R. P. Richter2, P. J. Hu1, R. M. Uhlich1, M. Shroyer3, J. D. Kerby1, J. F. Pittet4, R. T. Russell3, J. R. Richter1 1University Of Alabama at Birmingham,Acute Care Surgery,Birmingham, Alabama, USA 2University Of Alabama at Birmingham,Pediatric Critical Care Medicine,Birmingham, Alabama, USA 3University Of Alabama at Birmingham,Pediatric Surgery,Birmingham, Alabama, USA 4University Of Alabama at Birmingham,Critical Care Anesthesiology,Birmingham, Alabama, USA
Introduction: The mechanisms and effects of vascular endotheliopathy in pediatric trauma are poorly understood. Angiopoietins are known mediators of endothelial cell (EC) integrity and are dysregulated during inflammatory states. Angiopoietin-1 (Agpt-1) helps maintain endothelial cell homeostasis. Agpt-2 is released after direct or indirect EC injury and promotes EC destabilization, thereby disrupting vascular endothelial integrity. The balance of these cytokines, quantified as Agpt-2-to-Agpt-1 ratio (Agpt-2:Agpt-1), reflects overall endothelial health and stability. We have recently established that plasma levels of syndecan-1 (Syn-1), an essential proteoglycan in the endothelial glycocalyx and a biomarker of endotheliopathy, correlate with mortality in pediatric trauma patients. However, at present, the behavior of the angiopoietins and their association with Syn-1 are not known in pediatric trauma. The objective of the current study was to (1) measure plasma levels of Agpt-1 and Agpt-2 following pediatric trauma and (2) correlate Agpt levels with plasma levels of Syn-1. As Agpt-2 levels positively correlate with illness severity in adult trauma, we hypothesize that Agpt-2 and the Agpt-2:Agpt-1 ratio significantly increase in injured patients compared to controls and have a positive correlation with Syn-1.
Methods: We performed a prospective observational study comparing 45 pediatric trauma patients with 9 healthy pre-operative pediatric control patients at a level 1 pediatric trauma center from 2013 to 2016. Agpt-1 and Agpt-2 levels were measured in trauma patients upon hospital arrival and 24 hours after admission, from which Agpt-2:Agpt-1 ratios were derived. Syn-1 levels were measured at admission. The University of Alabama at Birmingham Institutional Review Board approved the study.
Results: Median age of trauma patients was 9 years (interquartile range, IQR, 6, 13), and the median injury severity score was 22 (IQR 16, 29). Compared to controls, Agpt-1 rose in trauma patients, though not significantly (p=0.335), and decreased to levels near control by 24 hours (p=0.112, Table). Agpt-2 rose significantly at admission (p=0.047) compared to controls and remained elevated after 24 hours (p=0.049), translating to a significantly elevated Agpt-2:Agpt-1 ratio at 24 hours (p=0.005). Syn-1 positively correlated with Agpt-2 levels at admission (r2=0.219, p=0.001) and 24 hours (r2=0.156, p=0.008) but not with Agpt-1 or the Agpt-2:Agpt-1 ratio.
Conclusion: Our findings reflect dysregulation of Agpt-1 and Agpt-2 after pediatric trauma. The correlation of Agpt-2 with Syn-1 suggests that Agpt-2 may be an important mediator of endotheliopathy after pediatric trauma and a potential therapeutic target.
