Thromboelastography Variables, Immune Markers, and Endothelial Factors Associated With Shock and NPMODS in Children With Severe Sepsis.

Arun Saini,Steven P Ignell,Philip C Spinella,John C Lin

doi:10.3389/fped.2019.00422

Abstract

Objective: Evaluate hemostatic dysfunction in pediatric severe sepsis by thromboelastography (TEG) and determine if TEG parameters are associated with new or progressive multiple organ dysfunction syndrome (NPMODS) or shock, defined as a lactate ≥2mmol/L. We explored the relationship between TEG variables, selective cytokines, and endothelial factors.Design: Prospective observational.Setting: Single-center, quaternary care pediatric intensive care unit.Patients: Children aged 6- months to 14- years with severe sepsis with expected PICU stay for >72 h.Interventions: None.Measurements and Main Results: Twenty-eight children were enrolled with median (IQR) age of 7.3 years (4.4–11.4), PELOD score (study day-1) of 11(1.25–13), and PICU length of stay of 10 days (5–28). TEG-defined hypercoagulable state occurred most commonly in 73% (94/129) of samples, followed by hypocoagulable state in 7.8% (10/129) and mixed coagulation state in 1.5% (2/129) of samples in the study cohort. In contrast, hypocoagulable state occurred most commonly in 66% (98/148) of samples based on standard coagulation parameters. In the seven children who developed shock with NPMODS compared to eight patients with shock without NPMODS and 12 patients with severe sepsis only, we found more profound coagulopathy [thrombocytopenia (p = 0.04), elevated INR (p = 0.038), low fibrinogen level (p = 0.049), and low TEG-G value (p = 0.01)] and higher peak of interleukin-6 (p = 0.0014) and IL-10 (p = 0.007). Peak lactate in the first 5 study days had moderate correlation with standard coagulation assays, TEG parameters, and selective cytokines. Peak lactate did not correlate with markers of endothelial activation. Lowest TEG -G value had moderate correlation with peak IL-10 (ρ −0.442, p =0.019), peak VCAM (ρ − 0.495, p = 0.007), and peak lactate (ρ −0.542, p = 0.004) in the first 5 study days. A combination of TEG-G value and IL-6 concentration best discriminated children with shock and NPMODS [AUC 0.979 (95%CI 0.929–1.00), p < 0.001].Conclusion: This exploratory analysis of hemostasis dysfunction on TEG in pediatric severe sepsis suggests that while hypercoagulability is more common, a hypocoagulable state is associated with shock and NPMODS. In addition, TEG abnormalities are also associated with immune and endothelial factors. A larger cohort study is needed to validate these findings.

Highlights

Pediatric severe sepsis is defined as sepsis with evidence of dysfunction in two or more organ systems with the presence of cardiovascular dysfunction defining septic shock [1]
In this study of children with severe sepsis or septic shock, we aimed to describe in detail the incidence of hemostatic dysfunction as defined using TEG variables
We explored the relationship between both TEG variables and TEG defined hemostatic dysfunction and [1] development of new or progressive multiple organ dysfunction syndrome (NPMODS), [2] development of shock, and [3] changes in markers of endothelial injury and cytokines involved in coagulation activation

Summary

Introduction

Pediatric severe sepsis is defined as sepsis with evidence of dysfunction in two or more organ systems with the presence of cardiovascular dysfunction defining septic shock [1]. Both severe sepsis and septic shock correlate with activation of immune, endothelial, and hemostatic systems [2,3,4]. Unlike in acute traumatic injury where tissue hypoperfusion and shock have been reported to contribute independently to hypocoagulability and increased risk of death in both adults and children [6,7,8,9], the causative mechanisms of how septic shock affects hemostatic dysfunction have not been as well-defined or demonstrated. A more thorough understanding of both the relationship between septic shock and hemostatic dysfunction and methods to measure this interaction may allow timely intervention and prevention of hemostatic dysfunction with subsequently improved outcomes

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Conclusion