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A prospective investigation of interleukin-8 levels in pediatric acute respiratory failure and acute respiratory distress syndrome.

ABSTRACT: BACKGROUND:The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure. METHODS:This was a prospective cohort study of children 2?weeks to 17?years of age with acute airways and/or parenchymal lung disease done in 22 pediatric intensive care units participating in the multi-center clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE). Plasma IL-8 levels were measured within 24?h of consent and 24 and 48?h later. DNA was purified from whole blood, and IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, were genotyped. RESULTS:Five hundred forty-nine patients were enrolled; 480 had blood sampling. Plasma IL-8 levels ranged widely from 4 to 7373?pg/mL. Highest IL-8 levels were observed on the day of intubation with subsequent tapering. Levels of IL-8 varied significantly across primary diagnoses with the highest levels occurring in patients with sepsis and the lowest levels in those with asthma. Plasma IL-8 was strongly correlated with oxygenation defect and severity of illness. IL-8 was consistently higher in PARDS patients compared to those without PARDS; levels were 4-12 fold higher in non-survivors compared to survivors. On multivariable analysis, IL-8 was independently associated with death, duration of mechanical ventilation, and PICU length of stay on all days measured, but was not associated with PARDS development. There was no association between the IL-8 single nucleotide polymorphisms, rs4073, rs2227306, and rs2227307, and PARDS development or plasma IL-8 level. CONCLUSIONS:When measured sequentially, plasma IL-8 was robustly associated with multiple, relevant clinical outcomes including mortality, but was not associated with PARDS development. The wide range of plasma IL-8 levels exhibited in this cohort suggests that further study into the heterogeneity of this patient population and its impact on individual responses to PARDS treatment is warranted.

SUBMITTER: Flori H

PROVIDER: S-EPMC6471952 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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A prospective investigation of interleukin-8 levels in pediatric acute respiratory failure and acute respiratory distress syndrome.

Flori Heidi H Sapru Anil A Quasney Michael W MW Gildengorin Ginny G Curley Martha A Q MAQ Matthay Michael A MA Dahmer Mary K MK

Critical care (London, England) 20190417 1

<h4>Background</h4>The association of plasma interleukin-8 (IL-8), or IL-8 genetic variants, with pediatric acute respiratory distress syndrome (PARDS) in children with acute respiratory failure at risk for PARDS has not been examined. The purpose of this study was to examine the association of early and sequential measurement of plasma IL-8 and/or its genetic variants with development of PARDS and other clinical outcomes in mechanically ventilated children with acute respiratory failure.<h4>Met ...[more]

PMID: 30995942

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Project description:ObjectivesTo test whether plasma interleukin-1 receptor antagonist or variants within the gene encoding for interleukin-1ra (IL1RN), or proteins involved in regulating interleukin-1β levels or interleukin-1β response, are associated with pediatric acute respiratory distress syndrome or outcomes in mechanically ventilated children with parenchymal lung disease.DesignProspective cohort study.SettingTwenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622).SubjectsChildren 2 weeks to 17 years old treated with invasive mechanical ventilation for acute airways and/or parenchymal lung disease.Measurements and main resultsThree-hundred seventy-eight of 549 patients had pediatric acute respiratory distress syndrome; DNA and plasma were obtained from 523 of 549 and 480 of 549 patients, respectively. Plasma interleukin-1ra was highest on the day of intubation (day 0) and decreased over the subsequent 3 days (p < 0.0001). Interleukin-1ra level was higher in patients with pediatric acute respiratory distress syndrome than those without pediatric acute respiratory distress syndrome (p < 0.0001). Multivariable regression analysis of data across all days demonstrated a significant association of interleukin-1ra (odds ratio, 1.30; 95% CI, 1.10-1.52; p = 0.002) and day (p < 0.05) with pediatric acute respiratory distress syndrome, independent of age and Pediatric Risk of Mortality-III score. Analysis on individual days indicated that plasma interleukin-1ra levels were associated with pediatric acute respiratory distress syndrome on days 0 and 2, independent of age and Pediatric Risk of Mortality-III score (p = 0.04 and 0.003, respectively), however did not quite reach significance on days 1 and 3 (p = 0.06 and 0.07, respectively). Interleukin-1ra was independently associated with mortality on day 1 (p = 0.02). Interleukin-1ra also correlated with length of mechanical ventilation, measures of oxygenation, and PICU length of stay. No genetic variants were associated with pediatric acute respiratory distress syndrome.ConclusionsPlasma interleukin-1ra is associated with pediatric acute respiratory distress syndrome, PICU length of stay, length of mechanical ventilation, and mortality in children with acute respiratory failure requiring mechanical ventilation.

Project description:ObjectivesTo identify and compare serum and lower respiratory tract fluid biomarkers of lung injury using well-characterized mouse models of lung injury. To explore the relationship between these preclinical biomarkers and clinical outcomes in a discovery cohort of pediatric patients with acute respiratory failure from pneumonia.DesignProspective, observational cohort study.SettingA basic science laboratory and the PICU of a tertiary-care children's hospital.PatientsPICU patients intubated for respiratory failure from a suspected respiratory infection.InterventionsProspective enrollment and collection of lower respiratory tract fluid samples.Measurements and main resultsC57BL6/J mice were intranasally inoculated with escalating doses of influenza A virus or toll-like receptor agonists to simulate varying degrees of lung injury. Serum and bronchoalveolar lavage fluid were measured for the presence of cytokines using commercially available multiplex cytokine assays. Elevated levels of C-C motif chemokine ligand 7 at the peak of inflammation in both bronchoalveolar lavage fluid and serum correlated with lethality, with the bronchoalveolar lavage fluid ratio of C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 providing the best prediction in the mouse models. These preclinical biomarkers were examined in the plasma and lower respiratory tract fluid of a discovery cohort of pediatric patients with acute respiratory failure from pneumonia. The primary clinical outcome measure was ventilator-free days, with secondary outcomes of pediatric acute respiratory distress syndrome severity and mortality. Elevation in peak lower respiratory tract fluid C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratios demonstrated a significant negative correlation with ventilator-free days (r = -0.805; p < 0.02).ConclusionsThis study provides evidence that lung immune profiling via lower respiratory tract fluid cytokine analysis is feasible and may provide insight into clinical outcomes. Further validation of markers, including the C-C motif chemokine ligand 7:C-C motif chemokine ligand 22 ratio in this limited study, in a larger cohort of patients is necessary.

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:Appropriate nutrition is an essential component of intensive care management of children with acute respiratory distress syndrome (ARDS) and is linked to patient outcomes. One out of every two children in the pediatric intensive care unit (PICU) will develop malnutrition or have worsening of baseline malnutrition and present with specific micronutrient deficiencies. Early and adequate enteral nutrition (EN) is associated with improved 60-day survival after pediatric critical illness, and, yet, despite early EN guidelines, critically ill children receive on average only 55% of goal calories by PICU day 10. Inadequate delivery of EN is due to perceived feeding intolerance, reluctance to enterally feed children with hemodynamic instability, and fluid restriction. Underlying each of these factors is large practice variation between providers and across institutions for initiation, advancement, and maintenance of EN. Strategies to improve early initiation and advancement and to maintain delivery of EN are needed to improve morbidity and mortality from pediatric ARDS. Both, over and underfeeding, prolong duration of mechanical ventilation in children and worsen other organ function such that precise calorie goals are needed. The gut is thought to act as a "motor" of organ dysfunction, and emerging data regarding the role of intestinal barrier functions and the intestinal microbiome on organ dysfunction and outcomes of critical illness present exciting opportunities to improve patient outcomes. Nutrition should be considered a primary rather than supportive therapy for pediatric ARDS. Precise nutritional therapies, which are titrated and targeted to preservation of intestinal barrier function, prevention of intestinal dysbiosis, preservation of lean body mass, and blunting of the systemic inflammatory response, offer great potential for improving outcomes of pediatric ARDS. In this review, we examine the current evidence regarding dose, route, and timing of nutrition, current recommendations for provision of nutrition to children with ARDS, and the current literature for immune-modulating diets for pediatric ARDS. We will examine emerging data regarding the role of the intestinal microbiome in modulating the response to critical illness.

Project description:OBJECTIVES:Investigations of acute respiratory distress syndrome in adults suggest hypoxemia is an uncommon cause of death. However, the epidemiology of death in pediatric acute respiratory distress syndrome is not well characterized. We aimed to describe the cause, mode, and timing of death in pediatric acute respiratory distress syndrome nonsurvivors. We hypothesized that most deaths would be due to nonpulmonary factors, rather than hypoxemia. DESIGN:Retrospective, decedent-only analysis. SETTING:Two large, academic PICUs. PATIENTS:Nonsurvivors with pediatric acute respiratory distress syndrome. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:Of 798 subjects with pediatric acute respiratory distress syndrome, there were 153 nonsurvivors (19% mortality). Median time to death was 6 days (interquartile range, 3-13 d) after pediatric acute respiratory distress syndrome onset. Patients dying less than 7 days after pediatric acute respiratory distress syndrome onset had greater illness severity and worse oxygenation. Patients dying less than 7 days were more likely to die of a neurologic cause, including brain death. Patients dying greater than or equal to 7 days after pediatric acute respiratory distress syndrome onset were more commonly immunocompromised. Multisystem organ failure predominated in deaths greater than or equal to 7 days. Withdrawal of therapy was the most common mode of death at all timepoints, accounting for 66% of all deaths. Organ dysfunction was common at time of death, irrespective of cause of death. Refractory hypoxemia accounted for only a minority of pediatric acute respiratory distress syndrome deaths (20%). CONCLUSIONS:In pediatric acute respiratory distress syndrome, early deaths were due primarily to neurologic failure, whereas later deaths were more commonly due to multisystem organ failure. Deaths from neurologic causes accounted for a substantial portion of nonsurvivors. Refractory hypoxemia accounted for only a minority of deaths. Our study highlights limitations associated with using death as an endpoint in therapeutic pediatric acute respiratory distress syndrome trials.

Project description:OBJECTIVES:In pediatric acute respiratory distress syndrome, lung injury is mediated by immune activation and severe inflammation. Therefore, we hypothesized that patients with elevated pro- and anti-inflammatory cytokines would have higher mortality rates and that these biomarkers could improve risk stratification of poor outcomes. DESIGN:Multicenter prospective observational study. SETTING:We enrolled patients from five academic PICUs between 2008 and 2015. PATIENTS:Patients were 1 month to 18 years old, used noninvasive or invasive ventilation, and met the American European Consensus Conference definition of acute respiratory distress syndrome. INTERVENTIONS:Eight proinflammatory and anti-inflammatory cytokines were measured on acute respiratory distress syndrome day 1 and correlated with mortality, ICU morbidity as measured by survivor Pediatric Logistic Organ Dysfunction score, and biomarkers of endothelial injury, including angiopoietin-2, von Willebrand Factor, and soluble thrombomodulin. MEASUREMENTS AND MAIN RESULTS:We measured biomarker levels in 194 patients, including 38 acute respiratory distress syndrome nonsurvivors. Interleukin-6, interleukin-8, interleukin-10, interleukin-18, and tumor necrosis factor-R2 were each strongly associated with all-cause mortality, multiple markers of ICU morbidity, and endothelial injury. A multiple logistic regression model incorporating oxygenation index, interleukin-8, and tumor necrosis factor-R2 was superior to a model of oxygenation index alone in predicting the composite outcome of mortality or severe morbidity (area under the receiver operating characteristic, 0.77 [0.70-0.83] vs 0.70 [0.62-0.77]; p = 0.042). CONCLUSIONS:In pediatric acute respiratory distress syndrome, pro- and anti-inflammatory cytokines are strongly associated with mortality, ICU morbidity, and biochemical evidence of endothelial injury. These cytokines significantly improve the ability of the oxygenation index to discriminate risk of mortality or severe morbidity and may allow for identification and enrollment of high-risk subgroups for future studies.

Dataset Information

A prospective investigation of interleukin-8 levels in pediatric acute respiratory failure and acute respiratory distress syndrome.

Publications

A prospective investigation of interleukin-8 levels in pediatric acute respiratory failure and acute respiratory distress syndrome.

Similar Datasets

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