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Optimising diagnosis and treatment of coagulopathy in severely injured trauma
patients
Balvers, K.
Publication date
2016
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Final published version
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Citation for published version (APA):
Balvers, K. (2016). Optimising diagnosis and treatment of coagulopathy in severely injured
trauma patients.
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OPTIMISING DIAGNOSIS AND TREATMENT OF
COAGULOPATHY IN SEVERELY INJURED
TRAUMA PATIENTS
Kirsten Balvers
OPTIMISING DIAGNOSIS AND TREA
TMENT OF COAGULOP A THY IN SEVEREL Y INJURED TRAUMA P A TIENTS KIRSTEN BAL VERS
OPTIMISING DIAGNOSIS AND TREATMENT OF
COAGULOPATHY IN SEVERELY INJURED
TRAUMA PATIENTS
Optimising diagnosis and treatment of coagulopathy in severely injured trauma patients
Thesis, University of Amsterdam, The Netherlands
Paranimfen: Susan Hatzmann, Monique Walenkamp, Elisa Ng, Sanne Taks ISBN: 978-94-028-0202-3
Cover design and layout: Susan Hatzmann Printed by: Ipskamp Printing
© K. Balvers, Amsterdam, The Netherlands, 2016
The copyright of the published and accepted articles has been transferred to the respective publishers. No part of this thesis may be reproduced, stored or transmitted, in any form or by any means, without permission of the author.
The printing of this thesis was financially supported by: Tem International GmbH, CSL Behring, Nederlandse Vereniging voor Traumachirurgie, TraumaNet AMC, Wetenschappelijk Fonds Chirurgie AMC, Academisch Medisch Centrum (AMC), ABN AMRO, Chipsoft B.V.
OPTIMISING DIAGNOSIS AND TREATMENT OF
COAGULOPATHY IN SEVERELY INJURED
TRAUMA PATIENTS
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad van doctor
aan de Universiteit van Amsterdam op gezag van de Rector Magnificus
prof. dr. D.C. van den Boom
ten overstaan van een door het College voor Promoties ingestelde commissie, in het openbaar te verdedigen in de Agnietenkapel
op vrijdag 24 juni 2016, te 14:00 uur door Kirsten Balvers
PROMOTIECOMMISSIE
Promotor: Prof. dr. J.C. Goslings Universiteit van Amsterdam
Co-promotor: Prof. dr. N.P. Juffermans Universiteit van Amsterdam
Overige leden: Prof. dr. C. Boer Vrije Universiteit Amsterdam
Dr. S.S. Zeerleder Universiteit van Amsterdam
Prof. dr. M.J. Schultz Universiteit van Amsterdam
Prof. dr. L.P.H. Leenen Universiteit Utrecht
Prof. dr. M.W. Hollmann Universiteit van Amsterdam
Prof. dr. K. Brohi Queen Mary University of London
CONTENTS
General introduction and outline of the thesis
PART 1 DIAGNOSIS
Chapter 1 The utility of thromboelastometry (ROTEM®) and
thromboelastography (TEG®) to detect coagulation disorders
in non-bleeding ICU patients
Chapter 2 Thromboelastometry and organ failure in trauma patients: a prospective cohort study
Chapter 3 Haemoglobin level and neurologic outcome in patients with severe traumatic brain injury
Chapter 4 Endogenous microparticles drive the pro-inflammatory host immune response in severely injured trauma patients
PART 2 TREATMENT
Chapter 5 Risk factors related to trauma-induced coagulopathy and resuscitation strategies for the development of multiple organ failure in severely injured trauma patients
Chapter 6 Is hypothermia at ICU admission an independent predictor of 28-days mortality?
Chapter 7 Effects of implementation of a massive transfusion protocol on the usage of blood products and transfusion strategies
Chapter 8 Are there any alternatives for transfusion of AB plasma as universal donor in an emergency release setting?
Chapter 9 Therapeutic strategies associated with improved outcomes in bleeding trauma patients
Chapter 10 Transfusion strategy associated with correction of coagulopathy as detected by ROTEM® in bleeding trauma patients 9 23 35 51 63 77 103 119 135 149 169
Summary and future perspectives Samenvatting en toekomstperspectieven Research portfolio List of publications Dankwoord Curriculum Vitae 195 207 221 225 229 223
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GENERAL INTRODUCTION
Trauma has a profound impact on public health around the world. Yearly approximately 5 million people die due to traumatic injury, which is 1 out of every 3 severely injured patients1. Therefore, improving survival after trauma is a major challenge in which timely therapy is of great importance. Although increased knowledge about the mechanisms and pathophysiology of traumatic injury to the human body have led to improved trauma care, surgical procedures, and critical care management over the last decades, still a large proportion of patients die after trauma. Better understanding of how the injury and treatment affect the outcome after trauma may result in a decreased mortality. However, in this field there is still a lot of work to do.
In trauma patients, massive haemorrhage is one of the leading causes of mortality. Exsanguination accounts for more than 30% of mortality in trauma patients2. The main part of the treatment of massive haemorrhage is to stop the bleeding. However, the development of trauma-induced coagulopathy (TIC) hampers this and exacerbates the bleeding. Therefore, treatment of coagulopathy is a cornerstone in achieving haemostasis and in therapy of bleeding trauma patients.
COAGULOPATHY
Coagulopathy is a condition of the blood in which the blood`s ability to coagulate is impaired. However, the term coagulopathy can relate to several divers conditions. Intensivists associate coagulopathy with disseminated intravascular coagulopathy (DIC), which is characterized by an increased tendency of clotting of the blood, also known as hypercoagulopathy, which is thought to contribute to organ failure and late mortality. Trauma surgeons interpret coagulopathy as a diminished clotting function, also known as hypocoagulopathy, which is associated with early mortality. Additionally, several terms in literature are used to refer to the same condition. Terms such as acute traumatic coagulopathy (ATC), early coagulopathy of trauma (ECT), trauma-induced coagulopathy (TIC), and the acute coagulopathy of trauma-shock (ACoTS) are commonly used. Both the various interpretations and terms used for coagulopathy, illustrate the lack of knowledge on the dynamics of the coagulation process in trauma. In this thesis we will further discuss coagulopathy after trauma. The term in this thesis used for coagulopathy is trauma-induced coagulopathy (TIC) and refers to a diminished clotting function, also knowns as a hypocoagulable state, upon arrival at the Emergency Department.
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11 INTRODUCTIONTRAUMA-INDUCED COAGULOPATHY
Almost 25% of the severely injured trauma patients have developed hypocoagulopathy on arrival to the Emergency Department3, 4. Compared to trauma patients without coagulopathy, patients with TIC have a fourfold higher risk for mortality. Early mortality is determined by a hypocoagulable state and bleeding to death, whereas late mortality is determined by a hypercoagulable state and the development of multiple organ failure2, 5.
The hypocoagulable state increases the risk for bleeding and exacerbates blood loss. This early mortality by haemorrhage is one of the leading causes of death in trauma patients, but it is also the most preventable cause of death6-8. Treatment of coagulopathy is a cornerstone in achieving haemostasis and in therapy of bleeding trauma patients, as controlling the bleeding by a surgical procedure is not possible without a good functioning clotting system. However, overtreatment of TIC may result in a hypercoagulable state, which is associated with the development of multiple organ failure and late mortality. Therefore, to treat TIC adequately, knowledge about the pathophysiology and dynamics of coagulopathy in the course of severe trauma is required.
PATHOGENESIS OF TRAUMA-INDUCED COAGULOPATHY
Conventional theory holds that early TIC was caused by hypothermia, acidosis and dilution, also known as the lethal triad. Hypothermia and acidosis result in the dysfunction of clotting enzymes, whereas administration of resuscitation fluids dilutes the concentration of clotting factors in blood9, 10. TIC results in an increased blood loss with exacerbation of hypovolemic shock and concomitant decreased perfusion of organs, which leads to hypothermia, acidosis and subsequently death2-4, 11.
However, nowadays it is suggested that early development of TIC is caused by external factors, like hypothermia, dilution and acidosis, in combination with a response of the body to tissue injury. After tissue injury, endothelial cell activation results in the initiation of the pro-inflammatory response system and the triggering of thrombo-thrombomodulin complexes. These complexes activate protein C, also known as the protein C pathway. Activated protein C inhibits clotting factors V and VIII thereby reducing the clotting function. However, in trauma, the presence of shock and sustained hypoperfusion, causes an increased release of thrombo-thrombomodulin complexes, which results in a widespread protein C activation and an impaired clot formation. Additionally, besides the fact that clotting factor V and VIII are inhibited by activated protein C,
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protein C depletes plasminogen inhibitors, including (PAI-1). Normally, plasminogen inhibitors have the function to inhibit the formation of plasminogen in to plasmin. The breakdown of the fibrin network and subsequently the clot is thereby prevented. However, depletion of plasminogen inhibitors by protein C results in an increased clot breakdown, also known as hyperfibrinolysis. This hypocoagulable effect is further enhanced by the release of small molecules of heparin-substances after endothelial damage. Together this aggravates a hypocoagulable state, blood loss and subsequently increases haemorrhagic-related deaths12-16. Figure 1 illustrates the pathogenesis of coagulopathy after trauma.
At the same time, consumption of activated protein C occurs after trauma. This depletion of protein C is a potential mechanism for the development of hypercoagulopathy. Due to depletion of protein C, clotting factor V and VIII and plasminogen inhibitors are no longer inhibited, which may result in a hypercoagulable state. It is suggested that this hypercoagulable state is associated with the formation of micro-thrombi, also known as DIC, and the formation of multiple organ failure after trauma17-20. Also, depletion of protein C leads potentially to an impaired immune response and subsequently a higher risk of infectious diseases12-16, 21-23. In line with this, previous studies reported lower levels of protein C levels in patients with sepsis and ventilator-associated pneumonia in critically ill trauma patients14, 24. This indicates that the immune system and the coagulation system are interlinked and that activation of the immune system is associated with a pro-coagulant effect in trauma patients. However, which mediators are responsible for this, is unknown. Results of previous studies suggest that a prompt release of microparticles, which are vesicles which are shed into the bloodstream by cells under conditions of stress, are associated with both a coagulant and a pro-inflammatory immune responses25-29. However, whether this also applies to trauma patients remains to be determined. Hypo- and hypercoagulopathy after trauma poses a challenge to the trauma team, with the need for awareness and timely treatment of the lethal triad while avoiding unnecessary transfusion. The diagnosis and treatment of TIC is a cornerstone in this process.
DIAGNOSIS OF TIC
Early detection and identification of trauma patients with coagulopathy is required to optimise therapy. Activated partial thromboplastin time (aPTT), prothrombin time (PT), the international normalized ratio (INR), platelet count, fibrinogen and d-dimer are conventional clotting tests, which are used frequently in the clinical setting. However, the use of these tests is rather based on tradition than on evidence based medicine supporting the use of these tests in trauma setting. Conventional clotting tests are
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13 INTRODUCTIONFIGURE 1:
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very time-consuming as results become available after at least 40-60 minutes. Also, these tests reflect only a part of the clotting profile. Thereby, these tests have minimal impact on transfusion practice in bleeding trauma patients30-33. Although these tests are commonly used to evaluate and to predict bleeding, these tests are originally designed to diagnose coagulation disorders and to evaluate anticoagulant medication. Therefore, transfusion practice is currently more an empiric procedure than based upon adequate clotting tests. This is alarming, as conventional clotting tests do not allow for correct diagnosis of TIC and hence no targeted therapy is possible. In conclusion, no adequate diagnostic and monitoring tools for coagulopathy in trauma patients are available nowadays.
Viscoelatic Heamostatic Assays (VHA), like thromboelastometry (ROTEM®) and thromboelastography (TEG®), are rapid tests which reflect the whole coagulation status. Within 5-10 minutes a first impression of the clotting function is visualized. VHA tests provide an impression for global haemostasis, including the measurement of the total coagulation process from clot formation until clot breakdown. Therefore the use of these VHA assays may be a valuable alternative for diagnosing and monitoring of the effectivity of treatment of TIC in bleeding trauma patients33-38. However, clear reference values for coagulopathy in trauma patients still need to be determined, as the manufacturer has provided only general reference values. Furthermore, it is unknown what the monitoring capacity of these VHA assays is and whether implementation of these tests results in optimization of transfusion by avoiding transfusion unnecessary blood products and pro-coagulants. Additionally, it remains to be determined whether VHA assays can be used to provide targeted transfusion in trauma patients and what the triggers and targets are for transfusion. Currently, the suspicion of bleeding, hypovolemia and the haemoglobin level are frequently used as triggers for transfusion, however it is unknown whether these factors predict bleeding adequately and are able to use as a transfusion target. Therefore, adequate and rapid diagnostic tools for coagulopathy are required to optimise and monitor treatment of coagulopathic trauma patients.
TREATMENT OF TIC
Over the last decades, research efforts in the field of transfusion practice in trauma patients have been directed towards treatment of the principle drivers of the lethal triad, including hypothermia, acidosis and coagulopathy. Therefore, supportive care in trauma consists of prevention of hypothermia and the administration of fewer fluids. From this point of view, prevention of hypothermia and a restricted fluid policy have become part of standard trauma care. Additionally, transfusion practice has evolved from
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15 INTRODUCTIONA
B
FIGURE 2: VHAs like ROTEM® (A) and TEG® (B)39, 40
administration of red blood cells (RBCs) towards earlier administration of fresh frozen plasma (FFPs) and platelets (PLTs) to red blood cells (RBCs)41-44. A RBC:FFP:platelet ratio of 1:1:1 is suggested to be the closest approximation of whole blood and contributes to the achievement of haemostasis thereby decreasing mortality33, 41, 45, 46, 47-51.
In order to obtain a balanced ratio of blood products, massive transfusion protocols (MTPs) are increasingly being used in trauma care. MTPs attempt to provide rapid and standardized issuing of blood products in a 1:1:1 ratio and aim to reduce time-to transfusion by keeping pre-thawed plasma available47-50. However, evidence for a beneficial effect of implementation of the MTP on obtaining a balanced transfusion ratio, coagulation profiles and overall survival is still lacking. Furthermore, it is unclear whether implementation of an MTP results in an increased incidence of overtransfusion of blood products. Overtransfusion is still a frequently observed phenomenon and is associated with adverse events like sepsis and multiple organ failure21-23.
Alternative transfusion strategies with early balanced resuscitation in order to control TIC and to decrease traumatic bleeding while avoiding unnecessary transfusion are therefore required. An alternative to empiric use of ratios may be transfusion practice
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guided by VHA assays, as these tests are rapid and reflect the coagulation status adequately. Furthermore, these tests have shown promising results in their ability to detect and to monitor coagulopathy34, 37, 38. As results become available within 5-10 minutes after initiating the VHA assays, these tests may be used to guide transfusion of blood products, pro-coagulant and antifibrinolytic agents. Subsequently, VHA assays could be incorporated in a transfusion algorithm, which supports rapid clinical management of severely injured trauma patients. However, the additional value of the use of VHA assays in trauma resuscitation has to be determined.
AIM AND OUTLINE OF THE THESIS
This thesis focusses on knowledge gaps in the field of diagnosis and treatment of TIC in severely injured trauma patients. In order to explore potential diagnostic tools for TIC and to investigate potential strategies to optimise treatment of TIC, the Academic Medical Center of Amsterdam has been participating in the International Trauma Research Network (INTRN) since 2012. The INTRN is a consortium of 6 European Level-1 trauma centres, which received funding from the European Union Framework Programme 7 (FP7) to perform research in the field of coagulopathy after trauma. This thesis is partly established by collaboration with INTRN and by using a large database of trauma patients. The aim of this thesis is to evaluate diagnostic tools for TIC and to investigate which transfusion strategy is associated with the best outcome after trauma. The first part of this thesis focusses on optimising diagnosis of TIC, whereas the second part of this thesis focusses on optimising treatment of TIC.
PART 1 DIAGNOSIS OF COAGULOPATHY
• Chapter 1 provides a narrative review of the utility of ROTEM® and TEG® to detect coagulopathy in critically ill non-bleeding patients.
• Chapter 2 assesses the predictive value of hypercoagulopathy detected by ROTEM® for the development of multiple organ failure.
• Chapter 3 determines the association between the haemoglobin level and the neurologic outcome of patients after traumatic brain injury.
• Chapter 4 investigates the role of microparticles in mediating the immune response following trauma.
TREATMENT OF COAGULOPATHY
• Chapter 5 gives a systematic overview of the risk factors related to coagulopathy and transfusion practice for adverse outcome after major trauma.
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17 INTRODUCTION• Chapter 6 emphasizes the detrimental effect of accidental hypothermia on mortality in coagulopathic trauma patients at admittance to the intensive care unit. • Chapter 7 studies the effect of the introduction of an MTP on the use of blood
products and transfusion ratios.
• Chapter 8 systematically determines alternatives for the transfusion of AB-plasma in massively bleeding patients
• Chapter 9 investigates which transfusion strategy is associated with best outcome in bleeding trauma patients
• Chapter 10 determines the response of ROTEM® to transfusion practice in bleeding trauma patients.
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19 REFERENCES 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 Disseminated intravascular coagulation and sustained systemic inflammatory response syndrome predict organ dysfunctions after trauma: application of clinical decision analysis. Ann Surg 1999;229(1):121-7. Paffrath T, Wafaisade A, Lefering R, Simanski C, Bouillon B, Spanholtz T, et al. Venous thromboembolism after severe trauma: incidence, risk factors and outcome. Injury. 2010;41(1):97-101.Sauaia A, Moore FA, Moore EE, Haenel JB, Read RA, Lezotte DC. Early predictors of postinjury multiple organ failure. Arch Surg 1994;129(1):39-45.
Dewar DC, Tarrant SM, King KL, Balogh ZJ. Changes in the epidemiology and prediction of multiple-organ failure after injury. J Trauma Acute Care Surg 2013;74(3):774-9.
Frohlich M, Lefering R, Probst C, Paffrath T, Schneider MM, Maegele M, et al. Epidemiology and risk factors of multiple-organ failure after multiple trauma: an analysis of 31,154 patients from the TraumaRegister DGU. J Trauma Acute Care Surg 2014;76(4):921-7. Choi Q, Hong KH, Kim JE, Kim HK. Changes in plasma levels of natural anticoagulants in disseminated intravascular coagulation: high prognostic value of antithrombin and protein C in patients with underlying sepsis or severe infection. Annals of laboratory medicine. 2014;34(2):85-91.
Fujimi S, Ogura H, Tanaka H, Koh T, Hosotsubo H, Nakamori Y, et al. Increased production of leukocyte microparticles with enhanced expression of adhesion molecules from activated polymorphonuclear leukocytes in severely injured patients. J Trauma. 2003;54(1):114-9.
Mastronardi ML, Mostefai HA, Meziani F, Martinez MC, Asfar P, Andriantsitohaina R. Circulating microparticles from septic shock patients exert differential tissue expression of enzymes related to inflammation and oxidative stress. Crit Care Med 2011;39(7):1739-48.
Morel O, Toti F, Hugel B, Bakouboula B, Camoin-Jau L, Dignat-George F, et al. Procoagulant microparticles: disrupting the vascular homeostasis equation? Arterioscler Thromb Vasc Biol 2006;26(12):2594-604. Ogura H, Kawasaki T, Tanaka H, Koh T, Tanaka R, Ozeki Y, et al. Activated platelets enhance microparticle formation and platelet-leukocyte interaction in severe trauma and sepsis. J Trauma. 2001;50(5):801-9.
Ogura H, Tanaka H, Koh T, Fujita K, Fujimi S, Nakamori Y, et al. Enhanced production of endothelial microparticles with increased binding to leukocytes in patients with severe systemic inflammatory response syndrome. J Trauma. 2004;56(4):823-30.
Holcomb JB, Minei KM, Scerbo ML, Radwan ZA, Wade CE, Kozar RA, et al. Admission rapid thrombelastography can replace conventional coagulation tests in the emergency department: experience with 1974 consecutive trauma patients. Annals of surgery. 2012;256(3):476-86.
Dzik WH. Predicting hemorrhage using preoperative coagulation screening assays. Current hematology reports. 2004;3(5):324-30.
Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, et al. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time. J Trauma. 2009;67(2):266-75; discussion 75-6.
Davenport R, Manson J, De’Ath H, Platton S, Coates A, Allard S, et al. Functional definition and characterization of acute traumatic coagulopathy. Crit Care Med 2011;39(12):2652-8.
Johansson PI, Stensballe J. Effect of Haemostatic Control Resuscitation on mortality in massively bleeding patients: a before and after study. Vox Sang 2009;96(2):111-8.
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Schochl H, Nienaber U, Hofer G, Voelckel W, Jambor C, Scharbert G, et al. Goal-directed coagulation management of major trauma patients using thromboelastometry (ROTEM)-guided administration of fibrinogen concentrate and prothrombin complex concentrate. Crit Care. 2010;14(2):R55. Schochl H, Nienaber U, Maegele M, Hochleitner G, Primavesi F, Steitz B, et al. Transfusion in trauma: thromboelastometry-guided coagulation factor concentrate-based therapy versus standard fresh frozen plasma-based therapy. Crit Care. 2011;15(2):R83. GmbH TI. Available from: https://www.rotem. de.
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Kutcher ME, Kornblith LZ, Narayan R, Curd V, Daley AT, Redick BJ, et al. A paradigm shift in trauma resuscitation: evaluation of evolving massive transfusion practices. JAMA Surg 2013;148(9):834-40.
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Zink KA, Sambasivan CN, Holcomb JB, Chisholm G, Schreiber MA. A high ratio of plasma and platelets to packed red blood cells in the first 6 hours of massive transfusion improves outcomes in a large multicenter study. Am J Surg 2009;197(5):565-70. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma. 2007;62(2):307-10.
Holcomb JB, Tilley BC, Baraniuk S, Fox EE, Wade CE, Podbielski JM, et al. Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA. 2015;313(5):471-82. Ball CG, Dente CJ, Shaz B, Wyrzykowski AD, Nicholas JM, Kirkpatrick AW, et al. The impact of a massive transfusion protocol (1:1:1) on major hepatic injuries: does it increase abdominal wall closure rates? Can J Surg 2013;56(5):E128-E34.
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21 REFERENCESmassive transfusion or massive confusion? Transfusion. 2010;50(7):1545-51.
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K. Balvers, M.C.A. Muller, N.P. Juffermans Annual Update in Intensive Care and Emergency Medicine 2014
THE UTILITY OF THROMBOELASTOMETRY (ROTEM
®)
OR THROMBOELASTOGRAPHY (TEG
®) IN
CHAPTER 1 24
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INTRODUCTION
A hypocoagulable state is highly prevalent in critically ill patients. An INR of >1.5 occurs in 30% of patients, associated with increased mortality1. Also, of critically ill patients, up to 40% develops thrombocytopenia during their intensive care unit (ICU) stay2-4, associated with increased length of stay, need for transfusion of blood products and increased mortality5. A hypercoagulable state is also associated with adverse outcome, as well as with increased thrombo-embolic events6. Disseminated intravascular coagulation (DIC) develops in 10 to 20% of ICU patients. A hypercoagulable state contributes to organ failure and is associated with a high mortality, ranging from 45% to 78%7. Coagulopathy is thought to result from an imbalance between activation of coagulation and impaired inhibition of coagulation and fibrinolysis. Activation is triggered by tissue factor, which is expressed in reaction to cytokines or endothelial damage. Impaired inhibition of coagulation is the consequence of reduced plasma levels of antithrombin (AT), depressed activity of the protein C system and decreased levels of tissue factor pathway inhibitor (TFPI). A decrease in the fibrinolytic system is due to increased levels of plasminogen activator inhibitor type 1 (PAI-1)8;9. This disturbance between components of the coagulation system leads to a variable clinical picture, ranging from patients with an increased bleeding tendency (hypocoagulable state) to those with DIC with (micro-) vascular thrombosis (hypercoagulable state).
Assessment of coagulation status in patients is complex. Global coagulation tests, including activated partial thromboplastin time (aPTT) and prothrombin time (PT), are used clinically. However, these tests are of limited value and their ability to accurately reflect in vivo hypocoagulable state is questioned10. Also, aPTT/PT reflects a part of the coagulation system and does not provide information on the full balance between coagulation, anti-coagulation and fibrinolysis. Hypercoagulable state can be assessed by increased levels of d-dimers, but specificity is limited10. Impaired function of the anticoagulant system can be diagnosed by measuring plasma levels of naturally occurring anticoagulant factors AT, protein C and TFPI. However, these are not readily available for clinical use. Apart from the DIC score, there are no diagnostic tests which evaluate a hypercoagulable state. Also, markers of the activity of the fibrinolytic system are not used at the bedside10.
TEG®/ROTEM® TESTS
Rotational thromboelastography (TEG®/ROTEM®) is a point of care test, which evaluates whole clot formation and degradation. The thromboelastogram arises through
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25 THE UTILITY OF ROTEM® OR TEG® IN NON-BLEEDING ICU PATIENTS1
movement of the cup (TEG®) or the pin (ROTEM®). As fibrin forms between the cup andthe pin, this movement is influenced and converted to a specific trace. The trace reflects different phases of the clotting process. Major parameters are R (reaction/clotting) time, the period from the initiation of the test until the beginning of clot formation. K-time is the period from the start of the clot formation until the curve reaches an amplitude of 20 mm. Kinetics of fibrin formation and cross-linking is expressed by the α-angle, which is the angle between the baseline and the tangent to the TEG®/ROTEM® curve. Clot strength is represented by the maximal amplitude (MA) of the trace. The degree of fibrinolysis is reflected by the difference between the maximal amplitude and the amplitude measured after 30 and/or 60 minutes. To describe these visco-elastic changes, both systems have their own terminology (Table 1). Both generate similar data. The technique is developed in the 1940s, but until recent, clinical application has been limited. However, technical developments have led to standardization and improved reproducibility of the method11. Also, the availability for bedside evaluation and a changing view regarding the use of blood and haemostatic therapy in massive bleeding, have both contributed to a renewed interest in this technique.
TEG®/ROTEM® may also facilitate diagnosis of clotting abnormalities in the critically ill. Detecting a hypocoagulable state, TEG®/ROTEM® may be a useful tool in the assessment of the risk of bleeding peri-operatively or prior to an invasive procedure. This could lead to a more tailored transfusion strategy, with an efficient use of blood products.
Also, TEG®/ROTEM® may diagnose a hypercoagulable state. With TEG®/ROTEM®, a hypercoagulable state can be detected by high maximal amplitude (MA), shortened reaction time, increased alfa angle and total cloth strength G (defined as (5000xA)/ (100-A), table 2) . Assessment of a hypercoagulable state could lead to prognostication of multiple organ failure (MOF) and risk for thrombo-embolic events. Also, another potential advantage could be a more tailor made administration of therapies that
TABLE 1: TEG® and ROTEM® parameters
ROTEM® TEG®
Time to initial fibrin formation
(to 2 mm amplitude) CT R
Clot strengthening, rapidity of fibrin build up CFT K Clot strengthening, rapidity of fibrin build up α α Clot strength, represents maximum dynamics of fibrin
and platelet bonding MCF MA
Clot breakdown,
CHAPTER 1 26
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interfere with the coagulation system. Difficulties in identifying responders from non-responders may in part have contributed to conflicting results from trials evaluating the effect of strategies that interfere with the coagulation system12-15.
UTILITY OF TEG®/ROTEM® TO DETECT SEPSIS-INDUCED COAGULOPATHY
ROTEM® clearly demonstrates a hypercoagulable state during endotoxemia16. In vitro, endotoxin-induced hypercoagulability was demonstrated with TEG®. In experiments where LPS was infused in healthy volunteers, a hypercoagulable state measured by TEG® had a strong correlation with plasma levels of prothrombin fragments F1+F217;18. In sepsis patients however, TEG®/ROTEM® measurements have shown differential results. Several studies observed no changes in parameters19-22, other studies reported a hypercoagulable23 or hypocoagulable state24. A few studies also reported patients showing both a hyper- and hypocoagulable state25-28. Taken together, results are heterogeneous. Also, there is a lack of clarity on interpretation of the test results. To date, no studies have compared conventional coagulation tests such as PT/APTT to TEG®/ROTEM® in sepsis patients. However, the utility of thromboelastography to detect disseminated intravascular coagulopathy (DIC) has been evaluated. It seems that thromboelastography can predict DIC. Patients with DIC present with hypocoagulable state26. This may be due to a decrease in coagulation factors used for formation of micro thrombi. In line with this, sepsis patients who met the ISTH DIC criteria showed
TABLE 2: Normal ranges, hypercoagulable state and hypocoagulable state of ROTEM® and TEG®
PARAMETERS NORMAL RANGES
FOR ROTEM NORMAL RANGES FOR TEG
HYPERCOAGULABLE
STATE HYPOCOAGULABLE STATE Reaction time, r or CT INTEM 137-246 sec
EXTEM 42-74 sec FIBTEM 43-69 sec
4-8 min Shortened Prolonged
Clot formation time, K
or CFT INTEM 40-100 secEXTEM 46-184 sec NA
0-4 min Shortened Prolonged
Alpha angle, Angle or α INTEM 71-82° EXTEM 63-81° NA 47-74 Increased Decreased Maximum amplitude, MA or MCF INTEM 52-72 mm EXTEM 49-71 mm FIBTEM 9-25 mm 54-72 mm Increased Decreased
A hypercoagulable state is defined as the presence of at least two of the following: shortened reaction time, increased alpha angle or increased maximum amplitude (46). *values for Kaolin- or Celite-activated TEG®
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27 THE UTILITY OF ROTEM® OR TEG® IN NON-BLEEDING ICU PATIENTS1
a hypocoagulable state when compared to healthy controls, while patients withoutDIC showed a non-significant trend towards hypercoagulation25. Also, patients with an underlying disease known to be associated with DIC and ISTH DIC scores >5 had significantly prolonged reaction and K times and decreased alpha-angle and MA (signs of a hypocoagulable state) compared to patients with low ISTH DIC scores. The authors developed a score, defined as the total number of parameters (R, K, MA, and alfa) that were deranged in the direction of a hypocoagulable state. With this score, the discriminatory value of thromboelastometry to detect DIC improved29. Impaired fibrinolysis in sepsis may contribute to a hypercoagulable state. Inhibition of the fibrinolytic system was found to discriminate sepsis from postoperative controls19;28;30. In terms of prognostication, a hypercoagulable state was not found to be a predictor of outcome. In contrast, the finding of a hypocoagulable state was repeatedly shown to be associated with a poor outcome. The TEG® MA value is an independent predictor for 28-day mortality on admission27. Hospital mortality was predicted by a hypocoagulable state due to a deficit in thrombin generation (30). A hypocoagulable state measured with TEG® is found to be associated with a pro-inflammatory response19;24. Also, the degree of a hypocoagulable state is associated with severity of organ failure in sepsis19;22. Taken together, results are heterogeneous. Timing of measurements may be relevant to these observations, as a hypocoagulable state may be more outspoken in the acute phase of sepsis and return to normal values towards discharge of ICU, or even to enhanced clot formation.
USE OF TEG®/ROTEM® TO GUIDE ANTICOAGULANT TREATMENT IN SEPSIS PATIENTS
In sepsis, activation of coagulation is a crucial step in the pathophysiological cascade of sepsis, with concomitant low levels of circulating natural anticoagulants8;9. From this perspective, various treatment modalities that interfere with the coagulation system have been studied (e.g. rhAPC, AT and heparin)12-15. However, efficacy has been questioned. It can be hypothesized that TEG®/ROTEM® may help to identify patients likely to respond to therapies that target coagulopathy. To date, there are no studies which have addressed this question. Only a few small patient series evaluated TEG®/ ROTEM® measurement during anticoagulant medication. ROTEM® parameters did not change during anticoagulant medication. Also, treatment with antithrombin did not induce changes in the ROTEM® measurements23.
USE OF TEG®/ROTEM® IN PATIENTS WITH INDUCED HYPOTHERMIA
Induced hypothermia is a common therapy in survivors of a cardiac arrest31-33. However, hypothermia is associated with coagulopathy, prolongation of aPTT and PT33;34 and
CHAPTER 1 28
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an increased risk of bleeding35. A test that reliably detects hypothermia induced coagulopathy would be helpful in identifying patients who have an increased bleeding risk while being cooled and sedated. Unfortunately, little is known about the value of TEG®/ROTEM® in these patients.
Spiel et al observed that ROTEM® measurements showed a prolonged CT at 1 hour after infusion of 4°C cold crystalloid solution. All other parameters remained within reference values. An important limitation of this study is that all measurements were performed at 37°C33. TEG® parameters were evaluated also in patients after cardiac arrest. On the contrary, the TEG® was performed at isothermal conditions and a hypocoagulable state was detected by TEG®36.
USE OF TEG®/ROTEM® IN PATIENTS WITH BRAIN INJURY
After severe traumatic brain injury and neurosurgery, up to 45% of patients develop a coagulopathy37-39. Given the serious consequences of intracranial bleeding, instant assessment of coagulation status is desirable. Two small trials have studied the value of TEG® to detect coagulopathy in these patients, which mostly found test results within reference values. However, the functional response of platelets as measured in a platelet mapping™ (TEG®-PM) assay, was significantly lower in brain injury patients than in control groups, with a particular low response in those patients who developed bleeding complications40. Furthermore, a hypocoagulable state on admission to the ICU is associated with worse outcome in patients with traumatic brain injury and intracranial bleeding41.
UTILITY OF TEG® TO DETECT A HYPERCOAGULABLE STATE AND PROGNOSTICATE
ORGAN FAILURE IN TRAUMA PATIENTS
Patients who survive the acute phase of trauma are prone to develop a hypercoagulable state with increased risk for thrombo-embolic events and DIC1. Conventional coagulation tests are not able to detect such a hypercoagulable state. Also, there is debate as to whether the syndrome DIC is applicable to coagulation abnormalities in trauma. With TEG®/ROTEM®, a hypercoagulable state can be detected by high maximal amplitude (MA) and shortened reaction time (Table 1). Several reports demonstrate a hypercoagulable state in severely injured patients with TEG®/ROTEM®. In trauma and burn patients admitted to the ICU, TEG® was found to be more sensitive in detecting a hypercoagulable state than conventional clotting assays42;43. A high MA was found to be an independent contributor of mortality in multiple logistic regression analysis42. A hypercoagulable state measured by TEG® predicted the development of thrombo-embolic events in trauma patients44 although not all studies have confirmed this
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291
THE UTILITY OF ROTEM® OR TEG® IN NON-BLEEDING ICU PATIENTSfinding45. It should be noted that the finding of a hypercoagulable state is not specific for DVT. A study on the use of ROTEM® to prognosticate the occurrence of multiple organ failure in a cohort of trauma patients is currently underway.
CONSIDERATIONS
In several non-bleeding critically ill patient populations, evidence supporting the use of TEG®/ROTEM® to diagnose a hypocoagulable or hypercagulable state is limited at this stage, mostly because of heterogeneity of the included studies in design, use of control groups and chosen endpoints. Heterogeneity of results can also be caused by differences in disease severity, as changes were more outspoken during severe illness. Timing of TEG®/ROTEM® measurements may greatly influence results, as coagulopathy is a dynamic process, eg. evolving from subtle activation of coagulation to overt DIC in sepsis and from a hypocoagulable to a hypercoagulable state in trauma. Performing sequential measurements will probably provide better insight in the development of coagulation derangements.
Another important issue is that no uniform definitions exist of a hypocoagulable and a hypercoagulable state. Reference values for non-bleeding patients with disorders of coagulation are not widely assessed and cut off values are often not defined in studies. To compare patient categories and possibly investigate therapeutic interventions in the coagulation system, validated universal reference values and definitions are essential. A study on TEG® reference intervals has been recently completed (NCT01357928). Presumably, as patients groups are relatively small, evaluation of larger patient groups may yield more clear results.
CONCLUSION
TEG®/ROTEM® can detect coagulopathy in the critically ill. Whether these tests are useful as diagnostic tools remains to be investigated when reference values and clear definitions have been established.
TEG®/ROTEM® may be useful for prognostication of outcome. A hypocoagulable status seems to be an independent predictor for organ failure and mortality in sepsis, also after correction for disease severity. In patients with brain injury, a hypocoagulable state on admission to the ICU is also associated with worse outcome. In patients who survive the acute phase of trauma, a hypercoagulable state as detected by TEG®/ROTEM® is a common finding. These tests could be helpful in identifying those patients at risk for thrombo-embolic complications, as a hypercoagulable state predicted the development of thrombo-embolic events in the majority of studies. Further research on this topic is forthcoming.
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Schochl H, Solomon C, Schulz A, Voelckel W, Hanke A, Van GM, Redl H, Bahrami S. Thromboelastometry (TEM) findings in disseminated intravascular coagulation in a pig model of endotoxinemia. Mol Med 2011 Mar;17(3-4):266-72.
Spiel AO, Mayr FB, Firbas C, Quehenberger P, Jilma B. Validation of rotation thrombelastography in a model of systemic activation of fibrinolysis and coagulation in humans. J Thromb Haemost 2006 Feb;4(2):411-6.
Zacharowski K, Sucker C, Zacharowski P, Hartmann M. Thrombelastography for the monitoring of lipopolysaccharide induced
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31 REFERENCES 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 activation of coagulation. Thromb Haemost 2006 Mar;95(3):557-61.Brenner T, Schmidt K, Delang M, Mehrabi A, Bruckner T, Lichtenstern C, Martin E, Weigand MA, Hofer S. Viscoelastic and aggregometric point-of-care testing in patients with septic shock - cross-links between inflammation and haemostasis. Acta Anaesthesiol Scand 2012 Nov;56(10):1277-90.
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Daudel F, Kessler U, Folly H, Lienert JS, Takala J, Jakob SM. Thromboelastometry for the assessment of coagulation abnormalities in early and established adult sepsis: a prospective cohort study. Crit Care 2009;13(2):R42. Gonano C, Sitzwohl C, Meitner E, Weinstabl C, Kettner SC. Four-day antithrombin therapy does not seem to attenuate hypercoagulability in patients suffering from sepsis. Crit Care 2006;10(6):R160.
Viljoen M, Roux LJ, Pretorius JP, Coetzee IH, Viljoen E. Hemostatic competency and elastase-alpha 1-proteinase inhibitor levels in surgery, trauma, and sepsis. J Trauma 1995 Aug;39(2):381-5.
Sivula M, Pettila V, Niemi TT, Varpula M, Kuitunen AH. Thromboelastometry in patients with severe sepsis and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 2009 Sep;20(6):419-26.
Collins PW, Macchiavello LI, Lewis SJ, Macartney NJ, Saayman AG, Luddington R, Baglin T, Findlay GP. Global tests of haemostasis in critically ill patients with severe
sepsis syndrome compared to controls. Br J Haematol 2006 Oct;135(2):220-7.
Ostrowski SR, Windelov NA, Ibsen M, Haase N, Perner A, Johansson PI. Consecutive thrombelastography clot strength profiles in patients with severe sepsis and their association with 28-day mortality: a prospective study. J Crit Care 2013 Jun;28(3):317-11.
Adamzik M, Langemeier T, Frey UH, Gorlinger K, Saner F, Eggebrecht H, Peters J, Hartmann M. Comparison of thrombelastometry with simplified acute physiology score II and sequential organ failure assessment scores for the prediction of 30-day survival: a cohort study. Shock 2011 Apr;35(4):339-42.
Sharma P, Saxena R. A novel thromboelastographic score to identify overt disseminated intravascular coagulation resulting in a hypocoagulable state. Am J Clin Pathol 2010 Jul;134(1):97-102.
Massion PB, Peters P, Ledoux D, Zimermann V, Canivet JL, Massion PP, Damas P, Gothot A. Persistent hypocoagulability in patients with septic shock predicts greater hospital mortality: impact of impaired thrombin generation. Intensive Care Med 2012 Aug;38(8):1326-35. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002 Feb 21;346(8):549-56. Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002 Feb 21;346(8):557-63. Spiel AO, Kliegel A, Janata A, Uray T, Mayr FB, Laggner AN, Jilma B, Sterz F. Hemostasis in cardiac arrest patients treated with mild hypothermia initiated by cold fluids. Resuscitation 2009 Jul;80(7):762-5.
Reed RL, Bracey AW, Jr., Hudson JD, Miller TA, Fischer RP. Hypothermia and blood coagulation: dissociation between enzyme activity and clotting factor levels. Circ Shock 1990 Oct;32(2):141-52.
THE UTILITY OF ROTEM® OR TEG® IN NON-BLEEDING ICU PATIENTS
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Sun Y, Wang J, Wu X, Xi C, Gai Y, Liu H, Yuan Q, Wang E, Gao L, Hu J, et al. Validating the incidence of coagulopathy and disseminated intravascular coagulation in patients with traumatic brain injury--analysis of 242 cases. Br J Neurosurg 2011 Jun;25(3):363-8. Lustenberger T, Talving P, Kobayashi L, Inaba K, Lam L, Plurad D, Demetriades D. Time course of coagulopathy in isolated severe traumatic brain injury. Injury 2010 Sep;41(9):924-8. Stein SC, Smith DH. Coagulopathy in traumatic brain injury. Neurocrit Care 2004;1(4):479-88. Nekludov M, Bellander BM, Blomback M, Wallen HN. Platelet dysfunction in patients with severe traumatic brain injury. J Neurotrauma 2007 Nov;24(11):1699-706. Windelov NA, Welling KL, Ostrowski SR, Johansson PI. The prognostic value of thrombelastography in identifying neurosurgical patients with worse prognosis. Blood Coagul Fibrinolysis 2011 Jul;22(5):416-9.
Park MS, Salinas J, Wade CE, Wang J, Martini W, Pusateri AE, Merrill GA, Chung K, Wolf SE, Holcomb JB. Combining early coagulation and inflammatory status improves prediction of mortality in burned and nonburned trauma patients. J Trauma 2008 Feb;64(2 Suppl):S188-S194.
Gonzalez E, Kashuk JL, Moore EE, Silliman CC. Differentiation of enzymatic from platelet hypercoagulability using the novel thrombelastography parameter delta (delta). J
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Schreiber MA, Differding J, Thorborg P, Mayberry JC, Mullins RJ. Hypercoagulability is most prevalent early after injury and in female patients. J Trauma 2005 Mar;58(3):475-80. Park MS, Martini WZ, Dubick MA, Salinas J, Butenas S, Kheirabadi BS, Pusateri AE, Vos JA, Guymon CH, Wolf SE, et al. Thromboelastography as a better indicator of hypercoagulable state after injury than prothrombin time or activated partial thromboplastin time. J Trauma 2009 Aug;67(2):266-75.
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33 THE UTILITY OF ROTEM® OR TEG® IN NON-BLEEDING ICU PATIENTSM.C.A. Müller, K. Balvers, J.M. Binnekade, N. Curry, S. Stanworth, C. Gaarder, K.M. Kolstadbraaten, C. Rourke, K. Brohi, J.C. Goslings, N.P. Juffermans
Critical Care 2014
THROMBOELASTOMETRY AND ORGAN FAILURE IN
TRAUMA PATIENTS: A PROSPECTIVE COHORT STUDY
36
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CHAPTER 2ABSTRACT
Introduction: Data on the incidence of a hypercoagulable state in trauma, as measured by thromboelastometry (ROTEM®), is limited and the prognostic value of hypercoagulability after trauma on outcome is unclear. We aimed to determine the incidence of hypercoagulability after trauma, and to assess whether early hypercoagulability has prognostic value on the occurrence of multiple organ failure (MOF) and mortality. Methods: This was a prospective observational cohort study in trauma patients who met the highest trauma level team activation. Hypercoagulability was defined as a G value of ≥11.7 dynes/cm2 and hypocoagulability as a G value of <5.0 dynes/cm2. ROTEM® was performed on admission and 24 hours later.
Results: A total of 1,010 patients were enrolled and 948 patients were analysed. Median age was 38 (interquartile range (IQR) 26 to 53), 77% were male and median injury severity score was 13 (IQR 8 to 25). On admission, 7% of the patients were hypercoagulable and 8% were hypocoagulable. Altogether, 10% of patients showed hypercoagulability within the first 24 hours of trauma. Hypocoagulability, but not hypercoagulability, was associated with higher sequential organ failure assessment scores, indicating more severe MOF. Mortality in patients with hypercoagulability was 0%, compared to 7% in normocoagulable and 24% in hypocoagulable patients (P <0.001). EXTEM CT, alpha and G were predictors for occurrence of MOF and mortality. Conclusion: The incidence of a hypercoagulable state after trauma is 10% up to 24 hours after admission, which is broadly comparable to the rate of hypocoagulability. Further work in larger studies should define the clinical consequences of identifying hypercoagulability and a possible role for very early, targeted use of anticoagulants.
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37 PREDICTIVE VALUE OF HYPERCOAGULOPATHY FOR MOF2
INTRODUCTIONMajor trauma is among the most common causes of death worldwide. Whereas uncontrolled bleeding accounts for 50 to 80% of mortality early following trauma1,2, multiple organ failure (MOF) is the most important cause of late mortality after trauma1,3. Traumatic injury induces a hypocoagulable state, as a result of acute traumatic coagulopathy (ATC) accompanied by loss, consumption and dilution of coagulation factors and fibrinolysis. Hypothermia, shock and acidosis further amplify the derangement of the coagulation system4. In addition to reduced haemostatic potential, trauma can also induce a hypercoagulable state5-7. Animal experiments have shown that hypercoagulability can arise within hours of the injury8, a phenomenon confirmed in humans5,9. However, uniform definitions of hypercoagulability are lacking and effects of this hypercoagulable state after trauma are not fully elucidated, with studies showing conflicting results. An association with adverse events such as an increased risk of venous thromboembolism has been reported7,10,11. However, early hypercoagulability has also been associated with decreased early mortality, which may suggest that hypercoagulability is a functional response in order to reduce blood loss9. In sepsis, it has been demonstrated that hypercoagulability, characterized by the formation of microthrombi with concurrent protein C deficiency and impaired fibrinolysis, contributes to MOF and adverse outcome12,13. Although sepsis and trauma are different entities, the accompanying coagulopathies show similarities and persistent protein C deficiency after trauma is also associated with occurrence of MOF14,15. Shock and hypoperfusion can induce activation of the endothelium and if the patient survives the initial bleeding episode, this can result in a procoagulant state. It is conceivable that therapy of ATC may add to this endogenous response, possibly resulting in an overshoot in coagulation over time, with subsequent enhancement of hypercoagulability and MOF. Diagnosing hypercoagulability is complex. Thrombin generation tests, or assessment of plasma levels of natural anticoagulants, as protein C, are not readily available for clinical use and not validated to detect hypercoagulability. Thromboelastometry (ROTEM®) provides real-time information on all aspects of the coagulation system, including the presence of hypercoagulability16,17. The use of thromboelastometry to diagnose hypocoagulability in trauma has frequently been explored in recent years18-21. However, reports on the use of ROTEM® to detect a hypercoagulable state are scarce.
We aimed to study the incidence of early hypercoagulability in multiple trauma patients and to establish whether hypercoagulability is associated with the occurrence of MOF and mortality. In addition, as transfusion strategies have shifted, we assessed whether transfusion strategy influenced the occurrence of hypercoagulability.
38
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CHAPTER 2METHODS
Study design and patients
A prospective observational cohort study was conducted in four level-1 trauma centres in London, Oxford, Oslo and Amsterdam. This study is part of the Activation of Coagulation and Inflammation in Trauma (ACIT) study, an ongoing prospective observational multicentre study in trauma patients. The ethics committees of the Academic Medical Center in Amsterdam, the Netherlands; of the Oslo University Hospital, Oslo, Norway; of the Royal London Hospital, London and of the John Radcliffe Hospital, Oxford, United Kingdom, all reviewed and approved the study. Written informed consent was obtained from all participating patients. All procedures have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Between January 2008 and March 2013, all adult trauma patients (18 years and older) who met the local criteria for highest trauma team level activation were eligible for enrolment in the study. Patients were excluded if arrival at the emergency department (ED) was >2 hours following injury; >2,000 ml of intravenous fluid was administered before ED admission; they were transferred from another hospital or if they had burns covering >5% of total body surface area. Patients were retrospectively excluded if they declined to give consent to use data, were receiving anticoagulation (not including aspirin), or had moderate or severe liver disease or a known bleeding diathesis.
Data collection
Data were prospectively collected on patient demographics, time from injury to arrival at the ED, mechanism of injury (blunt or penetrating), presence of traumatic brain injury, vital signs on arrival and 24 hours after injury and amount of fluid and blood products within the first 24 hours of injury. Trauma severity was assessed using the injury severity score (ISS)22. Furthermore, sequential organ failure assessment (SOFA) scores, with Glasgow coma scale to assess neurologic dysfunction, and mortality rates after 28 days were obtained.
Thromboelastometry
Thromboelastometric variables were measured with ROTEM (Tem International, Munich, Germany). Citrated blood samples were drawn within 1 hour after arrival in the ED and a second sample was collected 24 hours (±2 hours) after admission. All samples were processed within 1 hour. For EXTEM, 20 μL of 0.2 mol/L CaCl2 (star-tem™) and 20 μL of human recombinant tissue factor (r EXTEM™) were added to a test vial. Subsequently 300 μL of the citrated blood sample was added. For INTEM, 20 μL of 0.2 mol/L CaCl2 (star-tem™) and 20 μL of partial thromboplastin phospholipid
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39 PREDICTIVE VALUE OF HYPERCOAGULOPATHY FOR MOF2
made of rabbit brain and ellagic acid (in-tem™) were added as activator to 300 μL ofblood in the test cuvette. The electronic pipette program guided all test steps. For both assays, clotting time (CT), clot formation time (CFT), maximum clot firmness (MCF) and alpha angle were recorded. Total clot strength was assessed by G as calculated according to the formula: (5,000 × MCF)/100 - MCF and expressed as dynes/cm216. G has a curvilinear relation with MCF and reflects the contribution of enzymatic and platelet components to the hemostasis, hereby better reflecting haemostatic potential than individual thromboelastometry parameters7,23. G has been shown to be valuable in diagnosing hypo- and hypercoagulability7,16,23. Hypercoagulability was defined as a G value of ≥11.7 dynes/cm2 and hypocoagulability as a G value of <5.0 dynes/cm2 (values provided by manufacturer).
Outcome variables
Primary outcome was the occurrence of MOF, assessed by the SOFA score, which reliably assesses organ failure in trauma patients24. The score awards 0 (normal) to 4 (most abnormal) points for each organ system. MOF was defined by a score of 3 points or more3. Secondary outcome was 28-day mortality. In addition, effect of transfusion strategy (ratio of red blood cells (RBC) to fresh frozen plasma (FFP)) on ROTEM® profile and occurrence of hypercoagulability was determined.
Statistics
Continuous normally distributed variables are expressed by their mean and standard deviation. Not normally distributed variables are expressed as medians and their interquartile (IQR) ranges and categorical variables are expressed as n (%). ISS was treated as a continuous variable. Groups are compared by using Student’s t test or Mann-Whitney U test in case of not normally distributed data.
For comparison of categorical variables, the chi-square test or Fisher’s exact tests are used. The primary analysis focused on modelling the hypothesized relation between ROTEM-detected hypercoagulability, MOF and mortality in trauma patients. First, univariate logistic regression analysis was used to select independent factors achieving a P value ≤0.10, in addition to factors that were deemed clinically important (age, time to ED, presence of traumatic brain injury, injury mechanism, ISS, base excess, systolic blood pressure) in relation to the outcome variables. Subsequently, selected ROTEM® factors were entered in a multivariate logistic regression model. Patients who died on admission were not included in the analyses to assess the value of thromboelastometry to predict MOF, while patients who died later were included when a SOFA score was available. All deceased patients were included in the analyses to assess the value of ROTEM® to predict mortality.
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CHAPTER 2To compare the effect of transfusion strategies, transfused patients were divided based on RBC:FFP ratio. Statistical significance was considered to be at P= 0.05. Analyses were performed using R (version 2.3; R Foundation for Statistical Computing, Vienna, Austria). Graphs were created with Prism 5.0 (GraphPad Software, San Diego, CA, USA). RESULTS
During the study period, 1,245 patients were screened and 1,010 patients were enrolled in the study (Figure 1). For 62 of the patients, no data were available on occurrence of MOF or mortality, therefore, analyses were performed in the remaining 948 patients. Of these, 776 patients were admitted to the hospital (intensive care unit: n = 318 and ward: n = 458) and 76 were discharged home. Patient characteristics are listed in Table 1. The majority of included patients were males experiencing blunt injury. Median age was 38 years and median ISS was 13 (IQR 8 to 25). Eighteen patients died at admission, nine of them had traumatic brain injury (TBI). Of those who died between 24 hours and 28 days, mortality was 21% in TBI and 3.4% in non-TBI patients.
ROTEM® profiles and hypercoagulability on admission
Baseline thromboelastometry data were available for 886 patients upon ED admission. On admission, the G value was increased in 63 (7%) of the patients, while 71 (8%) were hypocoagulable and the remaining 85% had normal clot strength according to the G value. Patients showing hypercoagulability on admission were more often female (40% vs. 28%, P <0.001), had lower ISS scores (9 vs. 20, P <0.001) and higher base excess values (−1.3 mEq/L vs. −4.3 mEq/L, P <0.001) compared to hypocoagulable patients. Also, they received less RBC, FFP and platelet transfusions compared to hypocoagulable patients. In addition, hypocoagulable patients had longer time to arrival at ED and a trend toward a higher incidence of TBI (Table 1).
ROTEM® profiles and hypercoagulability 24 hours after admission
Twenty-four hours after admission, for 451 out of 776 admitted patients, ROTEM® profiles were available, 26 (6%) patients were hypercoagulable and 35 (8%) were hypocoagulable (Figure S1 in Additional file 1). In accordance with the hypercoagulable patients at ED admission, the hypercoagulable patients 24 hours after admission had lower ISS scores (14 vs. 25, P = 0.04), higher base excess values (−1.4 mEq/L vs. −6.2 mEq/L, P <0.001) and received less RBC transfusions compared to the hypocoagulable patients. Amount of FFP and platelets transfused did not differ between hyper-, normo- and hypocoagulable patients.
Altogether, during the first 24 hours after trauma, 88 (10%) patients were hypercoagulable at some point. Patients showing hypercoagulable ROTEM® profiles had higher platelet counts and fibrinogen levels.
