An exploratory assessment of serum biomarkers of post-cardiac arrest syndrome in children

Abstract

Aim: We hypothesized that serum biomarkers of inflammation including chemokine, cytokine, pituitary hormones, and growth factors following cardiac arrest in children would independently associate with 6-month neurologic outcome.

Methods: In this prospective observational single center study of children with in-hospital and out-of-hospital cardiac arrest surviving to intensive care unit admission, serum was obtained twice per 24 h period between 0 h and 96 h and once at approximately 196 h post-cardiac arrest. Inflammatory mediators, hormones, and growth factors were analyzed by Luminex Multiplex Bead Immunoassay. We recorded demographics, resuscitation characteristics, and Pediatric Cerebral Performance Category (PCPC) at 6 months. We analyzed the association and area under the curve (AUC) of biomarker levels with favorable (PCPC 1-3) or unfavorable (PCPC 4-6, or >1 increase from baseline) outcome.

Results: Forty-two children (50% female; median age of 2.5 [IQR: 0.4-10.2]) were enrolled and 18 (42%) died prior to 6-month follow up. Receiver operator curves for initial levels of ciliary neurotrophic factor (CNTF, AUC 0.84, 95% CI 0.73-0.96, p < 0.001) and interleukin (IL-17, AUC 0.84, 95% CI 0.73-0.97, p < 0.001) best classified favorable versus unfavorable 6-month outcome. In multivariable analysis, initial levels of CNTF and IL-17 remained associated with 6-month PCPC. Peak levels of interferon-γ-inducible protein 10 (IP-10), CNTF, and hepatocyte growth factor (HGF) were also independently associated with outcome.

Conclusion: Increased serum concentrations of CNTF and IL-17 associated with unfavorable 6-month neurologic outcome of children surviving cardiac arrest. Further investigation of the prognostic utility and roles of CNTF and IL-17 in the pathophysiology of post-cardiac arrest syndrome are warranted. This project is registered with clinicaltrials.gov (NCT00797680) as "Duration of Hypothermia for Neuroprotection after Pediatric Cardiac Arrest: A Randomized, Controlled Trial".

Keywords: Biomarkers; Child; Heart arrest; Hypoxia-ischaemia, brain; Outcome assessment (health care); Resuscitation.

Figure 1.

Log fold change of mean fluorescence intensity for measured cytokines, growth factors and hormone levels following pediatric cardiac over time in children with favorable (6-month Pediatric Cerebral Performance Category (PCPC) score of 1-3) and unfavorable outcome (PCPC score of 4-6 or change > 1). Initial and peak levels of biomarkers were compared between groups using Wilcoxon rank sum testing. Numbers of subjects included at each data point are provided in parentheses above point values in the IL-6 panel and do not differ across series. Initial levels differed between groups for interleukin (IL)-1β, IL-10, interferon (IFN)-α, IFN-γ, IL-15, IL-17, IL-8, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein alpha (MIP-1α), macrophage inflammatory protein beta (MIP-1β), eotaxin, regulated on activation, normal T cell expressed and secreted (RANTES), interferon gamma-induced protein 10 (IP-10), monokine induced by gamma interferon (MIG), ciliary neurotrophic factor (CNTF), and hepatocyte growth factor (HGF). Peak levels differed between groups for IL-1β, IL-6, IL-10, IFN-α, IFN-γ, granulocyte colony-stimulating factor (G-CSF), IL-15, IL-17, IL-1Ra, IL-8, MCP-1, eotaxin, RANTES, IP-10, MIG, CNTF, vascular endothelial growth factor (VEGF), and HGF.

Figure 2.

Results of mixed effects models testing to detect differences in biomarkers analyzed over the study period between patients with favorable versus unfavorable outcome. Interleukin (IL) -6, IL-1ra, IL-8, monocyte chemoattractant protein-1 (MCP-1), ciliary neurotrophic factor (CNTF), and vascular endothelial growth factor (VEGF) were significantly different between groups over the study period at p <0.05 following multiple test correction. Numbers of individuals sampled at each time point are displayed on the panel for IL-6. Individual pairwise comparisons between treatment group were made at each time point and statistically significant differences are indicated.

Figure 3.

Initial plasma levels of ciliary neurotrophic factor (CNTF), and interleukin (IL) -17 and peak plasma levels of CNTF, hepatocyte growth factor (HGF) and interferon gamma-induced protein 10 (IP-10) predict 6-month outcome in pediatric survivors of cardiac arrest. The area under the curve (AUC), standard error of the mean (SEM), 95% confidence interval (95% CI) and p-value are provided.