Intensive Care Med (2014) 40:1727–1730 DOI 10.1007/s00134-014-3388-3
Karim Asehnoune David Faraoni Karim Brohi
WHAT’S NEW IN INTENSIVE CA RE
What’s new in management of traumatic coagulopathy?
Received: 22 June 2014 Accepted: 27 June 2014 Published online: 8 July 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014 K. Asehnoune ()) Poˆle PHU3, Service d’Anesthe´sie Re´animation Chirurgicale, Hoˆtel Dieu, CHU Nantes, 44035 Nantes cedex 1, France e-mail: [email protected] Tel.: ? 33 240 08 30 05 K. Asehnoune Laboratoire UPRES EA 3826, The´rapeutiques cliniques et expe´rimentales des infections, Faculte´ de Me´decine, Faculte´ de Nantes, Universtie de Nantes, Nantes, France D. Faraoni Department of Anesthesiology, Centre Hospitalier Universitaire Brugmann-Hoˆpital Universitaire des Enfants Reine Fabiola, Free University of Brussels, 15 JJ Crocq Avenue, 1020 Brussels, Belgium e-mail: [email protected] K. Brohi Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK e-mail: [email protected]
Introduction One-third of traumatized patients have already developed acute traumatic coagulopathy (ATC) upon hospital admission [1]. Recent advances in the understanding of the initiators of ATC suggest that shock-induced tissue hypoperfusion and damage are the primary drivers for this coagulopathy. Iatrogenic dilution, hypothermia, and acidemia can then exacerbate ATC to produce a more complex coagulopathy. As a consequence, damage
control resuscitation (DCR) is now ‘standard of care’ and includes immediate arrest or temporization of ongoing bleeding (damage control surgery or angiography); permissive hypotension avoiding hemodilution; correction of coagulopathy; and restoration of organ perfusion and oxygen delivery [2].
Early fluid resuscitation: do volume and type matter? Although a systolic blood pressure of 90 mmHg is usually used to define hypotension, cardiac output rather than blood pressure mainly influences oxygen delivery. It should also be kept in mind that many traumatized patients will maintain a blood pressure within the normal range even in the presence of severe bleeding. Indeed, in the presence of active uncontrolled bleeding, volume replacement results in dilution and hypothermia without sustained increases in blood pressure or cardiac output. Permissive hypotension has therefore been advocated as a temporary strategy for trauma resuscitation and has been shown to decrease mortality in models of uncontrolled hemorrhagic shock. In older children and adults with severe trauma without traumatic brain injuries, ‘‘permissive hypotension’’ principles should therefore be applied [3] until causes of bleeding are cured [4]. It is unclear whether permissive hypotension in acutely hemorrhaging patients with a concomitant traumatic brain injury is harmful or beneficial. The choice of the best fluid is still matter of intense debate. A systematic Cochrane review [5] reported that colloids did not improve mortality compared to crystalloids, and the recent high-quality evidence suggested that the selection, timing, and doses of intravenous fluids should be evaluated carefully [6]. A judicious fluid strategy focusing on blood products to restore hemostasis and avoid dilution should be adopted.
1728
Updated strategies for management of ATC On the one hand, massive trauma will activate fibrinolysis soon after injury and increase clot instability. The CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage 2) trial [7] is the largest placebo-controlled trial reporting the effects of early administration of tranexamic acid (TXA) on death, vascular occlusive events, and the receipt of blood transfusion in traumatized patients. In this study, the authors observed that mortality was significantly reduced with TXA, and the risk of death due to bleeding was also significantly decreased, without an increase in fatal or non-fatal vascular occlusive events. They also reported strong evidence that early treatment (\1 h from injury) significantly reduced mortality due to bleeding. As a
Management of Acute Traumatic Coagulopathy
Pre-operative assessment
1. Assess the extent of traumatic hemorrhage 2. Identify source of bleeding/ Avoid hypothermia with heated blanket 3. Give tranexamic acid 1 g 4. 5. Mean arterial pressure 80 mmHg if traumatic brain injury 6. 7.
ED
8. Administration of factor concentrates?
1. Assess the extent of traumatic hemorrhage/ Identify source of bleeding 2. Damage control surgery or angiography 3. 4. Continue tranexamic acid 1 g over 8 hours
OR
5. Monitor hemoglobin level, pH, lactatemia, calcemia 6. Coagulation assays: 1. Standard lab. tests: aPTT, PT, INR, Platelet count 2. Point-of-care monitoring (thromboelastography/thromboelastometry) 7. Massive transfusion protocol: 1. RBC:FFP:PLT = 1:1:1 if uncontrolled massive bleeding 2. Hb target: 7-9 g/dL 3. Fibrinogen level: > 1.5 g/L
ICU
Fig. 1 Strategy for the management of acute traumatic coagulopathy. Bold recommendation with high level of recommendation; italics suggestion with a lack of evidence in the literature and that should be examined in further studies. ER emergency room, OR operative room, ICU intensive care unit, RBC red blood cells, FFP fresh frozen plasma, PLT platelet concentrate, PCC prothrombin complex concentrate
consequence, the systematic use of TXA in traumatized patients is now recommended in the updated version of the European trauma guideline (GRADE 1A, 1 g loading dose followed by 1 g over 8 h) [3] (Fig. 1). On the other hand, volume replacement that augments coagulation factors is the main strategy to treat ATC. This replacement could be achieved by the transfusion of fresh frozen plasma (FFP), platelet concentrates, and red blood cells (RBCs). A fixed 1:1:1 transfusion ratio strategy has been studied in different retrospective analyses that reported marked reduction in mortality [8]. However, current retrospective studies are limited by the heterogeneity of the included population, confounding factors, and survival bias. We are now waiting for further prospective trials (e.g., the PROPPR trial, clinicaltrials.gov NCT01545232) to better understand the benefit-to-risk
1. Fibrinogen concentrate or Cryo. in case of massive bleeding 4. Platelet count > 100 x 109/L 5. Administration of PCC restricted to massive bleeding in a context of vitamin K antagonist treatment. 8. Multidisciplinary algorithm based approach / Checklist / Quality assessment
1729
balance, and the feasibility of early administration of FFP patients are still lacking, and interventional trials with fibrinogen substitution in high-risk patients need to be as the first fluid administered for trauma resuscitation. undertaken. Prothrombin complex concentrates (PCC) or activated recombinant factor VII (rFVIIa) was used in different Rationale for goal-directed administration of factor clinical settings to treat massive bleeding. However, both PCC and rFVIIa are potent procoagulants and could be concentrates in ATC associated with severe thromboembolic complications. In An interesting aspect of utilizing factor concentrates in the absence of clinical data in the traumatized population, acute bleeding is the possibility to administer coagulation PCC should therefore only be recommended for the support closer to the time of injury in the prehospital emergency reversal of bleeding in the context of vitamin environment. This would be of particular interest in situ- K antagonist treatment, whereas rFVIIa should only be ations where transportation times are long, patients are considered in case of persistent massive bleeding despite entrapped, or for any other reasons when evacuation to a the administration of hemostatic therapies. trauma center is delayed. In the context of massive bleeding, fibrinogen is the first factor that reaches a critically low level, and fibrinogen supplementation could be considered as a rationale Conclusion approach. In a recent multicenter trial, hypofibrinogenemia was frequently reported in trauma and strongly Acute traumatic coagulopathy occurs soon after injury in associated with poor outcome [9]. Below an estimated a large proportion of traumatized patients. Damage concritical fibrinogen concentration value of 2.29 g/L a dra- trol resuscitation avoids massive fluid resuscitation and matic increase in mortality was detected. Interestingly, leads to an early management of the bleeding source Rourke et al. [10] observed that the administration of a through early blood product transfusion and immediate high ratio of plasma failed to normalize fibrinogen levels arrest or temporization of ongoing bleeding. Although during DCR, whereas ex vivo supplementation of fibrin- several advances have been made during the last few ogen either with cryoprecipitate or concentrate was able years, further studies are still needed to better define the to correct this coagulopathy, and patients who received ‘optimal’ RBCs, FFP-to-platelets transfusion ratio, and additional fibrinogen supplementations had better out- the benefit-to-risk balance of factor concentrates admincomes. Recent European guidelines [3] recommend istration as a first-line therapy in traumatized patients. treatment with fibrinogen concentrate or cryoprecipitate in the presence of significant bleeding accompanied by Conflicts of interest KA received fees as a speaker for LFB, signs of a functional fibrinogen deficit or a plasma level of B-Braun, and Fresenius-Kabi. DF has no conflict of interest. KB has received unrestricted grants for research from Tem Internaless than 1.5–2.0 g/L (GRADE 1C). However, data sup- tional GmbH and Haemonetics Inc. porting the efficacy and safety of fibrinogen supplementation as a first-line therapy in traumatized
References 1. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, Pittet JF (2008) Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 64:1211–1217 2. Ball CG (2014) Damage control resuscitation: history, theory and technique. Can J Surg 57:55–60 3. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, Filipescu D, Hunt BJ, Komadina R, Nardi G, Neugebauer E, Ozier Y, Riddez L, Schultz A, Vincent JL, Rossaint R (2013) Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 17:R76
4. Harris T, Thomas GO, Brohi K (2012) Early fluid resuscitation in severe trauma. BMJ 345:e5752 5. Perel P, Roberts I, Ker K (2013) Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2:CD000567 6. Myburgh JA, Mythen MG (2013) Resuscitation fluids. N Engl J Med 369:2462–2463
7. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, ElSayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejia-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S (2010) Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 376:23–32
1730
8. Hallet J, Lauzier F, Mailloux O, Trottier V, Archambault P, Zarychanski R, Turgeon AF (2013) The use of higher platelet: RBC transfusion ratio in the acute phase of trauma resuscitation: a systematic review. Crit Care Med 41:2800–2811
10. Rourke C, Curry N, Khan S, Taylor R, 9. Hagemo JS, Stanworth S, Juffermans Raza I, Davenport R, Stanworth S, NP, Brohi K, Cohen MJ, Johansson PI, Brohi K (2012) Fibrinogen levels Røislien J, Eken T, Næss PA, Gaarder C during trauma hemorrhage, response to (2014) Prevalence, predictors and replacement therapy, and association outcome of hypofibrinogenaemia in with patient outcomes. J Thromb trauma: a multicentre observational Haemost 10:1342–1351 study. Crit Care 18:R52
Karim Asehnoune David Faraoni Karim Brohi
WHAT’S NEW IN INTENSIVE CA RE
What’s new in management of traumatic coagulopathy?
Received: 22 June 2014 Accepted: 27 June 2014 Published online: 8 July 2014 Ó Springer-Verlag Berlin Heidelberg and ESICM 2014 K. Asehnoune ()) Poˆle PHU3, Service d’Anesthe´sie Re´animation Chirurgicale, Hoˆtel Dieu, CHU Nantes, 44035 Nantes cedex 1, France e-mail: [email protected] Tel.: ? 33 240 08 30 05 K. Asehnoune Laboratoire UPRES EA 3826, The´rapeutiques cliniques et expe´rimentales des infections, Faculte´ de Me´decine, Faculte´ de Nantes, Universtie de Nantes, Nantes, France D. Faraoni Department of Anesthesiology, Centre Hospitalier Universitaire Brugmann-Hoˆpital Universitaire des Enfants Reine Fabiola, Free University of Brussels, 15 JJ Crocq Avenue, 1020 Brussels, Belgium e-mail: [email protected] K. Brohi Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK e-mail: [email protected]
Introduction One-third of traumatized patients have already developed acute traumatic coagulopathy (ATC) upon hospital admission [1]. Recent advances in the understanding of the initiators of ATC suggest that shock-induced tissue hypoperfusion and damage are the primary drivers for this coagulopathy. Iatrogenic dilution, hypothermia, and acidemia can then exacerbate ATC to produce a more complex coagulopathy. As a consequence, damage
control resuscitation (DCR) is now ‘standard of care’ and includes immediate arrest or temporization of ongoing bleeding (damage control surgery or angiography); permissive hypotension avoiding hemodilution; correction of coagulopathy; and restoration of organ perfusion and oxygen delivery [2].
Early fluid resuscitation: do volume and type matter? Although a systolic blood pressure of 90 mmHg is usually used to define hypotension, cardiac output rather than blood pressure mainly influences oxygen delivery. It should also be kept in mind that many traumatized patients will maintain a blood pressure within the normal range even in the presence of severe bleeding. Indeed, in the presence of active uncontrolled bleeding, volume replacement results in dilution and hypothermia without sustained increases in blood pressure or cardiac output. Permissive hypotension has therefore been advocated as a temporary strategy for trauma resuscitation and has been shown to decrease mortality in models of uncontrolled hemorrhagic shock. In older children and adults with severe trauma without traumatic brain injuries, ‘‘permissive hypotension’’ principles should therefore be applied [3] until causes of bleeding are cured [4]. It is unclear whether permissive hypotension in acutely hemorrhaging patients with a concomitant traumatic brain injury is harmful or beneficial. The choice of the best fluid is still matter of intense debate. A systematic Cochrane review [5] reported that colloids did not improve mortality compared to crystalloids, and the recent high-quality evidence suggested that the selection, timing, and doses of intravenous fluids should be evaluated carefully [6]. A judicious fluid strategy focusing on blood products to restore hemostasis and avoid dilution should be adopted.
1728
Updated strategies for management of ATC On the one hand, massive trauma will activate fibrinolysis soon after injury and increase clot instability. The CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Hemorrhage 2) trial [7] is the largest placebo-controlled trial reporting the effects of early administration of tranexamic acid (TXA) on death, vascular occlusive events, and the receipt of blood transfusion in traumatized patients. In this study, the authors observed that mortality was significantly reduced with TXA, and the risk of death due to bleeding was also significantly decreased, without an increase in fatal or non-fatal vascular occlusive events. They also reported strong evidence that early treatment (\1 h from injury) significantly reduced mortality due to bleeding. As a
Management of Acute Traumatic Coagulopathy
Pre-operative assessment
1. Assess the extent of traumatic hemorrhage 2. Identify source of bleeding/ Avoid hypothermia with heated blanket 3. Give tranexamic acid 1 g 4. 5. Mean arterial pressure 80 mmHg if traumatic brain injury 6. 7.
ED
8. Administration of factor concentrates?
1. Assess the extent of traumatic hemorrhage/ Identify source of bleeding 2. Damage control surgery or angiography 3. 4. Continue tranexamic acid 1 g over 8 hours
OR
5. Monitor hemoglobin level, pH, lactatemia, calcemia 6. Coagulation assays: 1. Standard lab. tests: aPTT, PT, INR, Platelet count 2. Point-of-care monitoring (thromboelastography/thromboelastometry) 7. Massive transfusion protocol: 1. RBC:FFP:PLT = 1:1:1 if uncontrolled massive bleeding 2. Hb target: 7-9 g/dL 3. Fibrinogen level: > 1.5 g/L
ICU
Fig. 1 Strategy for the management of acute traumatic coagulopathy. Bold recommendation with high level of recommendation; italics suggestion with a lack of evidence in the literature and that should be examined in further studies. ER emergency room, OR operative room, ICU intensive care unit, RBC red blood cells, FFP fresh frozen plasma, PLT platelet concentrate, PCC prothrombin complex concentrate
consequence, the systematic use of TXA in traumatized patients is now recommended in the updated version of the European trauma guideline (GRADE 1A, 1 g loading dose followed by 1 g over 8 h) [3] (Fig. 1). On the other hand, volume replacement that augments coagulation factors is the main strategy to treat ATC. This replacement could be achieved by the transfusion of fresh frozen plasma (FFP), platelet concentrates, and red blood cells (RBCs). A fixed 1:1:1 transfusion ratio strategy has been studied in different retrospective analyses that reported marked reduction in mortality [8]. However, current retrospective studies are limited by the heterogeneity of the included population, confounding factors, and survival bias. We are now waiting for further prospective trials (e.g., the PROPPR trial, clinicaltrials.gov NCT01545232) to better understand the benefit-to-risk
1. Fibrinogen concentrate or Cryo. in case of massive bleeding 4. Platelet count > 100 x 109/L 5. Administration of PCC restricted to massive bleeding in a context of vitamin K antagonist treatment. 8. Multidisciplinary algorithm based approach / Checklist / Quality assessment
1729
balance, and the feasibility of early administration of FFP patients are still lacking, and interventional trials with fibrinogen substitution in high-risk patients need to be as the first fluid administered for trauma resuscitation. undertaken. Prothrombin complex concentrates (PCC) or activated recombinant factor VII (rFVIIa) was used in different Rationale for goal-directed administration of factor clinical settings to treat massive bleeding. However, both PCC and rFVIIa are potent procoagulants and could be concentrates in ATC associated with severe thromboembolic complications. In An interesting aspect of utilizing factor concentrates in the absence of clinical data in the traumatized population, acute bleeding is the possibility to administer coagulation PCC should therefore only be recommended for the support closer to the time of injury in the prehospital emergency reversal of bleeding in the context of vitamin environment. This would be of particular interest in situ- K antagonist treatment, whereas rFVIIa should only be ations where transportation times are long, patients are considered in case of persistent massive bleeding despite entrapped, or for any other reasons when evacuation to a the administration of hemostatic therapies. trauma center is delayed. In the context of massive bleeding, fibrinogen is the first factor that reaches a critically low level, and fibrinogen supplementation could be considered as a rationale Conclusion approach. In a recent multicenter trial, hypofibrinogenemia was frequently reported in trauma and strongly Acute traumatic coagulopathy occurs soon after injury in associated with poor outcome [9]. Below an estimated a large proportion of traumatized patients. Damage concritical fibrinogen concentration value of 2.29 g/L a dra- trol resuscitation avoids massive fluid resuscitation and matic increase in mortality was detected. Interestingly, leads to an early management of the bleeding source Rourke et al. [10] observed that the administration of a through early blood product transfusion and immediate high ratio of plasma failed to normalize fibrinogen levels arrest or temporization of ongoing bleeding. Although during DCR, whereas ex vivo supplementation of fibrin- several advances have been made during the last few ogen either with cryoprecipitate or concentrate was able years, further studies are still needed to better define the to correct this coagulopathy, and patients who received ‘optimal’ RBCs, FFP-to-platelets transfusion ratio, and additional fibrinogen supplementations had better out- the benefit-to-risk balance of factor concentrates admincomes. Recent European guidelines [3] recommend istration as a first-line therapy in traumatized patients. treatment with fibrinogen concentrate or cryoprecipitate in the presence of significant bleeding accompanied by Conflicts of interest KA received fees as a speaker for LFB, signs of a functional fibrinogen deficit or a plasma level of B-Braun, and Fresenius-Kabi. DF has no conflict of interest. KB has received unrestricted grants for research from Tem Internaless than 1.5–2.0 g/L (GRADE 1C). However, data sup- tional GmbH and Haemonetics Inc. porting the efficacy and safety of fibrinogen supplementation as a first-line therapy in traumatized
References 1. Brohi K, Cohen MJ, Ganter MT, Schultz MJ, Levi M, Mackersie RC, Pittet JF (2008) Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma 64:1211–1217 2. Ball CG (2014) Damage control resuscitation: history, theory and technique. Can J Surg 57:55–60 3. Spahn DR, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, Filipescu D, Hunt BJ, Komadina R, Nardi G, Neugebauer E, Ozier Y, Riddez L, Schultz A, Vincent JL, Rossaint R (2013) Management of bleeding and coagulopathy following major trauma: an updated European guideline. Crit Care 17:R76
4. Harris T, Thomas GO, Brohi K (2012) Early fluid resuscitation in severe trauma. BMJ 345:e5752 5. Perel P, Roberts I, Ker K (2013) Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev 2:CD000567 6. Myburgh JA, Mythen MG (2013) Resuscitation fluids. N Engl J Med 369:2462–2463
7. Shakur H, Roberts I, Bautista R, Caballero J, Coats T, Dewan Y, ElSayed H, Gogichaishvili T, Gupta S, Herrera J, Hunt B, Iribhogbe P, Izurieta M, Khamis H, Komolafe E, Marrero MA, Mejia-Mantilla J, Miranda J, Morales C, Olaomi O, Olldashi F, Perel P, Peto R, Ramana PV, Ravi RR, Yutthakasemsunt S (2010) Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 376:23–32
1730
8. Hallet J, Lauzier F, Mailloux O, Trottier V, Archambault P, Zarychanski R, Turgeon AF (2013) The use of higher platelet: RBC transfusion ratio in the acute phase of trauma resuscitation: a systematic review. Crit Care Med 41:2800–2811
10. Rourke C, Curry N, Khan S, Taylor R, 9. Hagemo JS, Stanworth S, Juffermans Raza I, Davenport R, Stanworth S, NP, Brohi K, Cohen MJ, Johansson PI, Brohi K (2012) Fibrinogen levels Røislien J, Eken T, Næss PA, Gaarder C during trauma hemorrhage, response to (2014) Prevalence, predictors and replacement therapy, and association outcome of hypofibrinogenaemia in with patient outcomes. J Thromb trauma: a multicentre observational Haemost 10:1342–1351 study. Crit Care 18:R52
