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Increased mortality in elderly patients with acute respiratory distress syndrome is not explained by host response.

ABSTRACT: BACKGROUND:Advanced 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. METHODS:This 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. RESULTS:Ninety-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] %). CONCLUSION:Little 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 REGISTRATION:This trial was registered at ClinicalTrials.gov (identifier NCT01905033 , date of registration July 23, 2013).

SUBMITTER: Schouten LRA

PROVIDER: S-EPMC6820655 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Increased mortality in elderly patients with acute respiratory distress syndrome is not explained by host response.

Schouten Laura R A LRA Bos Lieuwe D J LDJ Serpa Neto A A van Vught Lonneke A LA Wiewel Maryse A MA Hoogendijk Arie J AJ Bonten Marc J M MJM Cremer Olaf L OL Horn Janneke J van der Poll Tom T Schultz Marcus J MJ Wösten-van Asperen Roelie M RM

Intensive care medicine experimental 20191029 1

<h4>Background</h4>Advanced 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.<h4>Methods</h4>This was a prospective longitudinal observational cohort study, performed in the ICUs of two university-affiliate ...[more]

PMID: 31664603

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Project description:BackgroundThere 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.MethodsMetabolomic 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.ResultsThe 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.ConclusionIncreased mortality of acute respiratory distress syndrome was associated with high levels of plasma Phenylalanine.Trial registrationChinese Clinical Trial Registry, ChiCTR1800015930. Registered 29 April 2018, http://www.chictr.org.cn/edit.aspx?pid=25609&htm=4.

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:Rationale: Clinicians commonly use short-term physiologic markers to assess the benefit of ventilator adjustments. Improved arterial oxygen tension/pressure (PaO2)/fraction of inspired oxygen (FiO2) after ventilator adjustment in acute respiratory distress syndrome is associated with lower mortality. However, as driving pressure (ΔP) reflects lung stress and strain, changes in ΔP may more accurately reflect benefits or harms of ventilator adjustments compared with changes in oxygenation.Objectives: We aimed to compare the association between mortality and the changes in PaO2/FiO2 and ΔP following protocolized ventilator changes.Methods: We assessed associations between mortality and changes in PaO2/FiO2 (ΔPaO2/FiO2) and ΔP (ΔΔP) after postrandomization positive end-expiratory pressure (PEEP) and tidal volume adjustment in reanalyses of the ALVEOLI (Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury) and ExPress (Expiratory Pressure) trials. We included subjects with available pre- and postintervention PaO2/FiO2 and ΔP (372 in ALVEOLI and 596 in ExPress). In each separate trial cohort, we performed multivariable Cox regression testing the association between ΔPaO2/FiO2 and ΔΔP with mortality.Results: In ALVEOLI, when analyzed as separate variables, ΔPaO2/FiO2 was associated with mortality only in subjects in whom PEEP increased, whereas ΔΔP was associated with mortality irrespective of direction of PEEP change. When modeled together, improved ΔPaO2/FiO2 was not associated with mortality, whereas ΔΔP remained associated with mortality (adjusted hazard ratio [aHR], 1.50 per 5 cm H2O increase; 95% confidence interval [95% CI], 1.21-1.85). When modeled together in ExPress, ΔΔP (aHR, 1.42; 95% CI, 1.14-1.78) was more strongly associated with mortality than ΔPaO2/FiO2 (aHR, 0.95 per 25 mm Hg increase; 95% CI, 0.90-1.00).Conclusions: Reduced ΔP following protocolized ventilator changes was more strongly and consistently associated with lower mortality than was increased PaO2/FiO2, making ΔΔP more informative about benefit from ventilator adjustments. Our results reinforce the primacy of ΔP, rather than oxygenation, as the key variable associated with outcome.

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Increased mortality in elderly patients with acute respiratory distress syndrome is not explained by host response.

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Increased mortality in elderly patients with acute respiratory distress syndrome is not explained by host response.

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