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Endothelial Biomarkers Are Associated With Indirect Lung Injury in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome.

ABSTRACT: Objectives: Acute respiratory distress syndrome occurring in the setting of direct versus indirect lung injury may reflect different pathobiologies amenable to different treatment strategies. We sought to test whether a panel of plasma biomarkers differed between children with sepsis-associated direct versus indirect acute respiratory distress syndrome. We hypothesized that a biomarker profile indicative of endothelial activation would be associated with indirect acute respiratory distress syndrome.

Design: Observational cohort.

Setting: Academic PICU.

Subjects: Patients less than 18 years old with sepsis-associated direct (pneumonia, n = 52) or indirect (extrapulmonary sepsis, n = 46) acute respiratory distress syndrome.

Interventions: None.

Measurements and main results: Of 58 biomarkers examined, 33 differed by acute respiratory distress syndrome subtype. We used classification and regression tree methodology to examine associations between clinical and biochemical markers and acute respiratory distress syndrome subtype. The classification and regression tree model using only clinical variables (age, sex, race, oncologic comorbidity, and Pediatric Risk of Mortality-III score) performed worse than the classification and regression tree model using five clinical variables and 58 biomarkers. The best classification and regression tree model used only four endothelial biomarkers, including elevated angiopoietin-2/angiopoietin-1 ratio, vascular cell-adhesion molecule, and von Willebrand factor, to identify indirect acute respiratory distress syndrome. Test characteristics were 89% (80-97%) sensitivity, 80% (69-92%) specificity, positive predictive value 84% (74-93%), and negative predictive value 86% (76-96%).

Conclusions: Indirect lung injury in children with acute respiratory distress syndrome is characterized by a biomarker profile indicative of endothelial activation, excess inflammation, and worse outcomes. A model using four biomarkers has the potential to be useful for more precisely identifying patients with acute respiratory distress syndrome whose pathobiology may respond to endothelial-targeted therapies in future trials.

SUBMITTER: Whitney JE

PROVIDER: S-EPMC7721219 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Endothelial Biomarkers Are Associated With Indirect Lung Injury in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome.

Whitney Jane E JE Feng Rui R Koterba Natalka N Chen Fang F Bush Jenny J Graham Kathryn K Lacey Simon F SF Melenhorst Jan Joseph JJ Parikh Samir M SM Weiss Scott L SL Yehya Nadir N

Critical care explorations 20201204 12

<h4>Objectives</h4>Acute respiratory distress syndrome occurring in the setting of direct versus indirect lung injury may reflect different pathobiologies amenable to different treatment strategies. We sought to test whether a panel of plasma biomarkers differed between children with sepsis-associated direct versus indirect acute respiratory distress syndrome. We hypothesized that a biomarker profile indicative of endothelial activation would be associated with indirect acute respiratory distres ...[more]

PMID: 33299985

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Project description:BackgroundIn the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS.MethodsWe conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14.ResultsThe study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range.ConclusionsRosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

Project description:ObjectivesSystemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome.DesignObservational cohort.SettingAcademic PICU.PatientsPatients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19).InterventionsNone.Measurements and main resultsEndothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course.ConclusionsChildren with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

Project description:The role of early, serial measurements of protein biomarkers in sepsis-induced acute respiratory distress syndrome (ARDS) is not clear.ObjectivesTo determine the differences in soluble receptor for advanced glycation end-products (sRAGEs), angiopoietin-2, and surfactant protein-D (SP-D) levels and their changes over time between sepsis patients with and without ARDS.Design setting and participantsProspective observational cohort study of adult patients admitted to the medical ICU at Grady Memorial Hospital within 72 hours of sepsis diagnosis.Main outcomes and measuresPlasma sRAGE, angiopoietin-2, and SP-D levels were measured for 3 consecutive days after enrollment. The primary outcome was ARDS development, and the secondary outcome of 28-day mortality. The biomarker levels and their changes over time were compared between ARDS and non-ARDS patients and between nonsurvivors and survivors.ResultsWe enrolled 111 patients, and 21 patients (18.9%) developed ARDS. The three biomarker levels were not significantly different between ARDS and non-ARDS patients on all 3 days of measurement. Nonsurvivors had higher levels of all three biomarkers than did survivors on multiple days. The changes of the biomarker levels over time were not different between the outcome groups. Logistic regression analyses showed association between day 1 SP-D level and mortality (odds ratio, 1.52; 95% CI, 1.03-2.24; p = 0.03), and generalized estimating equation analyses showed association between angiopoietin-2 levels and mortality (estimate 0.0002; se 0.0001; p = 0.04).Conclusions and relevanceAmong critically ill patients with sepsis, sRAGE, angiopoietin-2, and SP-D levels were not significantly different between ARDS and non-ARDS patients but were higher in nonsurvivors compared with survivors. The trend toward higher levels of sRAGE and SP-D, but not of angiopoietin-2, in ARDS patients may indicate the importance of epithelial injury in sepsis-induced ARDS. Changes of the biomarker levels over time were not different between the outcome groups.

Project description:BACKGROUND:Neuromuscular blockade (NMB) is a therapy for acute respiratory distress syndrome (ARDS). However, the mechanism by which NMB may improve outcome for ARDS patients remains unclear. We sought to determine whether NMB attenuates biomarkers of epithelial and endothelial lung injury and systemic inflammation in ARDS patients, and whether the association is dependent on tidal volume size and the initial degree of hypoxemia. METHODS:We performed a secondary analysis of patients enrolled in the ARDS network low tidal volume ventilation (ARMA) study. Our primary predictor variable was the number of days receiving NMB between study enrollment and day 3. Our primary outcome variables were the change in concentration of biomarkers of epithelial injury (serum surfactant protein-D (SP-D)), endothelial injury (von Willebrand factor (VWF)), and systemic inflammation (interleukin (IL)-8). Multivariable regression analysis was used to compare the change in biomarker concentration controlling for multiple covariates. Patients were stratified by treatment arm (12 versus 6 cm3/kg) and by an initial arterial oxygen tension (PaO2) to fractional inspired oxygen (FiO2) (P/F) ratio of 120. RESULTS:A total of 446 (49%) patients had complete SP-D, VWF, and IL-8 measurements on study enrollment and day 3. After adjusting for baseline differences, each day of NMB was associated with a decrease in SP-D (-23.7 ng/ml/day, p = 0.029), VWF (-33.5% of control/day, p = 0.015), and IL-8 (-362.6 pg/ml/day, p = 0.030) in patients with an initial P/F less than or equal to 120 and receiving low tidal volume ventilation. However, patients with a P/F ratio of greater than 120 or receiving high tidal volume ventilation had either no change or an increase in SP-D, WVF, or IL-8 concentrations. CONCLUSION:NBM is associated with decreased biomarkers of epithelial and endothelial lung injury and systemic inflammation in ARDS patients receiving low tidal volume ventilation and those with a P/F ratio less than or equal to 120.

Project description:ObjectivesTo assess the incidence, severity, and outcomes of pediatric acute respiratory distress syndrome following trauma using Pediatric Acute Lung Injury Consensus Conference criteria.DesignRetrospective cohort study.SettingLevel 1 pediatric trauma center.PatientsTrauma patients less than or equal to 17 years admitted to the ICU from 2009 to 2017.InterventionsNone.Measurements and main resultsWe queried electronic health records to identify patients meeting pediatric acute respiratory distress syndrome oxygenation criteria for greater than or equal to 6 hours and determined whether patients met complete pediatric acute respiratory distress syndrome criteria via chart review. We estimated associations between pediatric acute respiratory distress syndrome and outcome using generalized linear Poisson regression adjusted for age, injury mechanism, Injury Severity Score, and serious brain and chest injuries. Of 2,470 critically injured children, 103 (4.2%) met pediatric acute respiratory distress syndrome criteria. Mortality was 34.0% among pediatric acute respiratory distress syndrome patients versus 1.7% among patients without pediatric acute respiratory distress syndrome (adjusted relative risk, 3.7; 95% CI, 2.0-6.9). Mortality was 50.0% for severe pediatric acute respiratory distress syndrome at onset, 33.3% for moderate, and 30.5% for mild. Cause of death was neurologic in 60.0% and multiple organ failure in 34.3% of pediatric acute respiratory distress syndrome nonsurvivors versus neurologic in 85.4% of nonsurvivors without pediatric acute respiratory distress syndrome (p = 0.001). Among survivors, 77.1% of pediatric acute respiratory distress syndrome patients had functional disability at discharge versus 30.7% of patients without pediatric acute respiratory distress syndrome patients (p < 0.001), and only 17.5% of pediatric acute respiratory distress syndrome patients discharged home without ongoing care versus 86.4% of patients without pediatric acute respiratory distress syndrome (adjusted relative risk, 1.5; 1.1-2.1).ConclusionsIncidence and mortality associated with pediatric acute respiratory distress syndrome following traumatic injury are substantially higher than previously recognized, and pediatric acute respiratory distress syndrome development is associated with high risk of poor outcome even after adjustment for underlying injury type and severity.

Dataset Information

Endothelial Biomarkers Are Associated With Indirect Lung Injury in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome.

Publications

Endothelial Biomarkers Are Associated With Indirect Lung Injury in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome.

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