Publications by authors named "Lorraine B Ware"

292 Publications

Standardization of Methods for Sampling the Distal Airspace in Mechanically Ventilated Patients using Heat Moisture Exchange Filter Fluid.

Am J Physiol Lung Cell Mol Physiol 2021 Mar 3. Epub 2021 Mar 3.

Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University, United States.

Non-invasive sampling of the distal airspace in patients with Acute Respiratory Distress Syndrome (ARDS) has long eluded clinical and translational researchers. We recently reported that fluid collected from Heat Moisture Exchange filters (HME) closely mirrors fluid directly aspirated from the distal airspace. In the current study, we sought to determine fluid yield from different HME types, optimal HME circuit dwell time and reliability of HME fluid in reflecting the distal airspace. We studied fluid yield from 4 different filter types by loading increasing volumes of saline and measuring volume of fluid recovered. We collected filters after 1, 2 and 4 hours of dwell time for measurement of fluid volume and total protein from 13 subjects. After identifying 4 hours as the optimal dwell time, we measured total protein and IgM in HME fluid from 42 subjects with ARDS and 9 with hydrostatic pulmonary edema (HYDRO). We found that the fluid yield varies greatly by filter type. With timed sample collection, fluid recovery increased with increasing circuit dwell time with a median volume of 2.0 mL (IQR 1.2-2.7) after 4 hours. Total protein was higher in the 42 subjects with ARDS compared to 9 with HYDRO (median 708 µg/ml (IQR 244-2017) vs 364 µg/ml (IQR 136-578), p=0.047) confirming that total protein concentration in HME is higher in ARDS compared to hydrostatic edema. These studies establish a standardized HME fluid collection protocol and confirm that HME fluid analysis is a novel non-invasive tool for study of the distal airspace in ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajplung.00595.2020DOI Listing
March 2021

Risk of primary graft dysfunction following lung transplantation in selected adults with connective tissue disease-associated interstitial lung disease.

J Heart Lung Transplant 2021 Jan 23. Epub 2021 Jan 23.

Division of Rheumatology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York. Electronic address:

Background: Previous studies have reported similarities in long-term outcomes following lung transplantation for connective tissue disease-associated interstitial lung disease (CTD-ILD) and idiopathic pulmonary fibrosis (IPF). However, it is unknown whether CTD-ILD patients are at increased risk of primary graft dysfunction (PGD), delays in extubation, or longer index hospitalizations following transplant compared to IPF patients.

Methods: We performed a multicenter retrospective cohort study of CTD-ILD and IPF patients enrolled in the Lung Transplant Outcomes Group registry who underwent lung transplantation between 2012 and 2018. We utilized mixed effects logistic regression and stratified Cox proportional hazards regression to determine whether CTD-ILD was independently associated with increased risk for grade 3 PGD or delays in post-transplant extubation and hospital discharge compared to IPF.

Results: A total of 32.7% (33/101) of patients with CTD-ILD and 28.9% (145/501) of patients with IPF developed grade 3 PGD 48-72 hours after transplant. There were no significant differences in odds of grade 3 PGD among patients with CTD-ILD compared to those with IPF (adjusted OR 1.12, 95% CI 0.64-1.97, p = 0.69), nor was CTD-ILD independently associated with a longer post-transplant time to extubation (adjusted HR for first extubation 0.87, 95% CI 0.66-1.13, p = 0.30). However, CTD-ILD was independently associated with a longer post-transplant hospital length of stay (median 23 days [IQR 14-35 days] vs17 days [IQR 12-28 days], adjusted HR for hospital discharge 0.68, 95% CI 0.51-0.90, p = 0.008).

Conclusion: Patients with CTD-ILD experienced significantly longer postoperative hospitalizations compared to IPF patients without an increased risk of grade 3 PGD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.healun.2021.01.1391DOI Listing
January 2021

Angiopoietin-2 outperforms other endothelial biomarkers associated with severe acute kidney injury in patients with severe sepsis and respiratory failure.

Crit Care 2021 02 4;25(1):48. Epub 2021 Feb 4.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, T1218 MCN, 1161 21st, Avenue S, Nashville, TN, 37232, USA.

Background: Endothelial dysfunction and injury is a major pathophysiologic feature of sepsis. Sepsis is also the most frequent cause of acute kidney injury (AKI) in critically ill patients. Though most studies of AKI in sepsis have focused on tubular epithelial injury, the role of endothelial dysfunction and injury is less well studied. The goal of this study was first to investigate whether endothelial dysfunction and injury biomarkers were associated with severe AKI in sepsis patients. The second goal was to determine the best performing biomarker for severe AKI and whether this biomarker was associated with severe AKI across different etiologies of sepsis and clinical outcomes.

Methods: We studied adults with severe sepsis and acute respiratory failure (ARF) enrolled in the prospective observational Validating Acute Lung Injury markers for Diagnosis (VALID) study. Plasma endothelial dysfunction and injury biomarkers, including angiopoietin-2, soluble vascular endothelial cadherin (sVE-cadherin), endocan and syndecan-1, were measured at study enrollment. Primary analysis focused on the association between endothelial biomarker levels with severe AKI (defined as Kidney Disease: Improving Global Outcomes [KDIGO] AKI stage 2 or 3), other organ dysfunctions (defined by Brussels organ failure scores), and comparison of pulmonary versus non-pulmonary sepsis.

Results: Among 228 sepsis patients enrolled, 141 developed severe AKI. Plasma levels of angiopoietin-2, endocan, sVE-cadherin, and syndecan-1 were significantly higher in sepsis patients with severe AKI compared to those without severe AKI. Among four endothelial biomarkers, only angiopoietin-2 was independently associated with severe AKI (odds ratio 6.07 per log increase, 95% CI 2.34-15.78, p < 0.001). Plasma angiopoietin-2 levels by quartile were significantly higher in sepsis patients with hepatic, coagulation, and circulatory failure. Plasma angiopoietin-2 levels were also significantly higher in patients with non-pulmonary sepsis compared to subjects with pulmonary sepsis.

Conclusion: Among four biomarkers of endothelial dysfunction and injury, angiopoietin-2 had the most robust independent association with development of severe AKI in patients with severe sepsis and ARF. Plasma angiopoietin-2 levels were also associated with other organ dysfunctions, non-pulmonary sepsis, and death. These findings highlight the importance of early endothelial dysfunction and injury in the pathogenesis of sepsis-induced AKI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13054-021-03474-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859898PMC
February 2021

Precision medicine in acute respiratory distress syndrome: workshop report and recommendations for future research.

Eur Respir Rev 2021 Mar 2;30(159). Epub 2021 Feb 2.

Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Dept of Medicine, University of California, San Francisco, CA, USA.

Acute respiratory distress syndrome (ARDS) is a devastating critical illness that can be triggered by a wide range of insults and remains associated with a high mortality of around 40%. The search for targeted treatment for ARDS has been disappointing, possibly due to the enormous heterogeneity within the syndrome. In this perspective from the European Respiratory Society research seminar on "Precision medicine in ARDS", we will summarise the current evidence for heterogeneity, explore the evidence in favour of precision medicine and provide a roadmap for further research in ARDS. There is evident variation in the presentation of ARDS on three distinct levels: 1) aetiological; 2) physiological and 3) biological, which leads us to the conclusion that there is no typical ARDS. The lack of a common presentation implies that intervention studies in patients with ARDS need to be phenotype aware and apply a precision medicine approach in order to avoid the lack of success in therapeutic trials that we faced in recent decades. Deeper phenotyping and integrative analysis of the sources of variation might result in identification of additional treatable traits that represent specific pathobiological mechanisms, or so-called endotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1183/16000617.0317-2020DOI Listing
March 2021

Biomarkers of inflammation and repair in kidney disease progression.

J Clin Invest 2021 Feb;131(3)

Division of Nephrology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

INTRODUCTIONAcute kidney injury and chronic kidney disease (CKD) are common in hospitalized patients. To inform clinical decision making, more accurate information regarding risk of long-term progression to kidney failure is required.METHODSWe enrolled 1538 hospitalized patients in a multicenter, prospective cohort study. Monocyte chemoattractant protein 1 (MCP-1/CCL2), uromodulin (UMOD), and YKL-40 (CHI3L1) were measured in urine samples collected during outpatient follow-up at 3 months. We followed patients for a median of 4.3 years and assessed the relationship between biomarker levels and changes in estimated glomerular filtration rate (eGFR) over time and the development of a composite kidney outcome (CKD incidence, CKD progression, or end-stage renal disease). We paired these clinical studies with investigations in mouse models of renal atrophy and renal repair to further understand the molecular basis of these markers in kidney disease progression.RESULTSHigher MCP-1 and YKL-40 levels were associated with greater eGFR decline and increased incidence of the composite renal outcome, whereas higher UMOD levels were associated with smaller eGFR declines and decreased incidence of the composite kidney outcome. A multimarker score increased prognostic accuracy and reclassification compared with traditional clinical variables alone. The mouse model of renal atrophy showed greater Ccl2 and Chi3l1 mRNA expression in infiltrating macrophages and neutrophils, respectively, and evidence of progressive renal fibrosis compared with the repair model. The repair model showed greater Umod expression in the loop of Henle and correspondingly less fibrosis.CONCLUSIONSBiomarker levels at 3 months after hospitalization identify patients at risk for kidney disease progression.FUNDINGNIH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI139927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843225PMC
February 2021

Biomarkers in acute respiratory distress syndrome.

Curr Opin Crit Care 2021 Feb;27(1):46-54

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine.

Purpose Of Review: This article provides an overview of protein biomarkers for acute respiratory distress syndrome (ARDS) and their potential use in future clinical trials.

Recent Findings: The protein biomarkers studied as indices of biological processes involved in the pathogenesis of ARDS may have diagnostic and/or prognostic value. Recently, they also proved useful for identifying ARDS phenotypes and assessing heterogeneity of treatment effect in retrospective analyses of completed clinical trials.

Summary: This article summarizes the current research on ARDS biomarkers and provides insights into how they should be integrated as prognostic and predictive enrichment tools in future clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCC.0000000000000786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774234PMC
February 2021

Prospective Cohort Study of Renin-Angiotensin System Blocker Usage after Hospitalized Acute Kidney Injury.

Clin J Am Soc Nephrol 2020 Dec 3;16(1):26-36. Epub 2020 Dec 3.

Division of Nephrology, University of California, San Francisco School of Medicine, San Francisco, California

Background And Objectives: The risk-benefit ratio of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy after AKI may be altered due to concerns regarding recurrent AKI. We evaluated, in a prospective cohort, the association between use (versus nonuse) of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the subsequent risk of AKI and other adverse outcomes after hospitalizations with and without AKI.

Design, Setting, Participants, & Measurements: We studied 1538 patients recently discharged from the hospital who enrolled in the multicenter, prospective ASSESS-AKI study, with approximately half of patients experiencing AKI during the index hospitalization. All participants were seen at a baseline visit 3 months after their index hospitalization and were categorized at that time on whether they were using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or not. We used multivariable Cox regression, adjusting for demographics, comorbidities, eGFR, urine protein-creatinine ratio, and use of other medications, to examine the association between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and subsequent risks of AKI, death, kidney disease progression, and adjudicated heart-failure events.

Results: The use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers was 50% (386/769) among those with AKI during the index hospitalization and 47% (362/769) among those without. Among those with AKI during the index hospitalization, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was not associated with a higher risk of recurrent hospitalized AKI (adjusted hazard ratio, 0.88; 95% confidence interval, 0.69 to 1.13). Associations between angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use and death, kidney disease progression, and adjudicated heart-failure events appeared similar in study participants who did and did not experience AKI during the index hospitalization (all interaction values >0.05).

Conclusions: The risk-benefit ratio of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy after hospital discharge appears to be similar regardless of whether AKI occurred during the hospitalization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.10840720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792656PMC
December 2020

Phenotypes and personalized medicine in the acute respiratory distress syndrome.

Intensive Care Med 2020 12 18;46(12):2136-2152. Epub 2020 Nov 18.

Department of Anesthesia, University of California San Francisco, San Francisco, CA, USA.

Although the acute respiratory distress syndrome (ARDS) is well defined by the development of acute hypoxemia, bilateral infiltrates and non-cardiogenic pulmonary edema, ARDS is heterogeneous in terms of clinical risk factors, physiology of lung injury, microbiology, and biology, potentially explaining why pharmacologic therapies have been mostly unsuccessful in treating ARDS. Identifying phenotypes of ARDS and integrating this information into patient selection for clinical trials may increase the chance for efficacy with new treatments. In this review, we focus on classifying ARDS by the associated clinical disorders, physiological data, and radiographic imaging. We consider biologic phenotypes, including plasma protein biomarkers, gene expression, and common causative microbiologic pathogens. We will also discuss the issue of focusing clinical trials on the patient's phase of lung injury, including prevention, administration of therapy during early acute lung injury, and treatment of established ARDS. A more in depth understanding of the interplay of these variables in ARDS should provide more success in designing and conducting clinical trials and achieving the goal of personalized medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06296-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673253PMC
December 2020

Hyperoxemia and Cerebral Vasospasm in Aneurysmal Subarachnoid Hemorrhage.

Neurocrit Care 2020 Nov 4. Epub 2020 Nov 4.

Department of Neurological Surgery, Vanderbilt University Medical Center, 1161 21st Avenue South, T4224 Medical Center North, Nashville, TN, 37232-2380, USA.

Background: Cerebral vasospasm is a major contributor to disability and mortality after aneurysmal subarachnoid hemorrhage. Oxidation of cell-free hemoglobin plays an integral role in neuroinflammation and is a suggested source of tissue injury after aneurysm rupture. This study sought to determine whether patients with subarachnoid hemorrhage and cerebral vasospasm were more likely to have been exposed to early hyperoxemia than those without vasospasm.

Methods: This single-center retrospective cohort study included adult patients presenting with aneurysmal subarachnoid hemorrhage to Vanderbilt University Medical Center between January 2007 and December 2017. Patients with an ICD-9/10 diagnosis of aneurysmal subarachnoid hemorrhage were initially identified (N = 441) and subsequently excluded if they did not have intracranial imaging, arterial PaO values or died within 96 h post-rupture (N = 96). The final cohort was 345 subjects. The degree of hyperoxemia was defined by the highest PaO measured within 72 h after aneurysmal rupture. The primary outcome was development of cerebral vasospasm, which included asymptomatic vasospasm and delayed cerebral ischemia (DCI). Secondary outcomes were mortality and modified Rankin Scale.

Results: Three hundred and forty five patients met inclusion criteria; 218 patients (63%) developed vasospasm. Of those that developed vasospasm, 85 were diagnosed with delayed cerebral ischemia (DCI, 39%). The average patient age of the cohort was 55 ± 13 years, and 68% were female. Ninety percent presented with Fisher grade 3 or 4 hemorrhage (N = 310), while 42% presented as Hunt-Hess grade 4 or 5 (N = 146). In univariable analysis, patients exposed to higher levels of PaO by quintile of exposure had a higher mortality rate and were more likely to develop vasospasm in a dose-dependent fashion (P = 0.015 and P = 0.019, respectively). There were no statistically significant predictors that differentiated asymptomatic vasospasm from DCI and no significant difference in maximum PaO between these two groups. In multivariable analysis, early hyperoxemia was independently associated with vasospasm (OR = 1.15 per 50 mmHg increase in PaO2 [1.03, 1.28]; P = 0.013), but not mortality (OR = 1.10 [0.97, 1.25]; P = 0.147) following subarachnoid hemorrhage.

Conclusions: Hyperoxemia within 72 h post-aneurysmal rupture is an independent predictor of cerebral vasospasm, but not mortality in subarachnoid hemorrhage. Hyperoxemia is a variable that can be readily controlled by adjusting the delivered FiO and may represent a modifiable risk factor for vasospasm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12028-020-01136-6DOI Listing
November 2020

Designing an ARDS trial for 2020 and beyond: focus on enrichment strategies.

Intensive Care Med 2020 Dec 2;46(12):2153-2156. Epub 2020 Nov 2.

Department of Anaesthesia and Critical Care, Lariboisière Hospital, APHP; Inserm UMR-S942 Mascot, FHU PROMICE and Université de Paris, Paris, France.

With the exception of a few successes in trials of supportive care, the majority of interventional clinical trials for acute respiratory distress syndrome (ARDS) have not led to new therapies. To improve the likelihood of benefit from clinical trial interventions in ARDS, clinical trial design must be improved. To optimize trial design, many factors need to be considered including the type of therapy to be tested, the type of trial (phase 2 or 3), how patients will be selected, primary and secondary end-points, and strategy for conduct of the trial, including potential newer trial designs such as platform or adaptive trials. Of these, optimization of patient selection is central to the likelihood of success and is particularly relevant in ARDS, which is a heterogeneous clinical syndrome, not a homogeneous disease. Recent advances including improved understanding of pathophysiologic mechanisms and better tools for outcome prediction in ARDS should facilitate both predictive and prognostic enrichment. This commentary focuses on new information and novel methods for prognostic and predictive enrichment that may be useful to optimize patient selection and increase the likelihood of positive clinical trials in ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06232-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605340PMC
December 2020

The NLRP3 inflammasome in macrophages is stimulated by cell-free hemoglobin.

Physiol Rep 2020 11;8(21):e14589

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Cell-free hemoglobin (CFH) is associated with severe lung injury in human patients and is sufficient to induce airspace inflammation and alveolar-capillary barrier dysfunction in an experimental model of acute lung injury. The mechanisms through which this occurs are unknown. One key pathway which regulates inflammation during acute lung injury is the NLRP3 inflammasome. Because CFH can act as a damage-associated molecular pattern, we hypothesized that CFH may activate the NLRP3 inflammasome during acute lung injury. Primary mouse alveolar macrophages and cultured murine macrophages exposed to CFH (0-1 mg/ml) for 24 hr demonstrated robust upregulation of the NLRP3 inflammasome components NLRP3, caspase-1, and caspase-11. Maximal induction of the NLRP3 inflammasome by CFH required TLR4. Compared to wild-type controls, mice lacking NLRP3 developed less airspace inflammation (2.7 × 10  cells/ml in bronchoalveolar lavage fluid versus. 1.1 × 10 /ml, p = .006) after exposure to intratracheal CFH. Together, these data demonstrate that CFH can stimulate the NLRP3 inflammasome in macrophages and that this pathway may be important in the pathogenesis of CFH-induced acute lung injury.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14814/phy2.14589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601531PMC
November 2020

Cigarette Smoke and Nicotine-Containing Electronic-Cigarette Vapor Downregulate Lung WWOX Expression, Which Is Associated with Increased Severity of Murine Acute Respiratory Distress Syndrome.

Am J Respir Cell Mol Biol 2021 01;64(1):89-99

Division of Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Illinois, Chicago, Illinois.

A history of chronic cigarette smoking is known to increase risk for acute respiratory distress syndrome (ARDS), but the corresponding risks associated with chronic e-cigarette use are largely unknown. The chromosomal fragile site gene, WWOX, is highly susceptible to genotoxic stress from environmental exposures and thus an interesting candidate gene for the study of exposure-related lung disease. Lungs harvested from current versus former/never-smokers exhibited a 47% decrease in WWOX mRNA levels. Exposure to nicotine-containing e-cigarette vapor resulted in an average 57% decrease in WWOX mRNA levels relative to vehicle-treated controls. In separate studies, endothelial (EC)-specific WWOX knockout (KO) versus WWOX flox control mice were examined under ARDS-producing conditions. EC WWOX KO mice exhibited significantly greater levels of vascular leak and histologic lung injury. ECs were isolated from digested lungs of untreated EC WWOX KO mice using sorting by flow cytometry for CD31 CD45cells. These were grown in culture, confirmed to be WWOX deficient by RT-PCR and Western blotting, and analyzed by electric cell impedance sensing as well as an FITC dextran transwell assay for their barrier properties during methicillin-resistant or LPS exposure. WWOX KO ECs demonstrated significantly greater declines in barrier function relative to cells from WWOX flox controls during either methicillin-resistant or LPS treatment as measured by both electric cell impedance sensing and the transwell assay. The increased risk for ARDS observed in chronic smokers may be mechanistically linked, at least in part, to lung WWOX downregulation, and this phenomenon may also manifest in the near future in chronic users of e-cigarettes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1165/rcmb.2020-0145OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780991PMC
January 2021

Inflammation and Coagulation during Critical Illness and Long-Term Cognitive Impairment and Disability.

Am J Respir Crit Care Med 2020 Oct 8. Epub 2020 Oct 8.

University of Pittsburgh, 6614, Department of Critical Care Medicine, Pittsburgh, Pennsylvania, United States;

RATIONALE The biological mechanisms of long-term cognitive impairment and disability after critical illness are unclear. OBJECTIVES To test the hypothesis that markers of acute inflammation and coagulation are associated with subsequent long-term cognitive impairment and disability. METHODS We obtained plasma samples from adults with respiratory failure or shock on study days 1, 3, and 5 and measured concentrations of C-reactive protein, interferon gamma, interleukin [IL]-1 beta, IL-6, IL-8, IL-10, IL-12, matrix metalloproteinase-9, tumor necrosis factor-alpha, TNF-receptor 1, and protein C. At 3- and 12-months post-discharge, we assessed global cognition, executive function, and activities of daily living. We analyzed associations between markers and outcomes using multivariable regression, adjusting for age, sex, education, comorbidities, baseline cognition, doses of sedatives and opioids, stroke risk (in cognitive models), and baseline disability scores (in disability models). MEASUREMENTS AND MAIN RESULTS We included 548 participants who were a median (interquartile range) of 62 (53-72) years old, 88% of whom were mechanically ventilated, and who had an enrollment SOFA of 9 (7-11). After adjusting for covariates, no markers were associated with long-term cognitive function. Two markers, CRP and MMP-9, were associated with greater disability in basic and instrumental activities of daily living at 3 and 12 months. No other markers were consistently associated with disability outcomes. CONCLUSIONS Markers of systemic inflammation and coagulation measured early during critical illness are not associated with long-term cognitive outcomes and demonstrate inconsistent associations with disability outcomes. Future studies that pair longitudinal measurement of inflammation and related pathways throughout the course of critical illness and during recovery with long-term outcomes are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201912-2449OCDOI Listing
October 2020

Physiological and biological heterogeneity in COVID-19-associated acute respiratory distress syndrome.

Authors:
Lorraine B Ware

Lancet Respir Med 2020 12 27;8(12):1163-1165. Epub 2020 Aug 27.

Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232-2650, USA. Electronic address:

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2213-2600(20)30369-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836300PMC
December 2020

Single-cell RNA sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis.

Sci Adv 2020 Jul 8;6(28):eaba1972. Epub 2020 Jul 8.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by pathologic epithelial remodeling and accumulation of extracellular matrix (ECM). To comprehensively define the cell types, mechanisms, and mediators driving fibrotic remodeling in lungs with PF, we performed single-cell RNA sequencing of single-cell suspensions from 10 nonfibrotic control and 20 PF lungs. Analysis of 114,396 cells identified 31 distinct cell subsets/states. We report that a remarkable shift in epithelial cell phenotypes occurs in the peripheral lung in PF and identify several previously unrecognized epithelial cell phenotypes, including a / pathologic, ECM-producing epithelial cell population that was highly enriched in PF lungs. Multiple fibroblast subtypes were observed to contribute to ECM expansion in a spatially discrete manner. Together, these data provide high-resolution insights into the complexity and plasticity of the distal lung epithelium in human disease and indicate a diversity of epithelial and mesenchymal cells contribute to pathologic lung fibrosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aba1972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439444PMC
July 2020

A deliberate path toward diversity, equity, and inclusion within the ASCI.

J Clin Invest 2020 10;130(10):5031-5032

Editor, Journal of Clinical Investigation, , 2018-2022; Johns Hopkins University, Baltimore, Maryland, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI142423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524472PMC
October 2020

A prospective cohort study of acute kidney injury and kidney outcomes, cardiovascular events, and death.

Kidney Int 2021 02 22;99(2):456-465. Epub 2020 Jul 22.

Division of Nephrology, Department of Medicine, University of California, San Francisco School of Medicine, San Francisco, California, USA; Division of Research, Kaiser Permanente Northern California, Oakland, California, USA; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA; Departments of Medicine (Nephrology), Health Research and Policy, Stanford University, Stanford, California, USA. Electronic address:

Acute kidney injury (AKI) has been reported to be associated with excess risks of death, kidney disease progression and cardiovascular events although previous studies have important limitations. To further examine this, we prospectively studied adults from four clinical centers surviving three months and more after hospitalization with or without AKI who were matched on center, pre-admission CKD status, and an integrated priority score based on age, prior cardiovascular disease or diabetes mellitus, preadmission estimated glomerular filtration rate (eGFR) and treatment in the intensive care unit during the index hospitalization between December 2009-February 2015, with follow-up through November 2018. All participants had assessments of kidney function before (eGFR) and at three months and annually (eGFR and proteinuria) after the index hospitalization. Associations of AKI with outcomes were examined after accounting for pre-admission and three-month post-discharge factors. Among 769 AKI (73% Stage 1, 14% Stage 2, 13% Stage 3) and 769 matched non-AKI adults, AKI was associated with higher adjusted rates of incident CKD (adjusted hazard ratio 3.98, 95% confidence interval 2.51-6.31), CKD progression (2.37,1.28-4.39), heart failure events (1.68, 1.22-2.31) and all-cause death (1.78, 1.24-2.56). AKI was not associated with major atherosclerotic cardiovascular events in multivariable analysis (0.95, 0.70-1.28). After accounting for degree of kidney function recovery and proteinuria at three months after discharge, the associations of AKI with heart failure (1.13, 0.80-1.61) and death (1.29, 0.84-1.98) were attenuated and no longer significant. Thus, assessing kidney function recovery and proteinuria status three months after AKI provides important prognostic information for long-term clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374148PMC
February 2021

Early Changes Over Time in the Radiographic Assessment of Lung Edema Score Are Associated With Survival in ARDS.

Chest 2020 Dec 10;158(6):2394-2403. Epub 2020 Jul 10.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.

Background: The Radiographic Assessment of Lung Edema (RALE) score is associated with the severity of ARDS, and treatments targeted at reducing pulmonary edema such as conservative fluid management cause a reduction in RALE score over time.

Research Question: Are early changes in RALE score over time associated with survival in patients with ARDS?

Study Design And Methods: Data from patients enrolled in three centers in the Lung Imaging for Ventilation sEtting in ARDS (LIVE) trial with available chest radiographs at baseline (day 0) and days 2 or 3 were used. The RALE was scored by two independent reviewers. The primary end point was death by day 90, considering RALE score both at baseline and as a time-varying covariate in a marginal Cox survival model.

Results: RALE was scored from 135, 64, and 88 radiographs on days 0, 2, and 3, respectively. Both baseline RALE (hazard ratio [HR] for each one-point increment, 1.04; 95% CI, 1.01-1.08; P = .006) and the change in RALE over time (HR for each one-point decrease per unit of time, 0.99; 95% CI, 0.99-0.99; P = .03) were associated with death by day 90, even after adjustment for age, sex, BMI, Simplified Acute Physiology Score II, vasopressor use, and total volume of fluids received since study entry.

Interpretation: The change in RALE during the first days after ARDS onset is independently associated with survival and may be useful as a surrogate end point in future clinical trials of new therapeutics in ARDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.chest.2020.06.070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768934PMC
December 2020

Long-term ozone exposure is positively associated with telomere length in critically ill patients.

Environ Int 2020 08 8;141:105780. Epub 2020 May 8.

Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Rationale: Chronic air pollutant exposure has been associated with development of Acute Respiratory Distress Syndrome (ARDS) in patients at risk, particularly from severe trauma. We recently reported that shorter peripheral blood leukocyte (PBL) telomere length (TL) was associated with worse outcomes and higher severity of ARDS in critically ill patients. Since most major air pollutants are potent oxidants that can induce cellular oxidative stress, and oxidative stress can accelerate telomere shortening, we hypothesized that higher levels of chronic air pollutant exposure would be associated with shorter telomere length in critically ill patients including patients with ARDS.

Methods: PBL-TL was measured in genomic DNA collected on the morning of ICU day 2 in 772 critically ill patients enrolled in a prospective observational study. Exposures to air pollutants including ozone (warm-season only), particulate matter < 2.5 µm (PM), particulate matter < 10 µm (PM), CO, NO and SO, were estimated by weighted average of daily levels from all monitors within 50 km of each patient's residential address for the 3 years prior to admission. Associations of each air pollutant exposure and PBL-TL were investigated by multivariable linear regression models adjusting for age, ethnicity, sex, smoking history, alcohol abuse, insurance status, median household income, history of malignancy and APACHE II.

Results: Contrary to our hypothesis, TL increased across exposure quartiles in both ozone and PM analyses (p < 0.05). In a regression model controlling for potential confounders, long term ozone exposure was significantly associated with an increase in TL in the entire cohort (0.31 kb per 10 ppb), as well as in subgroups with sepsis, trauma and ARDS (all p < 0.05). In multivariable models, entire-year exposure to PM, PM, CO, NO and SO was not associated with TL after adjustment for potential confounders. In an analysis restricted to warm-season levels to assess the effect of seasonality, higher warm-season PM and CO exposures were independently associated with longer TL.

Conclusions: Long-term exposure to ozone is associated with longer peripheral blood TL in critically ill patients. Further studies are needed to investigate the potential underlying mechanisms for this unexpected positive association between telomere length and air pollution exposure in critical illness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envint.2020.105780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7535086PMC
August 2020

The Role of Circulating Cell-Free Hemoglobin in Sepsis-Associated Acute Kidney Injury.

Semin Nephrol 2020 03;40(2):148-159

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville TN. Electronic address:

Sepsis is a heterogeneous clinical syndrome that is complicated commonly by acute kidney injury (sepsis-AKI). Currently, no approved pharmacologic therapies exist to either prevent sepsis-AKI or to treat sepsis-AKI once it occurs. A growing body of evidence supports a connection between red blood cell biology and sepsis-AKI. Increased levels of circulating cell-free hemoglobin (CFH) released from red blood cells during hemolysis are common during sepsis and can contribute to sepsis-AKI through several mechanisms including tubular obstruction, nitric oxide depletion, oxidative injury, and proinflammatory signaling. A number of potential pharmacologic therapies targeting CFH in sepsis have been identified including haptoglobin, hemopexin, and acetaminophen, and early phase clinical trials have suggested that acetaminophen may have beneficial effects on lipid peroxidation and kidney function in patients with sepsis. Bedside measurement of CFH levels may facilitate predictive enrichment for future clinical trials of CFH-targeted therapeutics. However, rapid and reliable bedside tests for plasma CFH will be required for such trials to move forward.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.semnephrol.2020.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7172012PMC
March 2020

Acute respiratory distress syndrome subphenotypes and therapy responsive traits among preclinical models: protocol for a systematic review and meta-analysis.

Respir Res 2020 Apr 7;21(1):81. Epub 2020 Apr 7.

Department of Perioperative Medicine, CHU Clermont-Ferrand, Clermont-Ferrand, France.

Background: Subphenotypes were recently reported within clinical acute respiratory distress syndrome (ARDS), with distinct outcomes and therapeutic responses. Experimental models have long been used to mimic features of ARDS pathophysiology, but the presence of distinct subphenotypes among preclinical ARDS remains unknown. This review will investigate whether: 1) subphenotypes can be identified among preclinical ARDS models; 2) such subphenotypes can identify some responsive traits.

Methods: We will include comparative preclinical (in vivo and ex vivo) ARDS studies published between 2009 and 2019 in which pre-specified therapies were assessed (interleukin (IL)-10, IL-2, stem cells, beta-agonists, corticosteroids, fibroblast growth factors, modulators of the receptor for advanced glycation end-products pathway, anticoagulants, and halogenated agents) and outcomes compared to a control condition. The primary outcome will be a composite of the four key features of preclinical ARDS as per the American Thoracic Society consensus conference (histologic evidence of lung injury, altered alveolar-capillary barrier, lung inflammatory response, and physiological dysfunction). Secondary outcomes will include the single components of the primary composite outcome, net alveolar fluid clearance, and death. MEDLINE, Embase, and Cochrane databases will be searched electronically and data from eligible studies will be extracted, pooled, and analyzed using random-effects models. Individual study reporting will be assessed according to the Animal Research: Reporting of In Vivo Experiments guidelines. Meta-regressions will be performed to identify subphenotypes prior to comparing outcomes across subphenotypes and treatment effects.

Discussion: This study will inform on the presence and underlying pathophysiological features of subphenotypes among preclinical models of ARDS and should help to determine whether sufficient evidence exists to perform preclinical trials of subphenotype-targeted therapies, prior to potential clinical translation.

Systematic Review Registration: PROSPERO (ID: CRD42019157236).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12931-020-01337-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137453PMC
April 2020

E-Cigarette or Vaping Product Use-associated Lung Injury: Developing a Research Agenda. An NIH Workshop Report.

Am J Respir Crit Care Med 2020 09;202(6):795-802

Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina.

The NHLBI convened a working group on October 23, 2019, to identify the most relevant and urgent research priorities and prevailing challenges in e-cigarette or vaping product use-associated lung injury (EVALI). Experts across multiple disciplines discussed the complexities of the EVALI outbreak, identified research priorities, and recommended strategies to address most effectively its causal factors and improve diagnosis, treatment, and prevention of this disease. Many research priorities were identified, including the need to create national and international registries of patients with EVALI, to track accurately those affected and assess outcomes. The group concluded that biospecimens from subjects with EVALI are urgently needed to help define EVALI pathogenesis and that vaping has disease risks that are disparate from smoking, with the occurrence of EVALI highlighting the importance of broadening e-cigarette research beyond comparators to smoking-related diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201912-2332WSDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491408PMC
September 2020

Acute respiratory distress syndrome-attributable mortality in critically ill patients with sepsis.

Intensive Care Med 2020 06 23;46(6):1222-1231. Epub 2020 Mar 23.

Cardiovascular Research Institute, University of California, San Francisco, CA, USA.

Purpose: Previous studies assessing impact of acute respiratory distress syndrome (ARDS) on mortality have shown conflicting results. We sought to assess the independent association of ARDS with in-hospital mortality among intensive care unit (ICU) patients with sepsis.

Methods: We studied two prospective sepsis cohorts drawn from the Early Assessment of Renal and Lung Injury (EARLI; n = 474) and Validating Acute Lung Injury markers for Diagnosis (VALID; n = 337) cohorts. ARDS was defined by Berlin criteria. We used logistic regression to compare in-hospital mortality in patients with and without ARDS, controlling for baseline severity of illness. We also estimated attributable mortality, adjusted for illness severity by stratification.

Results: ARDS occurred in 195 EARLI patients (41%) and 99 VALID patients (29%). ARDS was independently associated with risk of hospital death in multivariate analysis, even after controlling for severity of illness, as measured by APACHE II (odds ratio [OR] 1.65 (95% confidence interval [CI] 1.02, 2.67), p = 0.04 in EARLI; OR 2.12 (CI 1.16, 3.92), p = 0.02 in VALID). Patients with severe ARDS (P/F < 100) primarily drove this relationship. The attributable mortality of ARDS was 27% (CI 14%, 37%) in EARLI and 37% (CI 10%, 51%) in VALID. ARDS was independently associated with ICU mortality, hospital length of stay (LOS), ICU LOS, and ventilator-free days.

Conclusions: Development of ARDS among ICU patients with sepsis confers increased risk of ICU and in-hospital mortality in addition to other important outcomes. Clinical trials targeting patients with severe ARDS will be best poised to detect measurable differences in these outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00134-020-06010-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224051PMC
June 2020

The long-lasting effects of the acute respiratory distress syndrome.

Expert Rev Respir Med 2020 06 17;14(6):577-586. Epub 2020 Mar 17.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

: Acute respiratory distress syndrome (ARDS) is a severe form of acute lung injury common in critically ill patients and characterized by significant morbidity and mortality. It frequently manifests long-lasting effects beyond hospitalization, from cognitive impairment to physical weakness.: Several complications of ARDS have been identified in patients after hospital discharge. The authors conducted literature searches to identify observational studies, randomized clinical trials, systematic reviews, and guidelines. A summary of is presented here to outline the sequelae of ARDS and their risk factors with a focus on the limited but growing research into possible therapies. Long term sequelae of ARDS commonly identified in the literature include long-term cognitive impairment, psychological morbidities, neuromuscular weakness, pulmonary dysfunction, and ongoing healthcare utilization with reduced quality of life.: Given the public health significance of long-term complications following ARDS, the development of new therapies for prevention and treatment is of vital importance. Furthering knowledge of the pathophysiology of these impairments will provide a framework to develop new therapeutic targets to fuel future clinical trials in this area of critical care medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17476348.2020.1743182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454121PMC
June 2020

Eyes wide open on bronchial aeration in acute respiratory distress syndrome.

Anaesth Crit Care Pain Med 2020 Apr 4;39(2):191-192. Epub 2020 Mar 4.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.accpm.2020.03.003DOI Listing
April 2020

Cell-free hemoglobin increases inflammation, lung apoptosis, and microvascular permeability in murine polymicrobial sepsis.

PLoS One 2020 3;15(2):e0228727. Epub 2020 Feb 3.

Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN, United States of America.

Increased endothelial permeability is central to the pathogenesis of sepsis and leads to organ dysfunction and death but the endogenous mechanisms that drive increased endothelial permeability are not completely understood. We previously reported that cell-free hemoglobin (CFH), elevated in 80% of patients with sepsis, increases lung microvascular permeability in an ex vivo human lung model and cultured endothelial cells. In this study, we augmented a murine model of polymicrobial sepsis with elevated circulating CFH to test the hypothesis that CFH increases microvascular endothelial permeability by inducing endothelial apoptosis. Mice were treated with an intraperitoneal injection of cecal slurry with or without a single intravenous injection of CFH. Severity of illness, mortality, systemic and lung inflammation, endothelial injury and dysfunction and lung apoptosis were measured at selected time points. We found that CFH added to CS increased sepsis mortality, plasma inflammatory cytokines as well as lung apoptosis, edema and inflammation without affecting large vessel reactivity or vascular injury marker concentrations. These results suggest that CFH is an endogenous mediator of increased endothelial permeability and apoptosis in sepsis and may be a promising therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228727PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996826PMC
May 2020

Gender Differences in Authorship of Critical Care Literature.

Am J Respir Crit Care Med 2020 04;201(7):840-847

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California.

Gender gaps exist in academic leadership positions in critical care. Peer-reviewed publications are crucial to career advancement, and yet little is known regarding gender differences in authorship of critical care research. To evaluate gender differences in authorship of critical care literature. We used a validated database of author gender to analyze authorship of critical care articles indexed in PubMed between 2008 and 2018 in 40 frequently cited journals. High-impact journals were defined as those in the top 5% of all journals. We used mixed-effects logistic regression to evaluate the association of senior author gender with first and middle author gender, as well as association of first author gender with journal impact factor. Among 18,483 studies, 30.8% had female first authors, and 19.5% had female senior authors. Female authorship rose slightly over the last decade (average annual increases of 0.44% [ < 0.01] and 0.51% [ < 0.01] for female first and senior authors, respectively). When the senior author was female, the odds of female coauthorship rose substantially (first author adjusted odds ratio [aOR], 1.93; 95% confidence interval [CI], 1.71-2.17; middle author aOR, 1.48; 95% CI, 1.29-1.69). Female first authors had higher odds than men of publishing in lower-impact journals (aOR, 1.30; 95% CI, 1.16-1.45). Women comprise less than one-third of first authors and one-fourth of senior authors of critical care research, with minimal increase over the past decade. When the senior author was female, the odds of female coauthorship rose substantially. However, female first authors tend to publish in lower-impact journals. These findings may help explain the underrepresentation of women in critical care academic leadership positions and identify targets for improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1164/rccm.201910-1957OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7124723PMC
April 2020

Haptoglobin genotype predicts severe acute vaso-occlusive pain episodes in children with sickle cell anemia.

Am J Hematol 2020 Jan 9. Epub 2020 Jan 9.

Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343605PMC
January 2020

Association of neuronal repair biomarkers with delirium among survivors of critical illness.

J Crit Care 2020 04 16;56:94-99. Epub 2019 Dec 16.

Department of Anesthesiology, Division of Anesthesiology Critical Care Medicine, Center for Health Services Research, Vanderbilt University Medical Center, Nashville, TN, United States.

Purpose: Delirium is prevalent but with unclear pathogenesis. Neuronal injury repair pathways may be protective. We hypothesized that higher concentrations of neuronal repair biomarkers would be associated with decreased delirium in critically ill patients.

Materials And Methods: We performed a nested study of hospital survivors within a prospective cohort that enrolled patients within 72 h of respiratory failure or shock. We measured plasma concentrations of ubiquitin carboxyl-terminal-esterase-L1 (UCHL1) and brain-derived neurotrophic factor (BDNF) from blood collected at enrollment. Delirium was assessed twice daily using the CAM-ICU. Multivariable regression was used to examine the associations between biomarkers and delirium prevalence/duration, adjusting for covariates and interactions with age and IL-6 plasma concentration.

Results: We included 427 patients with a median age of 59 years (IQR 48-69) and APACHE II score of 25 (IQR 19-30). Higher plasma concentration of UCHL1 on admission was independently associated with lower prevalence of delirium (p = .04) but not associated with duration of delirium (p = .06). BDNF plasma concentration was not associated with prevalence (p = .26) or duration of delirium (p = .36).

Conclusions: During critical illness, higher UCHL1 plasma concentration is associated with lower prevalence of delirium; BDNF plasma concentration is not associated with delirium. Clinical trial number: NCT00392795; https://clinicaltrials.gov/ct2/show/NCT00392795.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcrc.2019.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080575PMC
April 2020

Plasma biomarkers of inflammation, coagulation, and brain injury as predictors of delirium duration in older hospitalized patients.

PLoS One 2019 19;14(12):e0226412. Epub 2019 Dec 19.

The Critical Illness, Brain Dysfunction and Survivorship (CIBS) Center, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.

Background: Delirium's pathophysiology is poorly understood. We sought to determine if plasma biomarkers of inflammation, coagulation, endothelial activation, and blood brain barrier (BBB) injury were associated with emergency department (ED) delirium duration.

Methods: We enrolled hospitalized patients who were 65 years or older from the ED. Plasma biomarkers of inflammation (interleukin-6 [IL-6], IL-8, soluble tumor necrosis factor receptor I [sTNFRI]), coagulation (Protein C), endothelial activation (plasminogen activating inhibitor-1 [PAI-1]), and BBB injury (S100B) at were measured using blood obtained at enrollment. The dependent variable was ED delirium duration which was determined by the Brief Confusion Assessment Method assessed in the ED and hospitalization. Proportional odds logistic regression analyses were performed adjusted for relevant confounders and allowing for interaction by baseline dementia status.

Results: A total of 156 patients were enrolled. IL-6 (POR = 1.59, 95%CI: 1.09-2.32) and PAI-1 (POR = 2.96, 95%CI: 1.48 to 6.85) were independently associated with more prominent ED delirium duration in subjects without dementia only. No significant associations between IL-8, Protein C, sTNRFI, and S100B and ED delirium duration were observed.

Conclusions: Plasma Biomarkers of systemic inflammation and endothelial activation are associated with ED delirium duration in older ED patients without dementia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226412PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6922408PMC
March 2020