Objectives

To 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.

Design

Prospective cohort study.

Setting

Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622).

Subjects

Children 2 weeks to 17 years old treated with invasive mechanical ventilation for acute airways and/or parenchymal lung disease.

Measurements and main results

Three-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.

Conclusions

Plasma 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.

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.

Aims and objectives

Alveolar epithelial injury is a key determinant of acute respiratory failure (ARF) severity. Plasma surfactant protein D (SP-D), a biomarker of alveolar epithelial injury, is lower in obese adults with ARF compared to their lean peers. We aimed to determine if children with ARF have similar variance in plasma SP-D associated with their weight status on admission.

Methods

Plasma SP-D was measured on days 0, 1, or 2 in children (1-18 years) with ARF enrolled in the genetic variation and biomarkers in children with acute lung injury and RESTORE studies. Weight classification (underweight, normal, overweight, and obese) was based on body mass index or weight-for-height z-scores. Associations between weight group and SP-D on each day were tested.

Results

Inclusion criteria were met in 212 subjects, 24% were obese. There were no differences among weight groups in SP-D levels on days 0 and 1. However, on day 2, there was a statistically significant linear trend for lower SP-D levels as weight increased in both the univariate analysis (P = .02) and when adjusting for age, ethnicity, and diagnosis of pediatric acute respiratory distress syndrome (P = .05).

Conclusions

Obesity was associated with lower plasma SP-D levels on day 2 of ARF. This finding may be explained by altered ARF pathogenesis in obese individuals or a reduced incidence of ventilator-induced lung injury.

Background

Previous latent class analysis of adults with acute respiratory distress syndrome (ARDS) identified two phenotypes, distinguished by the degree of inflammation. We aimed to identify phenotypes in children with ARDS in whom developmental differences might be important, using a latent class analysis approach similar to that used in adults.

Methods

This study was a secondary analysis of data aggregated from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial and the Genetic Variation and Biomarkers in Children with Acute Lung Injury (BALI) ancillary study. We used latent class analysis, which included demographic, clinical, and plasma biomarker variables, to identify paediatric ARDS (PARDS) phenotypes within a cohort of children included in the RESTORE and BALI studies. The association of phenotypes with clinically relevant outcomes and the performance of paediatric data in adult ARDS classification algorithms were also assessed.

Findings

304 children with PARDS were included in this secondary analysis. Using latent class analysis, a two-class model was a better fit for the cohort than a one-class model (p<0·001). Latent class analysis identified two classes: class 1 (181 [60%] of 304 patients with PARDS) and class 2 (123 [40%] of 304 patients with PARDS), referred to as phenotype 1 and 2 hereafter. Phenotype 2 was characterised by higher concentrations of inflammatory biomarkers, a higher incidence of vasopressor use, and more frequent diagnosis of sepsis, consistent with the adult hyperinflammatory phenotype. All levels of severity of PARDS were observed across both phenotypes. Children with the hyperinflammatory phenotype (phenotype 2) had worse clinical outcomes than those with the hypoinflammatory phenotype (phenotype 1), with a longer duration of mechanical ventilation (median 10·0 days [IQR 6·3-21·0] for phenotype 2 vs 6·6 days [4·1-10·8] for phenotype 1, p<0·0001), and higher incidence of mortality (17 [13·8%] of 123 patients vs four [2·2%] of 181 patients, p=0·0001). When using adult phenotype classification algorithms in children, the soluble tumour necrosis factor receptor-1 (sTNFr1), vasopressor use, and interleukin (IL)-6 variables gave an area under the curve (AUC) of 0·956, and the sTNFr1, vasopressor use, and IL-8 variables gave an AUC of 0·954, compared with the gold standard of latent class analysis.

Interpretation

Latent class analysis identified two phenotypes in children with ARDS with characteristics similar to those in adults, including worse outcomes among patients with the hyperinflammatory phenotype. PARDS phenotypes should be considered in design and analysis of future clinical trials in children.

Funding

US National Institutes of Health.

OBJECTIVES: We sought to update our 2015 work in the Second Pediatric Acute Lung Injury Consensus Conference (PALICC-2) guidelines for the diagnosis and management of pediatric acute respiratory distress syndrome (PARDS), considering new evidence and topic areas that were not previously addressed. DESIGN: International consensus conference series involving 52 multidisciplinary international content experts in PARDS and four methodology experts from 15 countries, using consensus conference methodology, and implementation science. SETTING: Not applicable. PATIENTS: Patients with or at risk for PARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Eleven subgroups conducted systematic or scoping reviews addressing 11 topic areas: 1) definition, incidence, and epidemiology; 2) pathobiology, severity, and risk stratification; 3) ventilatory support; 4) pulmonary-specific ancillary treatment; 5) nonpulmonary treatment; 6) monitoring; 7) noninvasive respiratory support; 8) extracorporeal support; 9) morbidity and long-term outcomes; 10) clinical informatics and data science; and 11) resource-limited settings. The search included MEDLINE, EMBASE, and CINAHL Complete (EBSCOhost) and was updated in March 2022. Grading of Recommendations, Assessment, Development, and Evaluation methodology was used to summarize evidence and develop the recommendations, which were discussed and voted on by all PALICC-2 experts. There were 146 recommendations and statements, including: 34 recommendations for clinical practice; 112 consensus-based statements with 18 on PARDS definition, 55 on good practice, seven on policy, and 32 on research. All recommendations and statements had agreement greater than 80%. CONCLUSIONS: PALICC-2 recommendations and consensus-based statements should facilitate the implementation and adherence to the best clinical practice in patients with PARDS. These results will also inform the development of future programs of research that are crucially needed to provide stronger evidence to guide the pediatric critical care teams managing these patients.