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

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.

Hypocoagulable Tendency on Thromboelastometry Associated With Severity and Anticoagulation Timing in Pediatric Septic Shock: A Prospective Observational Study

“…Hypercoagulability was observed in the early stage of sepsis, consistent with the aforementioned hypothesis of "immunothrombosis" defense (1,3,15). The development of hypocoagulability is commonly associated with the increasing severity of each stage (severe sepsis and septic shock) (12,15,16,27). Previous studies observed hemostatic response by a rapid increase in clot mass development (with higher α and MCF), possibly indicating a hypercoagulable phase and potential thromboembolic risk in the early stage of sepsis followed by the progression of hypocoagulable trends (with prolonged CT and CFT) in the later phase (6,28).…”

“…Previous studies in adults reported the detection of hypercoagulability on viscoelastic assay as ranging from 30 to 100% (17). Hypercoagulability was observed in the early stage of sepsis, consistent with the aforementioned hypothesis of "immunothrombosis" defense (1,3,15). The development of hypocoagulability is commonly associated with the increasing severity of each stage (severe sepsis and septic shock) (12,15,16,27).…”

“…Additionally, these parameters are not reflective of the in vivo hemostatic process and do not provide qualitative or functional data (1,14). Moreover, their inability to detect hypercoagulable status and fibrinolytic activity has been revealed (15,16). Hence, methodological improvements in thromboelastography (TEG) or rotational thromboelastometry (ROTEM) have been widely utilized as point-of-care tests for optimal hemostatic resuscitation in patients with sepsis.…”

“…Hypocoagulable profile in viscoelastic parameters is associated with poor outcomes (11); therefore, clinicians should monitor the patients more strictly and adopt adequate diagnostic and therapeutic strategies earlier. Furthermore, the efficacy of the viscoelastic test for the guidance of blood transfusion practice has been reported (15,16). Prior studies using global clotting assay proved its ability to evaluate coagulation and prognosis.…”

“…Prior studies using global clotting assay proved its ability to evaluate coagulation and prognosis. However, these data were mainly obtained in adults and cases of non-septic shock, and the broader use of ROTEM remained controversial (8,15); therefore, additional studies are required. Our study aimed to evaluate hemostatic disturbance using the ROTEM assay and identify the association between these parameters and the severity of septic shock in pediatric patients.…”