Clinical paperAn exploratory assessment of serum biomarkers of post-cardiac arrest syndrome in children
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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Biomarkers associated with mortality in pediatric patients with cardiac arrest and acute respiratory distress syndrome
2022, ResuscitationCitation Excerpt :In adults, elevated levels of IL-6, TNF-α and other cytokines characterize this sepsis-like state of inflammation.9–11 While brain-specific biomarkers have been evaluated following pediatric cardiac arrest to prognosticate outcomes,12–14 limited pediatric studies to date have focused on the association of biomarkers of systemic inflammation with clinical outcomes; to date elevated levels IL-17 have been associated with unfavorable 6-month neurologic outcome in cardiac arrest survivors.15 Given the reported associations between innate immune markers and poor outcomes in adult cardiac arrest,10,16,17 we theorized a similar association in pediatric cardiac arrest.