’ κ 0.23 and 0.18, respectively). Seventeen percent of respondents classified one of the five cases as severe sepsis/septic shock, 27.7 % rated two cases, 33.0 % respondents rated three cases, 19.2 % rated four cases, and 3.2 % rated all five cases as severe sepsis/septic shock. Among respondents who felt strongly confident in their ability to use sepsis definitions (n = 45), agreement was no better (Fleiss’ κ 0.28 for the five-category classification, and Fleiss’ κ 0.21 for the dichotomized severe sepsis/septic shock classification). Cases were felt to be extremely or very realistic in 74 % of responses; only 3 % were deemed unrealistic. Conclusions Diagnosing sepsis is extremely subjective and variable. Objective criteria and standardized methodology are needed to enhance consistency and comparability in sepsis research, surveillance, benchmarking, and reporting. Electronic supplementary material The online version of this article (doi:10.1186/s13054-016-1266-9) contains supplementary material, which is available to authorized users.

Purpose The effects of stress-dose corticosteroid therapy were studied in a canine staphylococcal pneumonia model of septic shock.

Objective: Evaluate the effects of methylprednisolone on markers of inflammation, coagulation, and angiogenesis during early acute respiratory distress syndrome. Design: Retrospective analysis. Setting: Four intensive care units. Subjects: Seventy-nine of 91 patients with available samples enrolled in a randomized, blinded controlled trial. Interventions: Early methylprednisolone infusion (n = 55) compared with placebo (n = 24). Measurements and Main Results: Interleukin-6, tumor necrosis factor alpha, vascular endothelial growth factor, protein C, procalcitonin, and proadrenomedullin were measured in archived plasma. Changes from baseline to day 3 and day 7 were compared between groups and in subgroups based on the precipitating cause of acute respiratory distress syndrome. Methylprednisolone therapy was associated with greater improvement in Lung Injury Score (p = .003), shorter duration of mechanical ventilation (p = .005), and lower intensive care unit mortality (p = .05) than control subjects. On days 3 and 7, methylprednisolone decreased interleukin-6 and increased protein C levels (all p

Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia.Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ≤ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ≤ .05), consistent with adrenal suppression.In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.

Transcompartmental signaling during early inflammation may lead to propagation of disease to other organs. The time course and the mechanisms involved are still poorly understood. We aimed at comparing acute transcompartmental inflammatory responses in humans following lipopolysaccharide-induced pulmonary and systemic inflammation.Randomized, double-blind, placebo-controlled, crossover study.Healthy male volunteers.Fifteen volunteers (mean age, 23; SD, 2 yr) received Escherichia coli endotoxin (lipopolysaccharide, 4 ng/kg) IV or endobronchially on two different study days. Groups were evaluated by bronchoalveolar lavage at baseline (0 hr) and 2, 4, 6, 8, or 24 hours postchallenge. Cardiorespiratory variables were continuously recorded throughout the study day, and plasma and bronchoalveolar lavage fluid markers of inflammation were measured.IV endotoxin elicited a systemic inflammatory response with a time-dependent increase and peak in tumor necrosis factor-α, interleukin-6, and leukocyte counts (all p0.001). Furthermore, a delayed (6-8 hr) increase in bronchoalveolar lavage fluid interleukin-6 concentration (p0.001) and alveolar leukocyte count (p = 0.03) and a minor increase in bronchoalveolar lavage fluid tumor necrosis factor-α were observed (p = 0.06). Endobronchial endotoxin was followed by progressive alveolar neutrocytosis and increased bronchoalveolar lavage fluid tumor necrosis factor-α, interleukin-6, and albumin (all p0.001); a systemic inflammatory response was observed after 2-4 hours, with no change in plasma tumor necrosis factor-α.Acute lung or systemic inflammation in humans is followed by a transcompartmental proinflammatory response, the degree and differential kinetics of which suggests that the propagation of inflammation may depend on the primary site of injury.

In this paper, we address the issue of peptide ion peak detection for high resolution time-of-flight (TOF) mass spectrometry (MS) data. A novel Bayesian peptide ion peak detection method is proposed for TOF data with resolution of 10 000–15 000 full width at half-maximum (FWHW). MS spectra exhibit distinct characteristics at this resolution, which are captured in a novel parametric model. Based on the proposed parametric model, a Bayesian peak detection algorithm based on Markov chain Monte Carlo (MCMC) sampling is developed. The proposed algorithm is tested on both simulated and real datasets. The results show a significant improvement in detection performance over a commonly employed method. The results also agree with expert’s visual inspection. Moreover, better detection consistency is achieved across MS datasets from patients with identical pathological condition.

Objective: Clinical trial designs that randomize patients to fixed treatment regimens may disrupt preexisting relationships between illness severity and level of therapy. The practice misalignments created by such designs may have unintended effects on trial results and safety. Methods: To illustrate this problem, the Transfusion Requirements in Critical Care (TRICC) trial and the Acute Respiratory Distress Syndrome Network low tidal volume (ARMA) trial were analyzed. Results: Publications before TRICC indicated that clinicians used higher transfusion thresholds in patients with ischemic heart disease compared with younger, healthier patients (p = .001). The trial, however, randomized patients (n = 838) to liberal (10 g/dL hemoglobin) or restrictive (7 g/dL) transfusion thresholds. Thirty-day mortality was different and opposite in the liberal compared with the restrictive arm depending on presence (21 vs. 26%) or absence (25 vs. 16%) of ischemic heart disease (p = .03). At baseline in ARMA, consistent with prior publications, physicians set ventilator volumes lower in patients with high airway pressures and poor compliance (8.4-10.6 mL/kg interquartile range) than patients with less severe abnormalities (9.6-12 mL/kg) (p = .0001). In the trial, however, patients (n = 861) were randomized to low (6 mL/kg) or high (12 mL/kg) tidal volumes. In patients with low compliance (

Multiple clinical trials of adjunctive therapy for sepsis and septic shock have been conducted to neutralize bacterial components or to modulate host inflammatory responses to infection but with limited success. Many therapies are only beneficial only in patients with a high severity of illness and have minimal or harmful effects in patients that are less severely ill. Improved measures of severity of illness and discovery of biomarkers to help identify these high-risk patients are needed.

More than 26,000 cases of Ebola virus disease (EVD) have been reported in western Africa, with high mortality. Several patients have been medically evacuated to hospitals in the United States and Europe. Detailed clinical data are limited on the clinical course and management of patients with EVD outside western Africa.To describe the clinical characteristics and management of a cluster of patients with EVD, including the first cases of Ebola virus (EBOV) infection acquired in the United States.Retrospective clinical case series.Three U.S. hospitals in September and October 2014.First imported EVD case identified in the United States and 2 secondary EVD cases acquired in the United States in critical care nurses who cared for the index case patient.Clinical recovery, EBOV RNA level, resolution of Ebola viremia, survival with discharge from hospital, or death.The index patient had high EBOV RNA levels, developed respiratory and renal failure requiring critical care support, and died. Both patients with secondary EBOV infection had nonspecific signs and symptoms and developed moderate illness; EBOV RNA levels were moderate, and both patients recovered.Both surviving patients received uncontrolled treatment with multiple investigational agents, including convalescent plasma, which limits generalizability of the results.Early diagnosis, prompt initiation of supportive medical care, and moderate clinical illness likely contributed to successful outcomes in both survivors. The inability to determine the potential benefit of investigational therapies and the effect of patient-specific factors that may have contributed to less severe illness highlight the need for controlled clinical studies of these interventions, especially in the setting of a high level of supportive medical care.None.

Infectious disease epidemics in the past have given rise to psychologic and emotional responses among health-care workers (HCWs), stemming from fear of infection during patient care. Early experiences in the AIDS epidemic provide an example where fear of contagion resulted in differential treatment of patients infected with HIV. However, with a deeper understanding of AIDS pathogenesis and treatment, fear and discrimination diminished. Parallels exist between early experiences with AIDS and the present outbreak of Ebola virus disease in West Africa, particularly regarding discussions of medical futility in seriously ill patients. We provide a historical perspective on HCWs' risk of infection during the provision of CPR, discuss physicians' duty to treat in the face of perceived or actual HCW risk, and, finally, present the protocols implemented at the National Institutes of Health to reduce HCW risk while providing lifesaving and life-sustaining care.

To assess markers of lung inflammation, we used SELDI-TOF and 2-DE to study changes in bronchoalveolar lavage (BAL) protein in 33 subjects challenged with local bronchial lung endotoxin and saline and in 11 patients with acute respiratory distress syndrome (ARDS). Differences in the SELDI-TOF spectra were assessed by t-test after baseline subtraction, normalization to total ion current and alignment by m/z calibration. The temporal changes in acute inflammatory BAL (6, 24 and 48 h following endotoxin challenge) on hydrophobic binding chip surfaces revealed the differential presence of proteins of 9, 14, 18 and 28 kDa (all p

Engraftment syndrome (ES) encompasses a constellation of symptoms that occur during neutrophil recovery after both autologous and allogeneic hematopoietic stem cell transplantation (HCT). Although it is well characterized after conventional myeloablative procedures, limited data exist on this complication after nonmyeloablative allogeneic HCT. The clinical manifestations, incidence, and risk factors associated with ES were investigated in a consecutive series of patients undergoing cyclophosphamide/fludarabine-based nonmyeloablative allogeneic HCT from a related HLA-compatible donor. Fifteen (10%) of 149 patients (median age, 53 years; range, 27–66 years) developed ES; the onset of symptoms occurred at a median of 10 days (range, 3–14 days), and they consisted of fever (100%), cough (53%), diffuse pulmonary infiltrates (100%), rash (13%), and room air hypoxia (87%). ES was more likely to develop in patients who received empiric amphotericin formulations after transplant conditioning (Fisher exact test; P = .007). In a multivariate analysis, older patient age, female sex, and treatment with amphotericin were predictors for the development of ES. Intravenous methylprednisolone led to the rapid resolution of ES; however, transplant-related mortality was significantly higher (cumulative incidence, 49% versus 16%; P = .0005), and median survival was significantly shorter (168 versus 418 days; P = .005) in patients with ES compared with non-ES patients. In conclusion, ES occurs commonly after cyclophosphamide/fludarabine-based nonmyeloablative transplantation and responds rapidly to corticosteroid treatment, but it is associated with a higher risk of nonrelapse mortality and with shorter overall survival.

Background Multiplex bead array assays permit simultaneous cytometric quantitation of multiple cytokines in solution by capturing these to spectrally distinct beads. Because several manufacturers offer reagents to quantitate the same cytokines on a single instrument, a comparison should be made to determine whether these kits yield similar data and whether these data are comparable to enzyme-linked immunosorbent assay (ELISA). Methods This study compared cytokine detection kits by using Luminex 100. Twenty-six serum samples from seven subjects were analyzed for interferon-γ, interleukins 1β, 6, and 8, and tumor necrosis factor-α by using multiplex kits from LINCO Research, Bio-Rad Laboratories, R&D Systems, and BioSource International. Each assay was performed according to the manufacturers' specifications. Standard curves were generated by using reference concentrations supplied by each manufacturer. ELISAs for interleukin-8 were performed by using kits from R&D and BioSource. Results Cytokine levels followed similar patterns, although absolute concentrations differed among kits. ELISA and Luminex values for interleukin-8 were similar in kits from the same manufacturer. Conclusions Because relative cytokine measurements are often valuable when performed serially, it may be possible to make interlaboratory comparisons by using different kits. When comparison of absolute values is crucial, kits from the same supplier should be used. Within-vendor, bead array, and ELISA values appear comparable. Published 2004 Wiley-Liss, Inc.

Thymosin beta(4) (Tbeta(4)), a highly conserved peptide with immunomodulatory properties, is the major actin-sequestering peptide in mammalian cells. Recent studies have established that Tbeta(4) can accelerate wound healing in full thickness skin wounds and following burn injuries to the cornea. In the eye studies, the accelerated healing due to Tbeta(4) was accompanied by a significant reduction in polymorphonuclear leukocyte (PMN) infiltration and a several-fold decrease in interleukin-1beta (p< or =0.015) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF1alpha, p< or =0.05). Given the recognized role of proinflammatory cytokines in septic shock and of extracellular F- and G-actin in the pathophysiology of multiple organ dysfunction, we have investigated the role of Tbeta(4) in sepsis. We report that an LD(50) dose of LPS (24 mg/kg) in rats resulted in a significant reduction of Tbeta(4) levels in the blood. Furthermore, administration of 100 microg of Tbeta(4) immediately following and at 2 and 4 h after an LD(50) dose of LPS (60 mg/kg) in mice significantly reduced mortality rates (p< or =0.024) and lowered blood levels of a number of inflammatory cytokines, eicosanoids, and other molecules that are highly elevated following endotoxin administration. In studies in human subjects given low doses of endotoxin (4 ng/kg LPS) and in patients with septic shock, we have also observed significant decreases in blood levels of Tbeta(4). The rapid disappearance of Tbeta(4) in the blood following LPS administration or during septic shock suggests that Tbeta(4) may be involved in early events leading to activation of the inflammatory cascade and ultimately the clinical sequelae of sepsis. The results of this study indicate that Tbeta(4) may have utility in the clinic in the treatment of septic shock and in syndromes associated with actin toxicities.

A new hypothesis with implications for the treatment of sepsis has recently been tested — the hypothesis that part of the pathophysiology of sepsis is caused by unrestricted or inappropriate coagul...

SummaryAcute respiratory distress syndrome (ARDS) is characterized by a disruption of the alveolar-capillary barrier, due to both an epithelial and an endothelial dysfunction. Whereas epithelial apoptosis seems to be mainly mediated by Fas ligand, the mediators of endothelial damage remain to be identified. Angiostatin, a powerful inhibitor of angiogenesis in vivo, also specifically induces apoptosis in endothelial cells. The concentration of various enzymes that cleave angiostatin from plasminogen was reported to be significantly increased in bronchalveolar lavage (BAL) fluids from patients with ARDS. Therefore, in this study, we investigated whether angiostatin was generated during the pulmonary inflammatory response of both healthy subjects challenged with endobronchial endotoxin and in patients with ARDS. We found significantly elevated angiostatin levels in BAL fluids from patients at risk for and with early ARDS (up to 0.022% and 0.018% of total protein, respectively), as well as in BAL fluids from volunteers treated with endotoxin (up to 1.17% of total protein), as compared to BAL fluids from control patients (

The development of disseminated intravascular coagulation (DIC) is associated with increased sepsis mortality. Antithrombin (AT) is one of several anticoagulants that have been studied in randomized trials of sepsis without benefit. In a recent study, Iba and colleagues reviewed data from patients who were treated for sepsis-related DIC with two lower doses of AT concentrate than studied in prior trials. Patients received 1,500 IU/day (n = 259) or 3,000 IU/day (n = 48) of AT for 3 days. All patients had baseline antithrombin activity

Accurate segmentation of pathological lungs from computed tomography (CT) scans remains unsolved because available methods fail to provide a reliable generic solution for a wide spectrum of lung abnormalities. In this study, we propose a novel pathological lung segmentation method that takes into account neighbor prior constraints and a novel pathology recognition system. Our proposed framework has two stages; during stage one, we adapted the fuzzy connectedness (FC) image segmentation algorithm to perform initial lung parenchyma extraction. In parallel, we estimate the lung volume using rib-cage information without explicitly delineating lungs. This rudimentary, but intelligent lung volume estimation system allows comparison of volume differences between rib cage and FC based lung volume measurements. Significant volume difference indicates the presence of pathology, which invokes the second stage of the proposed framework for the refinement of segmented lung. In stage two, texture-based features are utilized to detect abnormal imaging patterns (consolidations, ground glass, interstitial thickening, tree-inbud, honeycombing, nodules, and micro-nodules) that might have been missed during the first stage of the algorithm. This refinement stage is further completed by a novel neighboring anatomy-guided segmentation approach to include abnormalities with weak textures, and pleura regions. We evaluated the accuracy and efficiency of the proposed method on more than 400 CT scans with the presence of a wide spectrum of abnormalities. To our best of knowledge, this is the first study to evaluate all abnormal imaging patterns in a single segmentation framework. The quantitative results show that our pathological lung segmentation method improves on current standards because of its high sensitivity and specificity and may have considerable potential to enhance the performance of routine clinical tasks.

BACKGROUND. Hepatitis C virus (HCV) infects approximately 170 million people worldwide and may lead to cirrhosis and hepatocellular carcinoma in chronically infected individuals. Treatment is rapidly evolving from IFN-α-based therapies to IFN-α-free regimens that consist of directly acting antiviral agents (DAAs), which demonstrate improved efficacy and tolerability in clinical trials. Virologic relapse after DAA therapy is a common cause of treatment failure; however, it is not clear why relapse occurs or whether certain individuals are more prone to recurrent viremia. METHODS. We conducted a clinical trial using the DAA sofosbuvir plus ribavirin (SOF/RBV) and performed detailed mRNA expression analysis in liver and peripheral blood from patients who achieved either a sustained virologic response (SVR) or relapsed. RESULTS. On-treatment viral clearance was accompanied by rapid downregulation of IFN-stimulated genes (ISGs) in liver and blood, regardless of treatment outcome. Analysis of paired pretreatment and end of treatment (EOT) liver biopsies from SVR patients showed that viral clearance was accompanied by decreased expression of type II and III IFNs, but unexpectedly increased expression of the type I IFN IFNA2. mRNA expression of ISGs was higher in EOT liver biopsies of patients who achieved SVR than in patients who later relapsed. CONCLUSION. These results suggest that restoration of type I intrahepatic IFN signaling by EOT may facilitate HCV eradication and prevention of relapse upon withdrawal of SOF/RBV. TRIAL REGISTRATION. ClinicalTrials.gov NCT01441180.

We review human studies where different body sites ( e.g. systemic — intravenous and local — skin or lung) are exposed to small amounts of bacterial components as a means to study innate immunity in vivo. Intravenous endotoxin administration is widely used to assess systemic inflammatory responses, and these have many similarities to those seen in early sepsis. While blood levels of cytokines, activated inflammatory cells, and stress hormones rise acutely, the alveolar space remains relatively protected from these inflammatory responses. Skin blister windows provide a means to study local neutrophil exudation without systemic inflammatory responses, and has been used to characterize defects in neutrophil transmigration. Recently, skin blister windows have been adapted to study phagocytic cell function in response to bacterial antigens in patients with cirrhosis. Inhalation of endotoxin leads to pulmonary inflammation with increases in broncho-alveolar lavage neutrophils and cytokines and mild systemic responses. Whole lung exposure to endotoxin provides a means to study the pathogenesis of occupational lung disease. These three models are important methods to study innate immune responses and their regulatory mechanisms in normal and diseased states.

To evaluate the effects of endotoxemia on respiratory controller function, 12 subjects were randomized to receive endotoxin or saline; six also received ibuprofen, a cyclooxygenase inhibitor, and six received placebo. Administration of endotoxin produced fever, increased respiratory frequency, decreased inspiratory time, and widened alveolar-arterial oxygen tension gradient (all p < or = 0.001); these responses were blocked by ibuprofen. Independent of ibuprofen, endotoxin produced dyspnea, and it increased fractional inspiratory time, minute ventilation, and mean inspiratory flow (all p < or = 0.025). Endotoxin altered the autocorrelative behavior of respiratory frequency by increasing its autocorrelation coefficient at a lag of one breath, the number of breath lags with significant serial correlations, and its correlated fraction (all p < 0.05); these responses were blocked by ibuprofen. Changes in correlated behavior of respiratory frequency were related to changes in arterial carbon dioxide tension (r = 0.86; p < 0.03). Endotoxin decreased the oscillatory fraction of inspiratory time in both the placebo (p < 0.05) and ibuprofen groups (p = 0.06). In conclusion, endotoxin produced increases in respiratory motor output and dyspnea independent of fever and symptoms, and it curtailed the freedom to vary respiratory timing-a response that appears to be mediated by the cyclooxygenase pathway.

To study local lung inflammation, 34 subjects had endotoxin (1-4 ng/kg) instilled into a lung segment and saline instilled into a contralateral segment followed by bronchoalveolar lavage (BAL) at 2 h, 6 h, 24 h, or 48 h. Endotoxin instillation resulted in a focal inflammatory response with a distinct time course. An early phase (2 h to 6 h) revealed an increase in neutrophils (p = 0.0001) with elevated cytokines (tumor necrosis factor [TNF]-alpha, TNF receptors [TNFR], interleukin [IL]-1beta, IL-1 receptor antagonist, IL-6, granulocyte-colony-stimulating factor [G-CSF], all por = 0.002, but no change in IL-10) and chemokines (IL-8, epithelial neutrophil activating protein-78, monocyte chemotactic protein-1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, all por = 0.001, but no change in growth-regulated peptide-alpha). A later phase (24 h to 48 h) showed increased neutrophils, macrophages, monocytes, and lymphocytes (all por = 0.02), and a return to basal levels of most mediators. Elevated levels of inflammatory markers (TNFR(1), TNFR(2), L-selectin, lactoferrin, and myeloperoxidase) persisted in the BAL at 48 h (por = 0.001). Increased permeability to albumin occurred throughout both phases (p = 0.001). Blood C-reactive protein, serum amyloid A, IL-6, IL-1ra, G-CSF, but not TNF-alpha increased by 8 h (all por = 0.008). The local pulmonary inflammatory response to endotoxin has a unique qualitative and temporal profile of inflammation compared with previous reports of intravenous endotoxin challenges. This model provides a means to investigate factors that initiate, amplify, and resolve local lung inflammation.