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Multicenter Study
. 2023 Sep 1;24(9):727-737.
doi: 10.1097/PCC.0000000000003286. Epub 2023 May 17.

A Targeted Analysis of Serial Cytokine Measures and Nonpulmonary Organ System Failure in Children With Acute Respiratory Failure: Individual Measures and Trajectories Over Time

Silvia M Ardila  1 , Heidi M Weeks  2 , Mary K Dahmer  1 , Niko Kaciroti  3   4 , Michael Quasney  1 , Anil Sapru  5 , Martha A Q Curley  1   2   3   4   5   6   7   8 , Heidi R Flori  1 ; Biomarkers in Children with Acute Lung Injury (BALI) and Randomized Evaluation for Sedation Titration for Respiratory Failure (RESTORE) Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network
Collaborators, Affiliations
Multicenter Study

A Targeted Analysis of Serial Cytokine Measures and Nonpulmonary Organ System Failure in Children With Acute Respiratory Failure: Individual Measures and Trajectories Over Time

Silvia M Ardila et al. Pediatr Crit Care Med. .

Abstract

Objectives: There is a need for research exploring the temporal trends of nonpulmonary organ dysfunction (NPOD) and biomarkers in order to identify unique predictive or prognostic phenotypes. We examined the associations between the number and trajectories of NPODs and plasma biomarkers of early and late inflammatory cascade activation, specifically plasma interleukin-1 receptor antagonist (IL-1ra) and interleukin-8 (IL-8), respectively, in the setting of acute respiratory failure (ARF).

Design: Secondary analysis of the Randomized Evaluation for Sedation Titration for Respiratory Failure clinical trial and Biomarkers in Acute Lung Injury (BALI) ancillary study.

Setting: Multicenter.

Patients: Intubated pediatric patients with ARF.

Interventions: NPODs were evaluated against plasma IL-1ra and IL-8 levels on individual days (1 to 4 d after intubation) and longitudinally across days.

Measurements and main results: Within the BALI cohort, 432 patients had at least one value for IL-1ra or IL-8 within days 0 through 5. 36.6% had a primary diagnosis of pneumonia, 18.5% had a primary diagnosis of sepsis and 8.1% died. Multivariable logistic regression models showed that increasing levels of both plasma IL-1ra and IL-8 were statistically significantly associated with increasing numbers of NPODs (IL-1ra: days 1-3; IL-8: days 1-4), independent of sepsis diagnosis, severity of oxygenation defect, age, and race/ethnicity. Longitudinal trajectory analysis identified four distinct NPOD trajectories and seven distinct plasma IL-1ra and IL-8 trajectories. Multivariable ordinal logistic regression revealed that specific IL-1ra and IL-8 trajectory groups were associated with greater NPOD trajectory group ( p = 0.004 and p < 0.0001, respectively), independent of severity of oxygenation defect, age, sepsis diagnosis, and race/ethnicity.

Conclusions: Both the inflammatory biomarkers and number of NPODs exhibit distinct trajectories over time with strong associations with one another. These biomarkers and their trajectory patterns may be useful in evaluating the severity of multiple organ dysfunction syndrome in critically ill children and identifying those phenotypes with time-sensitive, treatable traits.

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Conflict of interest statement

Drs. Dahmer’s, Quasney’s, Curley’s, and Flori’s institutions received funding from the National Heart, Lung, and Blood Institute. Dr. Dahmer’s institution received funding from the National Institute of Child Health and Human Development. Drs. Dahmer, Quasney, Sapru, Curley, and Flori received support for article research from the National Institutes of Health. Dr. Flori disclosed that she is a Board member of Michigan Thoracic Society, Executive Committee Board member of Pediatric Acute Lung Injury and Sepsis Investigators, Taskforce member for Lancet, and a Taskforce member for Society of Critical Care Medicine. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.. Plasma biomarker levels are associated with increasing numbers of nonpulmonary organ dysfunctions on days 1 through 3.
A, Comparison of plasma IL-1ra levels in children with 0, 1, 2, and ≥3 NPODs on each day. Day 1 IL-1ra levels were significantly different between all NPOD groups, except for 0 vs 1 NPODs. Day 2 IL-1ra levels were significantly different between all NPOD groups except for 1 vs 2 NPODs and 2 vs 3 or more NPODs. Day 3 IL-1ra levels were all significantly different except for those between 0 vs 1 NPODs and 2 vs 3 or more NPODs. B, Comparison of plasma IL-8 levels in children with 0, 1, 2, and ≥3 NPODs on each day. Day 1 IL-8 levels were significantly different between all NPOD groups. Day 2 IL-8 levels between all groups were significantly different except for 1 vs. 2 NPODS. Day 3 IL-8 levels were significantly different except for 2 vs. ≥3 NPODs. Brackets indicate p <0.05 determined by post-hoc analysis using the Dunn’s test. Numbers in bars indicate the number of subjects per group on each day. Analysis included 432 individuals with at least 1 and up to 3 samples assayed for IL-1ra and/or IL-8 on days 0–5. IL-1ra, interleukin-1 receptor antagonist, NPOD, nonpulmonary organ dysfunction, IL-8, interleukin-8.
Figure 2:
Figure 2:. Nonpulmonary organ dysfunction trajectory groups.
Trajectory analysis was completed across days 0 through 5 and included 431 patients.
Figure 3
Figure 3. Cytokine trajectory groups.
A, IL-1ra biomarker trajectory groups across days 1–4 (n=372). Group 1, indicated by stars, was assigned as the reference group for multivariable, ordinal logistic regression. B, IL-8 biomarker trajectory groups across days 1–4 (n=378). Group 2, indicated by stars, was assigned as the reference group. Biomarker levels were measured in natural logged values of pg/mL.
See this image and copyright information in PMC

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