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ORIGINAL ARTICLE
Year : 2021  |  Volume : 3  |  Issue : 1  |  Page : 5

TEG Parameters Maximum Amplitude, Reaction Time Predicts Sepsis-Induced Coagulopathy and Mortality: A Prospective, Observational Study


Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province, China

Date of Submission02-Feb-2021
Date of Acceptance08-Jun-2021
Date of Web Publication28-Sep-2021

Correspondence Address:
Xiaojuan Zhang
Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang 110001, Liaoning Province
China
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DOI: 10.4103/jtccm.jtccm_8_21

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  Abstract 


Introduction: The diagnostic and prognostic value of thromboelastogram (TEG) in sepsis has not been determined. This study aimed to assess whether TEG is an early predictor of coagulopathy and is associated with mortality in patients with sepsis. Methods: In total, 518 patients with sepsis on the intensive care unit (ICU) admission were prospectively evaluated. We measured TEG and conventional coagulation tests on preadmission to ICU and observed for the development of 1 and 3 days and 1, 3, and 7 days, respectively. Multivariable logistic regression was utilized to determine the odds of ICU/hospital mortality. The parameter of TEG (maximum amplitude, reaction time; MA/R ratio) was calculated to evaluate sepsis-induced coagulopathy. The patients were divided into three groups : MA/R0 group (MA/R = 5–14 mm/min); MA/R1 group (MA/R <5 mm/min); and MA/R2 group (MA/R >14 mm/min). Results: Four hundred and ten patients were included. At enrolment, 10.73%, 65.85%, and 23.41% of the patients had lower, normal, and higher MA/R state, respectively. Compared to MA/R0 group, patients with lower and higher MA/R both had significantly increase risk of hospital mortality (hazards ratio [HR] 2.83 [95% confidence interval [CI] 1.577–5.079], P < 0.01); (HR 1.982 [95% CI 1.073–3.66], P = 0.029), respectively (adjusted with Acute Physiology and Chronic Health Evaluation [APACHEII] score) and ICU mortality (HR 2.512 [95% CI 1.301–4.852], P = 0.006); (HR1.644 [95% CI 1.024–2.639], P = 0.002) (adjusted with APACHEII score). Patients with higher MA/R had significantly increase risk of hospital mortality APACHE II score (HR 1.635 [95% CI 1.016–2.632], P = 0.043). Conclusions: In our cohort of patients with severe sepsis, coagulopathy defined by MA/R ratio was associated with increased risk of ICU/hospital mortality.

Keywords: Disseminated intravascular coagulation, maximum amplitude, reaction time, sepsis-induced coagulopathy, sepsis, thromboelastogram


How to cite this article:
Li X, Wang L, Liang Y, Li L, Li X, Zhang Z, Zhang X. TEG Parameters Maximum Amplitude, Reaction Time Predicts Sepsis-Induced Coagulopathy and Mortality: A Prospective, Observational Study. J Transl Crit Care Med 2021;3:5

How to cite this URL:
Li X, Wang L, Liang Y, Li L, Li X, Zhang Z, Zhang X. TEG Parameters Maximum Amplitude, Reaction Time Predicts Sepsis-Induced Coagulopathy and Mortality: A Prospective, Observational Study. J Transl Crit Care Med [serial online] 2021 [cited 2021 Nov 30];3:5. Available from: http://www.tccmjournal.com/text.asp?2021/3/1/5/326915




  Introduction Top


Sepsis-related coagulation disorders can lead to organ dysfunction in sepsis and is independent factors influencing the mortality of sepsis.[1] Sepsis-related coagulation can progress to disseminated intravascular coagulation (DIC). At present, the methods for assessing coagulopathy are mainly divided into three categories: conventional coagulation indicators, biological markers, and viscoelasticity tests. Since 2001, the diagnosis of DIC has been based on validated scores for DIC developed by the International Society on Thrombosis and Hemostasis (ISTH).[2] The most commonly used scoring standard in the world is the ISTH score, but it does not distinguish the cause and uniformly applies different ranges of conventional coagulation indicators to calculate the score. With the update of diagnostic criteria and definitions of sepsis,[3] Japanese scholars proposed the definition and corresponding diagnostic criteria for sepsis-induced coagulopathy (SIC) in 2017 and introduced the sequential organ failure assessment (SOFA) score as a diagnostic indicator.[4] In 2019, Japanese scholars proposed a two-step method for diagnosing SIC with the aim of early detection and identification of sepsis-associated coagulopathy.[5] The function of the main component cannot be detected, and the complete coagulation profile cannot be fully reflected.[6] Coagulation dysfunction in sepsis is mainly caused by the tissue factor activation of exogenous coagulation pathways. Studies have shown that prothrombin time is prolonged, and international normalized ratio is prolonged in sepsis.[6] Even so, the incidence of bleeding in sepsis is not high,[7] indicating that the use of classical coagulation pathways in sepsis cannot explain this phenomenon. In other words, the criteria are not suitable for assessing coagulopathy in sepsis. The cell-based coagulation model proposed more than a decade ago may better explain the cross-linking of inflammation and coagulation in sepsis.[8] Thromboelastogram (TEG) detects whole blood specimens, which can reflect the whole process and dynamic process of blood coagulation. It is widely used in guiding traumatic blood transfusion, liver transplantation, and cardiac surgery. A large number of studies have shown that TEG-guided blood transfusion can reduce the use of blood products and avoid side damage caused by massive blood transfusions.[9],[10],[11] Compared to conventional coagulation indicators, TEG is more able to identify the dynamic process in sepsis. Previous studies have suggested that TEG in hypoxemia is hypocoagulable, hypercoagulable, or normal, but different studies have different definitions of hypocoagulability and hypercoagulability.[12],[13],[14] Therefore, for coagulopathy in sepsis, it is not appropriate to use a single indicator to define hypocoagulability and hypercoagulability. The MA-R ratio provides a snapshot of early clot function, focusing specifically on thrombin burst and clot strength, by incorporating values from the standard TEG and transforming them.[15]

Our study focused on describing changes in TEG parameters in the early stages of sepsis. We observed changes in conventional coagulation parameters and assessed the effect of maximum amplitude, reaction time (MA/R) on the changes of patient mortality. The aim is to expand the evaluation of coagulation dysfunction in sepsis.


  Methods Top


Study population

Ethical approval for our study (# AF-0G-3-1 003) was provided by the local ethics committee of the First Hospital of China Medical University. All participants signed an informed consent declaration.

This study was performed as a prospective observational study. Patients with sepsis were admitted to intensive care unit (ICU) of the Fist Hospital of China Medical University from August 1, 2017 to June 31, 2019. The study was strictly observational, and all interventions and laboratory tests were part of our routine practice.

Data collection

Patients were enrolled if they fulfilled the criteria for sepsis and age >18 years. Sepsis and septic shock were diagnosed according to the criteria of the 2016 International Sepsis Definitions Conference.[16] The exclusion criteria included: age of >85 years, pregnancy and/or breastfeeding, a history of massive bleeding in the last week, presence of hematologic tumor, organ transplant, acute thrombosis disease, death in 24 h in admission to ICU, and giving up further treatment in ICU.

Data collection for all patients included demographic variables and clinical data. Demographic data, including age, sex, the acute physiology and chronic health evaluation (APACHE) II score, the SOFA score, ISTH and Japanese Association for Acute Medicine (JAAM) score were recorded. APACHE II and SOFA scores were evaluated at the time of inclusion and continuous monitoring within 7 days. Any increase in score within 7 days was defined as an increase in APACHE II and SOFA score. Clinical data on admission (initial 24 h) such as site of infection, whether continuous renal replacement therapy (CRRT) or shock were collected. Conventional coagulation assays preadmission to ICU (preICU), admission and day 3, day 7 or discharge were detected. Continuously monitor the change of APACHE and SOFA score. The increase of score was defined as the increase of score at any time point within 7 days. TEG was evaluated on admission and day 3. The outcome measures were all-cause in ICU and hospital mortality.

TEG

In this study, TEG 5000 thromboelastogram analyzer (Hemoscope Corporation, Chicago, Illinois, USA) was used. The main measurement indicators include: R: coagulation reaction time; K: coagulation formation time; Angle: coagulation angle; MA: maximum amplitude; G: coagulation mechanical strength, i.e. maximum shear stress intensity; LY30: coagulation reduction rate within 30 min after the determination of MA value (reference range reported by Haemonetics Corp). TEG testing is strictly in accordance with the instructions of the instrument and reagent. TEG analyses were performed by trained personnel in accordance with a standardised procedure and the manufacturer's recommendations using a TEG 5000 Hemostasis Analyzer System (Hemoscope Corporation, Illinois, USA). Patients who received anticoagulants after admission to ICU were all tested for TEG with heparanase comparison test.

The MA-R ratio was calculated using the following simple formula: MA/R = MA-R ratio.

The MA-R ratio was calculated for all patients in the study, and patients were divided into groups based on the ratio. The ratio of MA/R0 group was between 5 and 14, MA/R1 group was <5 and MA/R2 group was more than 14.

Data analysis

The results are given as median, 25th and 75th quartile and minimum/maximum value unless stated otherwise.

Statistical differences between the three groups were analyzed using Kruskal–Wallis, the Wilcoxon rank-sum test, and the Chi-squared or Fisher's exact test as appropriate. Differences between ICU days among the three groups were compared to the one-way analysis of variance, followed by the Tukey–Kramer post hoc test. The predictive value of admission MA/R (crude: linear scale; bivariate: MA/R0, MA/R1, MA/R2 yes vs. no) for 28-day mortality was investigated by univariate and multivariate Cox-proportional hazards models, the latter after adjusting for APACHII scores, data presented with hazards ratio (HR) (95% confidence interval [CI]) and P values. All P values reported are two-tailed, and P < 0.05 was considered statistically significant. Data were analyzed using the Statistical Package for the Social Sciences software version 22 (SPSS, Chicago, Illinois, USA). Prism 6.0 statistical software (Graph Pad Software, Inc.) was used for the graphical layout.


  Results Top


Patients and admission data

Patient flow diagrams are shown in [Supplementary Figure 1]. Five hundred and forty-five patients with sepsis were admitted. A total of 144 patients fulfilled the exclusion criteria. Based on MA/R ratio, 270 patients were identified as MA/R0 group, 44 were classified as MA/R1, and 96 were classified as MA/R2 group.



The baseline and clinical characteristics and outcomes of the three groups are shown in [Table 1]. Compared to MA/R0 group, patients in MA/R1 group were with higher APACHE II and SOFA scores on ICU admission. Meanwhile, ISTH and JAAM scores were higher. The rates of septic shock and CRRT treatment in MA/R1 group were higher (79.5% vs. 56.3%, P = 0.004 ; 36.36% vs. 10.74%, P = 0.048, respectively). There were statistical differences in infection sites among the three groups, and the proportion of abdominal infection was more than half.
Table 1: Baseline and clinical characteristics

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Changes in TEG and conventional coagulation tests variables during intensive care unit stay

As shown in [Supplementary Table 1], compared to the 1st day, there was no significant difference in TEG parameters of MA/R0 group on the 3rd day. Compared to day 1, there were significant differences in R time and α angle between MA/R1 and MA/R2 groups on day 3 (14.85 vs. 10.75, P = 0.004 and 4.15 vs. 5.5, P = 0.00; 45.65 vs. 53, P = 0.013 and 74.1 vs. 71, P = 0.02, respectively).



The changes of conventional coagulation tests were shown in [Supplementary Figure 2]. Compared to preICU, PT and activated partial thromboplastin time were prolonged on day 1, and gradually shortened on day 7. Platelet showed a decreasing trend within 3 days, and the difference was statistically significant. Fib levels in the three groups did not change significantly. The D2 and FDP values of the three groups were significantly higher than those of the normal level during the 7 days. Compared to MA/R0 group, D2 and FDP levels of MA/R1 group increased significantly within 3 days.



During the study period, the dynamic changes of platelet (PLT) were as follows [Figure 1]. PLT decreased in different degrees in MA/R1 and MA/R2 group within 3 days and increased at day 7. Compared to day 1, MA/R increased in MA/R1 group and decreased in MA/R2 group, with statistical difference at day 3 [Figure 2].
Figure 1: PLT count decrease during the day 1–7

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Figure 2: Maximum amplitude, reaction time ratio profiles from day 1 to day 3

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TEG and mortality

Multivariate Cox regression was used to determine the HR of hospital and ICU mortality based on the MA/R subgroup. MA-R0 was used as the referent. Multivariate Cox regression analysis including the APACHE II score revealed that MA/R1 and MA/R2 (binary variable, yes or no) were the independent predictive marker for hospital and ICU mortality in patients with sepsis [Table 2]. Compared to MA-R0, lower and higher MA/R ratios were both significantly promotion to death. (MA-R1: HR, 2.83; 95% CI, 1.577–5.079; MA-R2: HR, 1.982; 95% CI, 1.073–3.66).
Table 2: Adjusted hazards ratios and 95% confidence interval of different thromboelastogram parameters for hospital and intensive care unit mortality using cox regression analysis

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TEG and acute physiology and chronic health evaluation II and sequential organ failure assessment score increase

We also performed logistic regression analyses adjusted for age [Table 3]. Compared to MA-R0, lower and higher MA/R ratios were the both independent factors of APACHEII and SOFA score increase during the research period (MA-R1: odds ratios [OR], 1.081; 95% CI, 0.571–2.047; MA-R2: OR,1.635; 95% CI, 1.016–2.632).
Table 3: Adjusted odds ratios and 95% confidence interval of different thromboelastogram parameters for hospital and intensive care unit mortality using logistic regression analysis

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  Discussion Top


The pathophysiological process of SIC is closely related to inflammatory response and activation of immune cells. According to the conventional coagulation text, a variety of DIC scores are derived, such as ISTH, JAAM,[17] and the SIC diagnostic standard newly developed according to the standard of sepsis 3.0, applying SOFA scoring and the platelet count to assess the coagulation dysfunction. All these methods use amount as an indicator that reflects the numeric results of blood components. They cannot be used for function assessment. In the early stage of sepsis, the hypercoagulable state after activation of the coagulation system is a protective mechanism that acts to inhibit bacterial spread and limit inflammation.[18] Hypercoagulable state is also a factor that causes microcirculatory disorders and organ dysfunction.

The coagulation mechanism of the cell model was proposed in the 1990s. Coagulation mechanism of the cell model is centered on platelet activation, in which the process of coagulation initiation and amplification occurs on the surface of activated platelets.[19] The coagulopathy of sepsis is theoretically more consistent with the coagulation mechanism of the cell model. Therefore, the function of platelets is especially important. TEG can reflect the coagulation process of whole blood and can depict the quantity and function of various important components involved in the coagulation process. Previous studies have shown that TEG indicators do not change significantly in sepsis, and the intervals of change are within the normal range.[20] Different studies have inconsistent descriptions and definitions of coagulopathy, which may be one of the factors limiting the use of TEG in sepsis.

This prospective, observational study was the first to use the ratio of MA/R in TEG to describe sepsis coagulopathy. The value of MA/R represents the ability of blood to coagulate, including the amount and function of the various components involved in coagulation. The factors that cause coagulopathy during sepsis include the effects of the inflammatory response itself on blood clotting, the dilution of blood components by fluid resuscitation, and the effect of therapeutic drugs (such as anticoagulants) on coagulation parameters. The R time was not described and compared in the 6s study due to the application of anticoagulant drugs.[19] In this study, the MA/R ratio was used to include the various components involved in the coagulation process, which can more fully describe the coagulation status in sepsis. Within 3 days after entering the ICU, with the PLT decreasing significantly, the Fib amount not changing significantly and the PT time prolonged. The MA/R value of the MA/R1 group increased, indicating that the function of PLT and Fib was enhanced, and an increase in the ability to form thrombus. The MA/R values of the MA/R2 group were slightly shorter than the 1st day, but the values were at a higher level. On the 1st day, both groups received CRRT (MA/R1: 36.36% vs. MA/R2: 7.87%), and the proportion of heparin anticoagulation was as high as 70%. The absolute value of MA/R changed more than 50% in the two groups. Heparin anticoagulation was applied. For this reason, the MA/R values of the MA/R2 group decreased on the 3rd day, indicating that the R value of this group prolonged. The proportion of shock in the MA/R1 group was as high as 79.5%. While receiving fluid resuscitation and anticoagulant therapy, the MA/R values of the MA/R1 group were still increasing.

However, coagulopathy caused by sepsis often has not many symptoms of bleeding, which is very different from coagulation dysfunction related to liver disease, obstetrics, and blood diseases. The application of TEG detected that the MA/R value increased during the consumption of coagulation components, possibly reflecting an increase in the ability to form microthrombus in the microcirculation and an increase in the hardness of the thrombus. D2 and FDP were the highest in the MA/R1 group, indicating that the fibrinolysis process was initiated during thrombus formation. The dynamic process that fully reflects thrombosis and thrombolysis in the early stages of sepsis. This is also one of the pathophysiological mechanisms of organ function damage, and it is also the reason why DIC needs to apply anticoagulant drugs.[20]

Our results found that MA/R was used to assess coagulation, and low MA/R and high MA/R were the factors influencing ICU and hospital mortality and were associated with increased disease severity within 7 days of observation. Under physiological conditions, the coagulation process remains stable. Once the coagulation system activated, both hypercoagulability and hypocoagulation represent a steady-state imbalance, triggering subsequent pathophysiological changes. It should be noted that there are 55 patients in the sample who have abandoned the ICU for further hospitalization, accounting for 10.09% of the total. Compared to the SOFA score, the APACHE II score included more items. Even so, MA/R2 is still an independent factor affecting the APACHE II score in multivariate analysis, indicating that the increase in MA/R value is important during ICU hospitalization. The factors may become targets for future interventions.

This study has several limitations. First, this is a single-center study and there may be selective bias. Second, we observed three time points within 7 days of ICU hospitalization. TEG only detected two time points. Without more intensive continuous observation, some information on clinical coagulation data may be missing. The application of MA/R values to reflect the status of coagulation function has not been widely used clinically, and its research significance needs more data to prove. Finally, in the treatment of sepsis, there are many factors including fluid resuscitation and specific therapeutic drugs affecting the patient's disease severity and short-term mortality. Although we have corrected the age and APACHE II score, there may still be other factors that need correction.


  Conclusions Top


In our cohort of patients with severe sepsis, coagulopathy defined by lower and higher MA/R ratio was associated with increased risk of ICU/hospital mortality and the increase of APACHE II score during 7 days in ICU stay.

Declarations

Ethical Approval and Consent to participate: Ethical approval for our study (# AF-0G-3-1 003) was provided by the local ethics committee of the First Hospital of China Medical University. All participants signed an informed consent declaration.

Availability of supporting data

The data sets supporting the results of this article are included within the article.

Financial support and sponsorship

This study was financially supported by Health and Birth Control Committee of Liaoning Province (Grant No. 2020.JH2/10300010) China.

Conflicts of interest

There are no conflicts of interest.



 
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