Abstract
BACKGRUND:
The coagulation status of burn patients is generally impaired and is a major factor of the deteriorating burn patients’ overall situation. In trauma and other patient groups, the differential diagnosis of coagulation impairment has been largely improved by the use of rotational thromboelastometry (ROTEM®). The aim of this prospective observational study was the differentiated observation of coagulopathy in severely burned patients using standard parameters and ROTEM® thrombelastometry during the relevant stages of burn disease.
PATIENTS AND METHODS:
Twelve patients that sustained at least 20% third degree burns of total body surface area (TBSA) were included in the study. Standard and ROTEM® coagulation analyses were performed on admission and then twice daily during the first 14 days following burn trauma.
RESULTS:
Although the initial assessment of DIC was similar for both standard labs and ROTEM® measurements, more patients were detected to be in a state of worsening coagulation status for a longer time in ROTEM® than in standard measurements. In addition, one patient was rated in to be in decompensated DIC for 3 days according to ROTEM® measurements, while no patient was rated to be in a decompensated DIC based on standard parameters.
CONCLUSION:
This study points towards a more complex picture and higher occurrence of DIC in burn patients when thrombelastometric measurements like ROTEM® are taken into account in addition to standard coagulation parameters.
Introduction
The treatment of severely burned patients is a challenging task, where both the extensive soft tissue damage and the pathophysiological and immunological responses to thermal injury, often times referred to as “burn disease”, have to be managed. The coagulation status of burn patients is generally impaired and is a major factor of the deteriorating burn patients’ overall situation [1]; as repetitive debridement of large surfaces and skin graft harvest result in major intra- and postoperative blood loss, components such as fresh frozen plasma (FFP), packed red blood cells (RBC), platelet concentrates and fibrinogen have to be carefully substituted according to the patient needs [2, 3]. Studies on other trauma patients demonstrated that targeted correction of trauma-induced coagulopathy with coagulation factor concentrates reduced transfusion requirements and improved survival [4, 5]. Unfortunately, no specific experiences or recommendations for targeted coagulopathy treatment have been reported to date for severely burned patients [4, 6–9], possibly due to extremely heterogenous data on hypo-/hypercoagulation, fibrinolysis, and even regular coagulation status [10–16].
Most studies of coagulopathy in burn trauma focus on single aspects of the coagulation cascade’s dynamic course, allowing no final conclusion of the real coagulation competency of the patient [10–16]. However, the differential diagnosis of coagulation impairment has been largely improved by the use of rotational thromboelastometry (ROTEM®). While single laboratory parameters only describe a specific part of the patient’s coagulation function, ROTEM® guarantees a rapid evaluation within minutes about the entire clinically relevant coagulation status [17].
The aim of this prospective observational study was the differentiated observation of coagulopathy in severely burned patients using standard parameters and ROTEM® thrombelastometry during the relevant stages of burn disease.
Materials and methods
The study was conducted according to the World Medical Association Declaration of Helsinki (June 1964) and subsequent amendments. The study protocol was approved by the Research Ethics Committee of the Bavarian Chamber of Physicians (Bayerische Landesärzekammer) (No. 10047).
Reporting standards
The study is reported according to the STARD statement, i.e. standards for the reporting of diagnostic accuracy studies [18].
Study population and recruitment
Inclusion criteria
Eligibility criteria were consecutive adult patients (≥18 years) treated at the burn intensive care unit (BICU) of the Clinic for Plastic, Reconstructive, Hand- and Burn Surgery, Academic Hospital Munich Bogenhausen, Technical University Munich, Germany from January 2nd, 2012 to December 15th, 2013 that sustained at least 20% third degree burns of total body surface area (TBSA).
Exclusion criteria
Patients receiving therapeutic anticoagulants before burn injury and patients with known coagulopathies were excluded. If initial laboratory tests were taken more than 6 hours after injury, patients were also excluded to account for the possible effect of fluid resuscitation on baseline laboratory tests.
Settings and test methods
ROTEM® coagulation analyses (ROTEM®delta, Tem International GmbH, Munich, Germany) were performed on admission and then twice daily during the first 14 days following burn trauma. Furthermore, prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), antithrombin III activity (ATIII), platelet count, fibrinogen, protein C and S activity, factor VII and XIII, prothrombin level and D-dimer were determined on admission and then once daily. The period of 14 days was chosen because it includes all the essential phases of “burn disease” and generally a minimum amount of surgery. In case of surgery, ROTEM® was additionally performed pre-, intra- (after wound debridement and removal of skin-graft) and postoperatively. All patients underwent one or more surgeries during their BICU course. However, only coagulation status analyses at the time of first surgery were used for this study.
The demographics, burn type and extent, vital signs, pathology results, associated injuries, fluid administration, surgical management, possible infections, Sequential Organ Failure Assessment (SOFA) score, Abbreviated Burn Severity Index (ABSI), administered coagulation modifying drugs, blood products (PRCS, FFP, PC) and outcome/mortality of all patients were documented.
Clinical management followed the guidelines of Adams and Vogt [19] and was standardized based on the recommendations for bleeding management. Study-related laboratory data were not available to the treating colleagues. Fluid administration was based on crystalloid infusion during the first 6 hours after trauma, followed by a mix of crystalloid, colloid and Albumin 20% infusion according to clinical and laboratory findings. No prophylactic antibiotics were used, except for additional second degree or higher inhalation injury. All patients received thromboembolic prophylaxis using unfractionated heparin in a dose of 10000 IE/ 24 h. In case of surgery, thromboembolic prophylaxis was paused 6 h before surgery and continued 4 h postoperatively.
Test reference methods
Laboratory test determining coagulation status
INR, PT, aPTT, ATIII, platelets, fibrinogen, protein C activity, protein S activity, factor XIII, factor VII, PT level and D-dimer were performed by the local laboratory (Medizet) of the Academic Hospital Munich Bogenhausen, Technical University Munich for the evaluation of the patients’ coagulation status.
Rotational thrombelastography
ROTEM® investigations consisted of four commercially available tests (INTEM®, EXTEM®, FIBTEM®, HEPTEM®). The technical details of ROTEM® have been described in detail by Luddington [20]. Intrinsically (INTEM®) and extrinsically activated (EXTEM®) tests (activation with tissue factor or phospholipid-ellagic acid, respectively) were used to analyze clot formation in citrated whole blood. Functional fibrinogen polymerization was separately evaluated with an extrinsically activated test containing the platelet-blocking substance cytochalasin D (FIBTEM®). HEPTEM® testing using Heparinase I were used to evaluate specific effects of heparin. Clot time (CT, lag time for clot formation to commence), alpha angle (rate of clot formation) and maximum clot firmness (MCF, measure of clot strength) were also measured where applicable. Measurements were done at 37°C.
Data collection and statistical analysis
A structured and anonymous review of the prospectively collected parameters was conducted. The database was scrutinized for a predetermined list of demographics, investigations and interventions during the course of BICU stay.
Acute burn induced coagulopathy (ABIC) was defined as an International Normalized Ratio (INR) of greater than 1.2 (PT lower than 70%) and an activated partial thromboplastin time (aPTT) of 45 sec or greater. These values represent our local laboratory's definition of coagulopathy and are in line with the definition of ABIC and acute trauma coagulopathy (ATC) in the literature.5,6 DIC was defined by decreased blood platelet count, decreased plasma fibrinogen concentration, increased D-Dimer and prolonged prothrombin time with an increased INR. The basic parameters for acute burn induced coagulopathy (ABIC) and relevant DIC score coagulation parameters are shown in Table 1. In this scoring system, a score of 5 or more meets the definition of decompensated DIC [21].
Disseminated Intravascular Coagulopathy (DIC) score and Acute Burn Induced Coagulopathy (ABIC). A DIC score of less than 5 meets the definition of compensated and of equal to or higher than 5 the definition of decompensated DIC
Disseminated Intravascular Coagulopathy (DIC) score and Acute Burn Induced Coagulopathy (ABIC). A DIC score of less than 5 meets the definition of compensated and of equal to or higher than 5 the definition of decompensated DIC
Acute Burn Induced Coagulopathy (ABIC). International Normalized Ratio (INR)>1.2. Prothrombin Time <70%.aPTT>45 sec.
In case of ROTEM® analysis, ABCI was defined as a 5-minute EXTEM® clot amplitude (A5) of 35 mm or less [22]. This has been shown to accurately identify acute traumatic coagulopathy and is predictive for massive transfusion in trauma patients [23]. INTEM®, EXTEM®, FIBTEM®, and HEPTEM® profiles including reference ranges are shown in the respective tables. Results were rated abnormal in terms of DIC if at least one of these profiles was out of the reference ranges. Association between coagulopathy and ROTEM® results, demographics, interventions and investigations during the ICU stay of the patients was analyzed. The decision to give transfusions or adjacent coagulation therapy was made by the treating physician based on conventional laboratory testing and clinical data without access to the ROTEM® results.
SPSS® for Mac 22.0.0 (IBM Corp.; Armonk, NY, USA) was used for statistical analysis. Datasets were displayed as mean values and standard deviation (SD). Statistical comparison was performed by unpaired t-test. Paired Wilcoxon tests were performed for comparison between individual time points. Analysis of diagnostic or prognostic values of receiver operating characteristic (ROC) and the determination of sensitivity, specificity and predictive value was performed. The significance level was set at p≤0.05.
Results
Twelve patients (6 male, 6 female) met the inclusion criteria. Patient characteristics and different burn/injury scores are presented in Table 2. Six patients received emergency escharatomy and/or fasciotomy in the first 12 h after admission. Two patients (mean TBSA 69%; mean ABSI 11.5) died during the course of BICU stay (second and eighth day) resulting in a mortality rate of 16.7%.
Demographic parameters and characteristics of the study population
Demographic parameters and characteristics of the study population
Abbreviations: BMI, body mass index (reference range: 18.5–25); TBSA, total body surface area; ABSI, Abbreviated Burn Severity Index; SOFA, Sepsis-related Organ Failure Assessment Score; APACHE, Acute Physiology and Chronic Health Evaluation; SAPS, Simplified Acute Physiology Score.
Survivors and non-survivors did not significantly differ in TBSA (58.4±16.4 vs. 69.0±12.7; p = 0.33) or ABSI (10.2±2.5 vs. 11.5±0.7; p = 0.19) on admission. However, they significantly differed in SOFA score (4.5±2.2 vs. 11.0±2.8; p < 0.05), APACHE II score (16.6±5.4 vs. 26.5±2.1; p < 0.01), and SAPS II score values (46.3±11.1 vs. 69.5±2.1; p < 0.01). Mean ventilation duration for the surviving patients was 38.7 days (range: 2–84; ±28.3), all of which received surgical debridement with or without grafting within the first 7 days after trauma (mean 4.0; range: 1–7; ±2.2).
In terms of standard coagulation parameters presented in Table 3, three patients fulfilled the criteria of compensated DIC with a mean DIC score value of 2.7±1.2 on admission, and none of the patients fulfilled the criteria for decompensated DIC. At that time there were no significant differences between patients with or without coagulopathy or DIC in TBSA (p > 0.15), ABSI score (p > 0.53), APACHE II score (p > 0.07) and SAPS II score (p > 0.34). The SOFA score was significantly higher in patients with coagulopathy than in patients without (p < 0.05). From admission to the fourteenth day all patients fulfilled the criteria for coagulopathy at least at one day. Mean point of maximal coagulopathy was 3.6 days (range: 0–9; ±2.2) after admission with a mean duration of 2.6 consecutive days (range: 1–5; ±1.6). ABIC occurred in three patients in the context of surgery, in two patients immediately following surgery and in one in the course of three days.
Results of routine laboratory tests at the characteristic points of “burn disease”. Values
According to ROTEM admission analysis, three patients fulfilled the coagulopathy criteria. All patients fulfilled the criteria for compensated DIC at least at one day during the follow-up period with one patient fulfilling criteria for decompensated DIC at three consecutive days. Seven patients fulfilled coagulopathy criteria at one or more days with a mean length of 2.7 (range: 1–7; ±2.1) days, however one patient that did not fulfill criteria of standard coagulation parameters fulfilled the criteria by ROTEM measurements. Additionally, the point (mean 4.6 days; range: 1–12; ±3.5 days) and length (mean 3.0 days; range: 1–7; ±2.2 days) of coagulopathy diagnosed by ROTEM was not equal to the time point by standard coagulation parameters. Mean time point of DIC was 6.7 (range: 0–14; ±4.0) days after admission with a mean length of 6.0 (range: 1–11; ±3.2) days per patient. The mean DIC score value was 1.7 (range: 1–5; ±1.3). In four of the patients with compensated DIC, the event occurred following surgery and lasted 4.0±4.8 days on average.
Most standard coagulation parameters demonstrated deviations compared to their reference ranges. Mean PT, plasma fibrinogen, factor XIII, and coagulation inhibitor values (AT III, protein C and S activity) were decreased, INR and D-dimer values were increased and aPTT value was prolonged. Platelet count, hemoglobin, factor VII activity, and body temperature were within reference ranges. Mean values at 14 days for fibrinogen and AT III as well as protein S activity increased significantly (p < 0.05). aPTT dropped significantly (p < 0.05), mean factor XIII activity and hemoglobin level decreased significantly (p < 0.05), whereas factor VII as well as protein C decreased non-significantly (p > 0.05). On admission the normal mean blood platelet count significantly decreased until the third day (p < 0.05) and increased significantly until the fourteenth day (p < 0.05) with achieving the reference range. INR, D-dimer and temperature showed no significant changes (p > 0.05).
All EXTEM® measurements were within their reference ranges during the observation, except an increase of mean value for EXTEM® A10 at day 14 (Table 4).
Results of rotational thrombelastometry (ROTEM®) EXTEM at the characteristic points
On admission, mean INTEM® CFT was significantly prolonged (p < 0.05) but decreased significantly until day 14 before returning to reference range (Table 5). The evaluation of this decrease interval of mean INTEM® CFT results showed no significant reduction till 72 h (p > 0.05) and 7 d (p > 0.05) after injury respectively. All other mean values for INTEM® were within their reference range, except for the mean values for INTEM® A10 and MCF at day 14, but never increased significantly compared to their reference interval (p > 0.05). All mean pre-, intra- and postoperative INTEM® measurements were within the reference ranges and showed no significant changes between these measurements. Pre-, intra- and postoperative FIBTEM® measurements were slightly elevated compared to reference ranges but without statistical significance (p > 0.05) (Table 6). Mean FIBTEM® A10 and MCF were within the reference range until 24 h after trauma but increased significantly 72 h after burn trauma (p < 0.05), however still staying within the upper limit of the reference range. On day 7 and 14 after injury, mean FIBTEM® values demonstrated a significant increase above the upper limits of normal (p < 0.05). HEPTEM® values for both 14-day-interval and perioperative values were all within the reference ranges and therefore omitted in this analysis.
Results of rotational thrombelastometry (ROTEM®) INTEM at the characteristic points
Results of rotational thrombelastometry (ROTEM®) FIBTEM at the characteristic points
Burn injury coagulopathies are triggered and maintained by several mediators of the immune response due to multiple organ system damage. This mediator release leads to early activation of the coagulation cascade, the complement system, and platelet activation [24]. Other pathological mechanisms include direct/indirect endothelial damage resulting in typical edema formation. Burkhardt and Zellner demonstrated that essential coagulation factors (e.g. factor XIII and fibrinogen) consequently leave the intravascular space, resulting in functional deterioration of the coagulation system [25]. Other possible explanations such as dilution due to fluid treatment have been considered as well [26, 27]. In the extensive coagulation analysis of King et al. on a small sample of burn patients, delayed coagulation abnormalities were observed, possibly secondary to a hypercoagulable state [28]. A clinical study examining disseminated intravascular coagulopathy (DIC) in severe burned patients demonstrated an initial hypercoagulopathy followed by subsequent micro-thrombosis leading to organ damage [16]. Thrombelastographic measurements usually show reduced clot strength as a first sign of dilutional coagulopathy due to impaired fibrinogen/fibrin polymerization, and might occur with moderate blood loss [29]. The activation of inflammation and coagulation mediators results in generalized systemic micro-thrombi formation that may lead to reduction in organ perfusion and initiate DIC [12].
Several studies already looked at the impact of thombelastometric studies in burn patients, however, despite promising studies describing the potential use of TEG and ROTEM® in the treatment of severely burned patients, there is still a lack of hard evidence and guidelines for burn related coagulopathic injury [30]. However, the treatment of coagulopathy is an important factor in burn treatment, as the difference between compensated and decompensated DIC has been shown to be of predictive value for the overall mortality [12]. Schaden et al. showed in a randomized controlled trial that the use of ROTEM® in burn patients decreased the use of blood products and optimized treatment care in a small study population [1]. Also, another study from the same group emphasized the better detection of fibrinogen level rise in severely burned patients and thus a more comprehensive and tailored coagulation therapy [31].
As we conducted an observational study of a confined patient population, the statistical significance of the measurements is limited; however, the difference between standard and ROTEM® treatment is still an important matter of investigation. The assessment of DIC in the phases of burn injury differs, depending on whether standard coagulation parameters or ROTEM® techniques are used. Although the initial assessment of DIC was similar for both standard labs and ROTEM® measurements, more patients were detected to be in a state of worsening coagulation status for a longer time in ROTEM® than in standard measurements in our study population. In addition, one patient was rated in to be in decompensated DIC for 3 days according to ROTEM® measurements, while no patient was rated to be in a decompensated DIC based on standard parameters. Therefore, a randomized controlled study is needed to evaluate if the increased and regular use of ROTEM® thrombelastometry in the treatment of burn coagulopathy is warranted.
Conclusion
In conclusion, this study points towards a more complex picture and higher occurrence of DIC in burn patients when thrombelastometric measurements like ROTEM® are taken into account in addition to standard coagulation parameters. Further studies should be conducted in a randomized controlled fashion to explore the use of ROTEM® in the routine evaluation of coagulation disorders in severely burned patients.
Disclosure of funding
The authors have no financial interest to declare in relation to the content of this article.