Elsevier

Resuscitation

Volume 167, October 2021, Pages 307-316
Resuscitation

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

https://doi.org/10.1016/j.resuscitation.2021.07.007Get rights and content

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”.

Introduction

Children resuscitated from cardiac arrest have significant neurologic morbidity1 and mortality.2., 3. Post-cardiac arrest syndrome is characterized by brain injury, distributive or cardiogenic shock with resultant hemodynamic instability, systemic ischaemia–reperfusion response, and unresolved underlying disease.4 Previous work describing post-cardiac arrest syndrome in adults showed markedly elevated blood concentrations of both pro-inflammatory cytokines and anti-inflammatory cytokines that associate with outcome.5., 6. Although required for repair, systemic inflammation may effect organ dysfunction and secondary neurologic injury contributing to morbidity and mortality.4., 7. However, the mechanistic underpinnings are not well understood.8 Critically, there are no proven treatments for pediatric cardiac arrest.2., 3., 8.

In addition, growth factors are required for tissue recovery, and may associate with outcome. However, the role of growth factors following arrest is poorly defined. Similarly endocrine dysfunction, an indicator of global stress, has been described in adults post-cardiac arrest, particularly in the adrenal gland.8 However in children, post-cardiac arrest changes in pituitary function have not been characterized. Insights into the growth factors and hormonal axes impacted post-arrest may better define cellular, tissue and organism level stresses and inform future interventional trials.

There remains a considerable knowledge gap in understanding of how inflammation, the endocrine system and growth factors function following pediatric cardiac arrest. Herein, we sought to explore the association of these biomarkers with outcome with the aim of identifying candidate predictors and markers of therapeutic efficacy in children resuscitated from in-hospital and out-of-hospital cardiac arrest for future study (IHCA and OHCA, respectively). We tested the hypothesis that these biomarkers independently associate with unfavorable 6-month functional outcome with the aim to identify promising biomarkers for follow up study. In univariate analysis, we report that several inflammatory markers and growth factors assessed following return of spontaneous circulation (ROSC) associate with outcome. After controlling for factors known to impact cardiac arrest outcome, initial levels of ciliary neurotrophic factor (CNTF) and IL-17, and peak levels of CNTF, hepatocyte growth factor (HGF), and interferon-γ-induced protein 10 (IP-10) remained independently associated with 6-months outcome. Initial CNTF and IL-17 performed best in discriminating favorable versus unfavorable outcome.

Section snippets

Design and setting

This is a secondary analysis of 42 serially screened pediatric cardiac arrest patients admitted to the UPMC Children’s Hospital of Pittsburgh between November 2009 and December 2011.9 All studies were approved by the University of Pittsburgh Institutional Review Board (IRB reference numbers 19100202, 19020377), and informed consent was obtained from the subject’s parent or guardian.

Inclusion and exclusion criteria

Children between 1 week and 17 years old admitted to the intensive care unit (ICU) between 2009 and 2011 after

Clinical parameters

Forty-two subjects were evaluated (Table 1) with a median age of 2.5 years. Fifty percent of the cohort was female and had pre-existing comorbidities. Asphyxia was the reason for arrest in 80% of cases. Treatment with therapeutic hypothermia occured in 76% of study participants, with no association with outcome.

At 6-month follow-up, 28 subjects (67%) were assigned to the unfavorable outcome group including 18 (42%) subjects who died. Subjects with unfavorable outcome more commonly had an

Discussion

In this exploratory analysis in children after cardiac arrest, we identified multiple inflammatory mediators and growth factors associated with unfavorable 6-month outcome. Initial serum IL-17 and CNTF had the best performance to discriminate outcome and remained independently associated after adjustment for first documented rhythm, witnessed status, and CPR duration.

Throughout the 168 h study period, CNTF remained ~2–30-fold higher in the unfavorable outcome group at each timepoint, though

Study limitations

Our study has several limitations. The PCPC was primarily obtained by telephone interview with parents/guardians. In addition, PCPC is a gross measure of function, that may not fully characterize arrest outcomes, with results impacted by dichotomization in this analysis. PCPC also faces significant limitations in depicting outcome in infants, while children less than 2 years of age represented 44% of the cohort. Multiplex data was only able to be determined as fluorescence intensity which

Conclusions

This exploratory analysis shows that increased serum CNTF and IL-17 are associated with unfavorable 6-month neurologic outcome of children following cardiac arrest. Further investigation of CNTF and IL-17 in post-cardiac arrest syndrome pathophysiology is warranted.

Funding

We appreciate the generous support from the following sources: NICHD K12 HD047349 (E.L.F.; K.F.K), NINDS K23 NS065132 (E.L.F.), NINDS NS115173 (D.W.S.), the Laerdal Foundation (E.L.F.), and NINDS R01 NS096714 (E.L.F.). This publication was also made possible by Grant Number 5UL1 RR024153-04 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors

Conflict of interest

None.

CRediT authorship contribution statement

Kate F. Kernan: Data curation, Formal analysis, Writing - original draft, Writing - review & editing. Rachel P. Berger: Writing - review & editing, Supervision. Robert S.B. Clark: Conceptualization, Methodology, Supervision. R. Scott Watson: Writing - review & editing, Supervision. Derek C. Angus: Conceptualization, Methodology, Supervision. Ashok Panigrahy: Conceptualization, Methodology, Supervision. Clifton W. Callaway: Conceptualization, Methodology, Supervision. Michael J. Bell:

Acknowledgements

Special thanks to Michelle Dragotta, Christine Kyper, and Alan Abraham for assistance in data acquisition and Keri Feldman for specimen care and measurement. We are grateful to the staff, nurses, and physicians of the ICU for their efforts in subject recruitment and provision of excellent clinical care.

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