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Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine.

ABSTRACT: BACKGROUND:There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such "functional metabolites" in ARDS using metabolomics and in vivo experiments in a mouse model. METHODS:Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healthy controls were captured using Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) assay. Univariate and multivariate statistical analysis were performed on metabolomic profiles from blood plasma of ARDS patients and healthy controls to screen for "functional metabolites", which were determined by variable importance in projection (VIP) scores and P value. Pathway analysis of all the metabolites was performed. The mouse model of ARDS was established to investigate the role of "functional metabolites" in the lung injury and mortality caused by the respiratory disorder. RESULTS:The metabolomic profiles of patients with ARDS were significantly different from healthy controls, difference was also observed between metabolomic profiles of the non-survivors and the survivors among the ARDS patient pool. Levels of Phenylalanine, D-Phenylalanine and Phenylacetylglutamine were significantly increased in non-survivors compared to the survivors of ARDS. Phenylalanine metabolism was the most notably altered pathway between the non-survivors and survivors of ARDS patients. In vivo animal experiments demonstrated that high levels of Phenylalanine might be associated with the severer lung injury and increased mortality of ARDS. CONCLUSION:Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine. TRIAL REGISTRATION:Chinese Clinical Trial Registry, ChiCTR1800015930. Registered 29 April 2018, http://www.chictr.org.cn/edit.aspx?pid=25609&htm=4.

SUBMITTER: Xu J

PROVIDER: S-EPMC7193408 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine.

Xu Jing J Pan Tingting T Qi Xiaoling X Tan Ruoming R Wang Xiaoli X Liu Zhaojun Z Tao Zheying Z Qu Hongping H Zhang Yi Y Chen Hong H Wang Yihui Y Zhang Jingjing J Wang Jie J Liu Jialin J

Respiratory research 20200430 1

<h4>Background</h4>There is a dearth of drug therapies available for the treatment of acute respiratory distress syndrome (ARDS). Certain metabolites play a key role in ARDS and could serve as potential targets for developing therapies against this respiratory disorder. The present study was designed to determine such "functional metabolites" in ARDS using metabolomics and in vivo experiments in a mouse model.<h4>Methods</h4>Metabolomic profiles of blood plasma from 42 ARDS patients and 28 healt ...[more]

PMID: 32354336

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Project description:ObjectivesCirculating nucleosomes and their component histones have been implicated as pathogenic in sepsis and acute respiratory distress syndrome in adults. However, their role in pediatric acute respiratory distress syndrome is unknown.DesignWe performed a prospective cohort study in children with acute respiratory distress syndrome, with plasma collection within 24 hours of acute respiratory distress syndrome onset. We associated nucleosome levels with severity of acute respiratory distress syndrome and with nonpulmonary organ failures and tested for association of nucleosomes with PICU mortality and ventilator-free days at 28 days in univariate and multivariable analyses. We also performed proteomics of DNA-bound plasma proteins in a matched case-control study of septic children with and without acute respiratory distress syndrome in order to identify specific histone proteins elevated in acute respiratory distress syndrome.SettingLarge academic tertiary-care PICU.PatientsIntubated children meeting Berlin criteria for acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsWe enrolled 333 children with acute respiratory distress syndrome, with 69 nonsurvivors (21%). Plasma nucleosomes were correlated with acute respiratory distress syndrome severity and with the number of nonpulmonary organ failures at acute respiratory distress syndrome onset. Nucleosomes were higher (p < 0.001) in nonsurvivors (0.40 [interquartile range, 0.20-0.71] arbitrary units) relative to survivors (0.10 [interquartile range, 0.04-0.25] arbitrary units). Nucleosomes were associated with PICU mortality in multivariable analysis (adjusted odds ratio 1.84 per 1 sd increase; 95% CI, 1.38-2.45; p < 0.001). Nucleosomes were also associated with a lower probability of being extubated alive by day 28 after multivariable adjustment (adjusted subdistribution hazard ratio, 0.74; 95% CI, 0.63-0.88; p = 0.001). Proteomic analysis demonstrated higher levels of the core nucleosome histones H2A, H2B, H3, and H4 in septic children with acute respiratory distress syndrome, relative to septic children without acute respiratory distress syndrome.ConclusionsPlasma nucleosomes are associated with acute respiratory distress syndrome severity, nonpulmonary organ failures, and worse outcomes in pediatric acute respiratory distress syndrome.

Project description:ObjectivesAcute respiratory distress syndrome is characterized by an overly exuberant inflammatory state in the lung. Specialized proresolving mediators are endogenous agonists for the resolution of lung inflammation and injury in health, yet their association with acute respiratory distress syndrome severity and outcomes remains to be defined. In the current study, we investigate associations between plasma levels of specialized proresolving mediators and acute respiratory distress syndrome severity and mortality.DesignTranslational pilot study nested within a large prospective cohort of patients with risk factors for acute respiratory distress syndrome.SettingICU from a large medical center.PatientsTwenty-six Caucasian patients with acute respiratory distress syndrome and available plasma from early in critical illness.InterventionsNone.Measurements and main resultsHere, in samples from 26 acute respiratory distress syndrome patients, we examined plasma levels of select specialized proresolving mediators that promote lung injury resolution in preclinical systems, namely lipoxin A4 and maresin 1, and select prophlogistic lipid mediators linked to acute respiratory distress syndrome pathogenesis, namely cysteinyl leukotrienes and thromboxane B2. These mediators were detected by sensitive enzyme-linked immunosorbent assay: lipoxin A4 (assay range) (8.2-5,000 pg/mL), maresin 1 (7.8-1,000 pg/mL), cysteinyl leukotrienes (7.8-1,000 pg/mL), and thromboxane B2 (15.6-2,000 pg/mL). Lower plasma levels of specialized proresolving mediators were associated with increased duration of ventilatory support and ICU length of stay. Even in this small sample size, trends were evident for increased cysteinyl leukotrienes to specialized proresolving mediator ratios (cysteinyl leukotrienes/maresin 1 and cysteinyl leukotrienes/lipoxin A4) in acute respiratory distress syndrome nonsurvivors.ConclusionsLower specialized proresolving mediator levels in acute respiratory distress syndrome patients may disrupt timely resolution of lung inflammation and/or injury and contribute to clinical severity and mortality.

Project description:The optimal method to assess fluid overload in acute respiratory distress syndrome is not known, and current techniques have limitations. Plasma volume status has emerged as a noninvasive method to assess volume status and is defined as the percentage alteration from ideal plasma volume. We hypothesized that plasma volume status would suggest the presence of significant excess volume and therefore correlate with mortality in acute respiratory distress syndrome.Design and settingThis is a retrospective cohort study of subjects enrolled in four previously completed National Heart Lung and Blood Institute-sponsored acute respiratory distress syndrome trials, using data from the National Institutes of Health Biologic Specimen and Data Repository Information Coordinating Center repository.PatientsStudy subjects included 3,165 patients with acute respiratory distress syndrome previously enrolled in National Heart Lung and Blood Institute-sponsored acute respiratory distress syndrome trials.Measurements and main resultsThe exposure variable of interest was plasma volume status, calculated as the percentage alteration of actual plasma volume calculated on the basis of weight and hematocrit using sex-specific constants. We performed Kaplan-Meier survival analysis and univariable and adjusted Cox proportional hazard models to determine the association of plasma volume status with 60-day mortality. The median age of subjects was 52 years (interquartile range, 40-63 yr). Median plasma volume status was 5.9% (interquartile range, -2.4% to 13.6%), and overall, 68% of subjects had positive plasma volume status suggesting plasma volume higher than ideal plasma volume. In adjusted models, plasma volume status greater than median was associated with 38% greater risk for mortality (hazard ratio, 1.38; 95% CI, 1.20-1.59; p < 0.001). Each interquartile range increase in plasma volume status was associated with greater mortality in adjusted models (hazard ratio, 1.24 per interquartile range increase; 95% CI, 1.13-1.36; p < 0.001). Plasma volume status greater than median was associated with fewer ventilator-free days (18 vs 19 d; p = 0.0026) and ICU-free days (15 vs 17 d; p = 0.0001).ConclusionsPlasma volume status is independently associated with mortality, ICU-free days, and ventilator-free days among subjects with acute respiratory distress syndrome. Plasma volume status could be considered for risk-stratification and to direct therapy, particularly fluid management.

Project description:OBJECTIVE:A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial. DESIGN:Retrospective analysis of randomized controlled clinical trial. SETTING:Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis. PATIENTS:Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population. INTERVENTIONS:Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge. MEASUREMENTS AND MAIN RESULTS:We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however. CONCLUSIONS:Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial.

Project description:ObjectivesPediatric acute respiratory distress syndrome is heterogeneous, with a paucity of risk stratification tools to assist with trial design. We aimed to develop and validate mortality prediction models for patients with pediatric acute respiratory distress syndrome.DesignLeveraging additional data collection from a preplanned ancillary study (Version 1) of the multinational Pediatric Acute Respiratory Distress syndrome Incidence and Epidemiology study, we identified predictors of mortality. Separate models were built for the entire Version 1 cohort, for the cohort excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths. Models were externally validated in a cohort of intubated pediatric acute respiratory distress syndrome patients from the Children's Hospital of Philadelphia.SettingThe derivation cohort represented 100 centers worldwide; the validation cohort was from Children's Hospital of Philadelphia.PatientsThere were 624 and 640 subjects in the derivation and validation cohorts, respectively.InterventionsNone.Measurements and main resultsThe model for the full cohort included immunocompromised status, Pediatric Logistic Organ Dysfunction 2 score, day 0 vasopressor-inotrope score and fluid balance, and PaO2/FIO2 6 hours after pediatric acute respiratory distress syndrome onset. This model had good discrimination (area under the receiver operating characteristic curve 0.82), calibration, and internal validation. Models excluding neurologic deaths, for intubated subjects, and for intubated subjects excluding neurologic deaths also demonstrated good discrimination (all area under the receiver operating characteristic curve ≥ 0.84) and calibration. In the validation cohort, models for intubated pediatric acute respiratory distress syndrome (including and excluding neurologic deaths) had excellent discrimination (both area under the receiver operating characteristic curve ≥ 0.85), but poor calibration. After revision, the model for all intubated subjects remained miscalibrated, whereas the model excluding neurologic deaths showed perfect calibration. Mortality models also stratified ventilator-free days at 28 days in both derivation and validation cohorts.ConclusionsWe describe predictive models for mortality in pediatric acute respiratory distress syndrome using readily available variables from day 0 of pediatric acute respiratory distress syndrome which outperform severity of illness scores and which demonstrate utility for composite outcomes such as ventilator-free days. Models can assist with risk stratification for clinical trials.

Project description:BackgroundAcute liver injury in patients with ARDS decreases survival but early stages may be easily missed due to the lack of sufficient biomarkers signalling its onset. Accordingly, we tested in ARDS patients the hypotheses that microRNA-122, the foremost liver-related microRNA (miR), 1) is an sensitive and specific early predictor for potential liver injury and 2) analysed its impact on 30-day-survival.MethodsWe collected clinical data and analysed blood samples from 119 ARDS patients within the first 24 h of ICU admission and from 20 patients undergoing elective abdominal non-liver surgery serving as controls. Total circulating miR was isolated from serum and relative miR-122 expression was measured (using specific probes and spiked-in miR-54), as were liver function and 30-day survival. Acute liver injury was defined as a total bilirubin concentration???3.0 mg/dl, an ALT activity ?350 U/l, and an INR ?2.0.Results30-day survival of the entire ARDS-cohort was 69% but differed between patients with normal liver function (77%) and acute liver injury (19% p?<? 0.001). miR-122 expression was 20fold higher in non-survivors (95%-CI 0.0149-0.0768; p?=?0.001) and almost 4fold greater in survivors (95%-CI: 0.0037-0.0122; p?=?0.005) compared to controls (95%-CI 0.0008-0.0034) and correlated with markers of liver cell integrity/function [ALT (p?<? 0.001, r?=?0.495), AST (p?<? 0.001, r?=?0.537), total bilirubin (p?=?0.025, r?=?0.206), INR (p?=?0.001, r?=?0.308), and GLDH (p?<? 0.001, r?=?0.489)]. miR-122 serum expression discriminated survivors and non-survivors (AUC: 0.78) better than total bilirubin concentration (AUC: 0.66). Multivariable Cox-regression analysis revealed both acute liver injury (HR 7.6, 95%-CI 2.9-19.8, p?<? 0.001) and miR-122 (HR 4.4, 95%-CI 1.2-16.1, p?=?0.02) as independent prognostic factors for 30-day mortality.ConclusionsIncreased miR-122 serum expression is an early and independent risk factor for 30-day mortality in ARDS patients and potentially reveal an acute liver injury earlier than the conventional markers of liver cell integrity.

Project description:BackgroundAdvanced age is associated with increased mortality in acute respiratory distress syndrome (ARDS) patients. Preclinical studies suggest that the host response to an injurious challenge is age-dependent. In ARDS patients, we investigated whether the association between age and mortality is mediated through age-related differences in the host response.MethodsThis was a prospective longitudinal observational cohort study, performed in the ICUs of two university-affiliated hospitals. The systemic host response was characterized in three predefined age-groups, based on the age-tertiles of the studied population: young (18 to 54 years, N = 209), middle-aged (55 to 67 years, N = 213), and elderly (67 years and older, N = 196). Biomarkers of inflammation, endothelial activation, and coagulation were determined in plasma obtained at the onset of ARDS. The primary outcome was 90-day mortality. A mediation analysis was performed to examine whether age-related differences in biomarker levels serve as potential causal pathways mediating the association between age and mortality.ResultsNinety-day mortality rates were 30% (63/209) in young, 37% (78/213) in middle-aged, and 43% (84/196) in elderly patients. Middle-aged and elderly patients had a higher risk of death compared to young patients (adjusted odds ratio, 1.5 [95% confidence interval 1.0 to 2.3] and 2.1 [1.4 to 3.4], respectively). Relative to young patients, the elderly had significantly lower systemic levels of biomarkers of inflammation and endothelial activation. Tissue plasminogen activator, a marker of coagulation, was the only biomarker that showed partial mediation (proportion of mediation, 10 [1 to 28] %).ConclusionLittle evidence was found that the association between age and mortality in ARDS patients is mediated through age-dependent differences in host response pathways. Only tissue plasminogen activator was identified as a possible mediator of interest.Trial registrationThis trial was registered at ClinicalTrials.gov (identifier NCT01905033 , date of registration July 23, 2013).

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Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine.

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Increased mortality of acute respiratory distress syndrome was associated with high levels of plasma phenylalanine.

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