Massive Posttraumatic Bleeding: Epidemiology, Causes, Clinical Features, and Therapeutic Management

Abstract

Bleeding typically results as a consequence of derangements of primary hemostasis, secondary hemostasis, or both, and can be dramatically amplified by the presence of other predisposing conditions, especially inherited bleeding disorders. Life-threatening hemorrhages are, however, almost exclusively caused by penetrating wounds, blunt traumas of chest and abdomen, suicide attempts, amputations, bone fractures with concomitant injury to internal organs and blood vessels, and shearing forces from sudden rotation, violent flexion, extension, or deceleration injuries. The pathogenesis of posttraumatic bleeding is complex and multifaceted. The most dramatic phenomenon that always accompanies major hemorrhages is the abrupt and considerable loss of intravascular volume, that further leads to hypovolemic shock, also known as hemorrhagic shock, culminating with peripheral ischemia, especially in those tissues where oxygen delivery is more critical (i.e., central nervous system and myocardium). The mortality rate of severe posttraumatic bleeding can be as high as 50%, especially when an appropriate treatment is not established in a timely manner. The damage control sequence basically entails a four-step approach including damage control surgery, damage control resuscitation with fluid restoration, and hemocomponents administration, as well as correction of the coagulopathy with platelets, antifibrinolytic (e.g., tranexamic acid), and/or procoagulant agents such as fresh frozen plasma, prothrombin complex concentrate, or recombinant-activated Factor VII.

Keywords

bleeding - hemorrhages - recombinant-activated factor VIII - trauma

• References

• 1 Gutierrez G, Reines HD, Wulf-Gutierrez ME. Clinical review: hemorrhagic shock. Crit Care 2004; 8 (5) 373-381
• 2 Marietta M, Pedrazzi P, Girardis M, Busani S, Torelli G. Posttraumatic massive bleeding: a challenging multidisciplinary task. Intern Emerg Med 2010; 5 (6) 521-531
• 3 Bourke DL, Smith TC. Estimating allowable hemodilution. Anesthesiology 1974; 41 (6) 609-612
• 4 Lippi G, Franchini M, Guidi GC. Diagnostic approach to inherited bleeding disorders. Clin Chem Lab Med 2007; 45 (1) 2-12
• 5 Jayandharan GR, Srivastava A, Srivastava A. Role of molecular genetics in hemophilia: from diagnosis to therapy. Semin Thromb Hemost 2012; 38 (1) 64-78
• 6 Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood 2008; 112 (2) 250-255
• 7 Favaloro EJ. Von Willebrand disease: local diagnosis and management of a globally distributed bleeding disorder. Semin Thromb Hemost 2011; 37 (5) 440-455
• 8 Lippi G, Franchini M, Montagnana M, Favaloro EJ. Inherited disorders of blood coagulation. Ann Med 2012; 44 (5) 405-418
• 9 Hayward CP, Bunimov N. Thrombocytopenic platelet disorders. Semin Thromb Hemost 2011; 37 (6) 617-620
• 10 Favaloro EJ, Lippi G, Franchini M. Contemporary platelet function testing. Clin Chem Lab Med 2010; 48 (5) 579-598
• 11 Tufano A, Coppola A, Cerbone AM, Ruosi C, Franchini M. Preventing postsurgical venous thromboembolism: pharmacological approaches. Semin Thromb Hemost 2011; 37 (3) 252-266
• 12 Linden MD, Tran H, Woods R, Tonkin A. High platelet reactivity and antiplatelet therapy resistance. Semin Thromb Hemost 2012; 38 (2) 200-212
• 13 Curry N, Hopewell S, Dorée C, Hyde C, Brohi K, Stanworth S. The acute management of trauma hemorrhage: a systematic review of randomized controlled trials. Crit Care 2011; 15 (2) R92
• 14 Kauvar DS, Wade CE. The epidemiology and modern management of traumatic hemorrhage: US and international perspectives. Crit Care 2005; 9 (Suppl. 05) S1-S9
• 15 Levi M. Disseminated intravascular coagulation: a disease-specific approach. Semin Thromb Hemost 2010; 36 (4) 363-365
• 16 Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60 (6) (Suppl) S3-S11
• 17 Society of Critical Care Medicine, Chinese Medical Association. [Guidelines for resuscitation of hypovolemic shock (2007)]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2008; 20 (3) 129-134
• 18 Gutierrez G, Reines HD, Wulf-Gutierrez ME. Clinical review: hemorrhagic shock. Crit Care 2004; 8 (5) 373-381
• 19 Gutierrez G, Marini C, Acero AL, Lund N. Skeletal muscle PO2 during hypoxemia and isovolemic anemia. J Appl Physiol 1990; 68 (5) 2047-2053
• 20 Gaarder C, Naess PA, Frischknecht Christensen E , et al. Scandinavian Guidelines—“The massively bleeding patient”. Scand J Surg 2008; 97 (1) 15-36
• 21 Lippi G, Cervellin G. Disseminated intravascular coagulation in trauma injuries. Semin Thromb Hemost 2010; 36 (4) 378-387
• 22 Lee JM, Grabb MC, Zipfel GJ, Choi DW. Brain tissue responses to ischemia. J Clin Invest 2000; 106 (6) 723-731
• 23 Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg 2002; 10 (6) 620-630
• 24 Reimer KA, Jennings RB. Energy metabolism in the reversible and irreversible phases of severe myocardial ischemia. Acta Med Scand Suppl 1981; 651: 19-27
• 25 Erecińska M, Silver IA. Tissue oxygen tension and brain sensitivity to hypoxia. Respir Physiol 2001; 128 (3) 263-276
• 26 Derikx JP, Matthijsen RA, de Bruïne AP , et al. Rapid reversal of human intestinal ischemia-reperfusion induced damage by shedding of injured enterocytes and reepithelialisation. PLoS ONE 2008; 3 (10) e3428
• 27 Huguet C, Gavelli A, Bona S. Hepatic resection with ischemia of the liver exceeding one hour. J Am Coll Surg 1994; 178 (5) 454-458
• 28 Kheirbek T, Kochanek AR, Alam HB. Hypothermia in bleeding trauma: a friend or a foe?. Scand J Trauma Resusc Emerg Med 2009; 17: 65
• 29 Cairns CB. Rude unhinging of the machinery of life: metabolic approaches to hemorrhagic shock. Curr Opin Crit Care 2001; 7 (6) 437-443
• 30 Lippi G, Banfi G. Exercise-related increase of cardiac troponin release in sports: An apparent paradox finally elucidated?. Clin Chim Acta 2010; 411 (7-8) 610-611
• 31 Hierholzer C, Billiar TR. Molecular mechanisms in the early phase of hemorrhagic shock. Langenbecks Arch Surg 2001; 386 (4) 302-308
• 32 Sethi AK, Sharma P, Mohta M, Tyagi A. Shock—a short review. Indian J Anaesth 2003; 47 (5) 345-359
• 33 Dutton RP. Current concepts in hemorrhagic shock. Anesthesiol Clin 2007; 25 (1) 23-34 , viii
• 34 Molitoris BA, Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney Int 2004; 66 (2) 496-499
• 35 Cervellin G, Comelli I, Lippi G. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med 2010; 48 (6) 749-756
• 36 Gross S. A System of Surgery: Pathological, Diagnostic, Therapeutic, and Operative. Philadelphia, PA: Henry C. Lea; 1862
• 37 Hinshaw LB, Cox BG. The Fundamental Mechanisms of Shock. New York, NY: Plenum Press; 1862
• 38 Kauvar DS, Lefering R, Wade CE. Impact of hemorrhage on trauma outcome: an overview of epidemiology, clinical presentations, and therapeutic considerations. J Trauma 2006; 60 (6, Suppl) S3-S11
• 39 Sharma OP, Hagler S, Oswanski MF. Prevalence of delayed hemothorax in blunt thoracic trauma. Am Surg 2005; 71 (6) 481-486
• 40 Dente CJ, Ustin J, Feliciano DV , et al. The accuracy of thoracic ultrasound for detection of pneumothorax is not sustained over time: a preliminary study. J Trauma 2007; 62 (6) 1384-1389
• 41 Cohen R, Woods H. Clinical and Biochemical Aspects of Lactic Acidosis. Boston, MA: Blackwell Scientific Publications; 1976
• 42 Levy B. Lactate and shock state: the metabolic view. Curr Opin Crit Care 2006; 12 (4) 315-321
• 43 Gunnerson KJ, Saul M, He S, Kellum JA. Lactate versus non-lactate metabolic acidosis: a retrospective outcome evaluation of critically ill patients. Crit Care 2006; 10 (1) R22
• 44 Lippi G, Montagnana M, Targher G. Higher random plasma glucose level is associated with increased plasma cardiac troponin in emergency department patients with suspected acute coronary syndrome. Am J Cardiol 2012; 109 (5) 775-776
• 45 Ceriotti F, Henny J, Queraltó J , et al; IFCC Committee on Reference Intervals and Decision Limits (C-RIDL); Committee on Reference Systems for Enzymes (C-RSE). Common reference intervals for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT) in serum: results from an IFCC multicenter study. Clin Chem Lab Med 2010; 48 (11) 1593-1601
• 46 Lippi G, Valentino M, Cervellin G. Laboratory diagnosis of acute pancreatitis: in search of the Holy Grail. Crit Rev Clin Lab Sci 2012; 49 (1) 18-31
• 47 Lippi G, Cervellin G. Degradation of troponin I in serum or plasma: mechanisms, and analytical and clinical implications. Semin Thromb Hemost 2012; 38 (2) 222-229
• 48 Lippi G, Plebani M. Neutrophil gelatinase-associated lipocalin (NGAL): the laboratory perspective. Clin Chem Lab Med 2012; 50 (9) 1483-1487
• 49 Cervellin G, di Somma S. Neutrophil gelatinase-associated lipocalin (NGAL): the clinician's perspective. Clin Chem Lab Med 2012; 50 (9) 1489-1493
• 50 Lippi G, Meschi T, Cervellin G. Inflammatory biomarkers for the diagnosis, monitoring and follow-up of community-acquired pneumonia: clinical evidence and perspectives. Eur J Intern Med 2011; 22 (5) 460-465
• 51 Favaloro EJ. Laboratory testing in disseminated intravascular coagulation. Semin Thromb Hemost 2010; 36 (4) 458-467
• 52 Ranucci M, Baryshnikova E, Colella D. Monitoring prohemostatic treatment in bleeding patients. Semin Thromb Hemost 2012; 38 (3) 282-291
• 53 Cervellin G, Benatti M, Carbucicchio A , et al. Serum levels of protein S100B predict intracranial lesions in mild head injury. Clin Biochem 2012; 45 (6) 408-411
• 54 Lippi G, Aloe R, Numeroso F, Cervellin G. The significance of protein S-100B testing in cardiac arrest patients. Clin Biochem 2011; 44 (8-9) 567-575
• 55 Shapiro MB, Jenkins DH, Schwab CW, Rotondo MF. Damage control: collective review. J Trauma 2000; 49 (5) 969-978
• 56 Rossaint R, Bouillon B, Cerny V , et al; Task Force for Advanced Bleeding Care in Trauma. Management of bleeding following major trauma: an updated European guideline. Crit Care 2010; 14 (2) R52
• 57 Committee on Fluid Resuscitation for Combat Casualties. Fluid Resuscitation: State of the Science for Treating Combat Casualties and Civilian Trauma (Report of the Institute of Medicine). Washington, DC: National Academies Press; 1999
• 58 Bickell WH, Wall Jr MJ, Pepe PE , et al. Immediate versus delayed fluid resuscitation for hypotensive patients with penetrating torso injuries. N Engl J Med 1994; 331 (17) 1105-1109
• 59 Cotton BA, Guy JS, Morris Jr JA, Abumrad NN. The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock 2006; 26 (2) 115-121
• 60 Mapstone J, Roberts I, Evans P. Fluid resuscitation strategies: a systematic review of animal trials. J Trauma 2003; 55 (3) 571-589
• 61 Morrison CA, Carrick MM, Norman MA , et al. Hypotensive resuscitation strategy reduces transfusion requirements and severe postoperative coagulopathy in trauma patients with hemorrhagic shock: preliminary results of a randomized controlled trial. J Trauma 2011; 70 (3) 652-663
• 62 Dutton RP, Mackenzie CF, Scalea TM. Hypotensive resuscitation during active hemorrhage: impact on in-hospital mortality. J Trauma 2002; 52 (6) 1141-1146
• 63 Tieu BH, Holcomb JB, Schreiber MA. Coagulopathy: its pathophysiology and treatment in the injured patient. World J Surg 2007; 31 (5) 1055-1064
• 64 Cannon W, Frawer J, Cowell E. The preventive treatment of wound shock. JAMA 1918; 70: 618-621
• 65 NATO. Emergency War Surgery. Third United States revision of the emergency war surgery NATO Handbook. Washington DC: US Department of Defense; 2004
• 66 Holcomb JB. Fluid resuscitation in modern combat casualty care: lessons learned from Somalia. J Trauma 2003; 54 (5, Suppl) S46-S51
• 67 Rotondo MF, Zonies DH. The damage control sequence and underlying logic. Surg Clin North Am 1997; 77 (4) 761-777
• 68 Alam HB, Bice LM, Butt MU , et al; Hemostatic Resuscitation Research Group. Testing of blood products in a polytrauma model: results of a multi-institutional randomized preclinical trial. J Trauma 2009; 67 (4) 856-864
• 69 McSwain NE, Champion HR, Fabian TC , et al. State of the art of fluid resuscitation 2010: prehospital and immediate transition to the hospital. J Trauma 2011; 70 (5, Suppl) S2-S10
• 70 Chiara O, Bucci L, Sara A, Bassi G, Vesconi S. Quality and quantity of volume replacement in trauma patients. Minerva Anestesiol 2008; 74 (6) 303-306
• 71 Kiraly LN, Differding JA, Enomoto TM , et al. Resuscitation with normal saline (NS) vs. lactated ringers (LR) modulates hypercoagulability and leads to increased blood loss in an uncontrolled hemorrhagic shock swine model. J Trauma 2006; 61 (1) 57-64 , discussion 64–65
• 72 Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R ; SAFE Study Investigators. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N Engl J Med 2004; 350 (22) 2247-2256
• 73 Ogilvie MP, Pereira BMT, McKenney MG , et al. First report on safety and efficacy of hetastarch solution for initial fluid resuscitation at a level 1 trauma center. J Am Coll Surg 2010; 210 (5) 870-880 , 880–882
• 74 Perner A, Haase N, Guttormsen AB , et al; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med 2012; 367 (2) 124-134
• 75 Gross D, Landau EH, Klin B, Krausz MM. Quantitative measurement of bleeding following hypertonic saline therapy in 'uncontrolled' hemorrhagic shock. J Trauma 1989; 29 (1) 79-83
• 76 Krausz MM, Landau EH, Klin B, Gross D. Hypertonic saline treatment of uncontrolled hemorrhagic shock at different periods from bleeding. Arch Surg 1992; 127 (1) 93-96
• 77 Kauvar DS, Holcomb JB, Norris GC, Hess JR. Fresh whole blood transfusion: a controversial military practice. J Trauma 2006; 61 (1) 181-184
• 78 Bombeli T, Spahn DR. Updates in perioperative coagulation: physiology and management of thromboembolism and haemorrhage. Br J Anaesth 2004; 93 (2) 275-287
• 79 Valeri CR, Cassidy G, Pivacek LE , et al. Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion 2001; 41 (8) 977-983
• 80 Ciesla DJ, Moore EE, Johnson JL, Burch JM, Cothren CC, Sauaia A. A 12-year prospective study of postinjury multiple organ failure: has anything changed?. Arch Surg 2005; 140 (5) 432-438 , discussion 438–440
• 81 Dewar DC, Butcher NE, King KL, Balogh ZJ. Post injury multiple organ failure. Trauma 2011; 13: 81-91
• 82 Napolitano L. Cumulative risks of early red blood cell transfusion. J Trauma 2006; 60 (6, Suppl) S26-S34
• 83 Offner PJ, Moore EE, Biffl WL, Johnson JL, Silliman CC. Increased rate of infection associated with transfusion of old blood after severe injury. Arch Surg 2002; 137 (6) 711-716 , discussion 716–717
• 84 Friese RS, Sperry JL, Phelan HA, Gentilello LM. The use of leukoreduced red blood cell products is associated with fewer infectious complications in trauma patients. Am J Surg 2008; 196 (1) 56-61
• 85 Nathens AB, Nester TA, Rubenfeld GD, Nirula R, Gernsheimer TB. The effects of leukoreduced blood transfusion on infection risk following injury: a randomized controlled trial. Shock 2006; 26 (4) 342-347
• 86 Lier H, Krep H, Schroeder S, Stuber F. Preconditions of hemostasis in trauma: a review. The influence of acidosis, hypocalcemia, anemia, and hypothermia on functional hemostasis in trauma. J Trauma 2008; 65 (4) 951-960
• 87 Vivien B, Langeron O, Morell E , et al. Early hypocalcemia in severe trauma. Crit Care Med 2005; 33 (9) 1946-1952
• 88 Lozano ML, Rivera J, Gónzález-Conejero R, Moraleda JM, Vicente V. Loss of high-affinity thrombin receptors during platelet concentrate storage impairs the reactivity of platelets to thrombin. Transfusion 1997; 37 (4) 368-375
• 89 Shakur H, Roberts I, Bautista R , et al; CRASH-2 trial collaborators. 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 2010; 376 (9734) 23-32
• 90 Roberts I, Shakur H, Afolabi A , et al; CRASH-2 collaborators. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet 2011; 377 (9771) 1096-1101 , 1101, e1–e2
• 91 Paran H, Gutman M, Mayo A. The effect of aprotinin in a model of uncontrolled hemorrhagic shock. Am J Surg 2005; 190 (3) 463-466
• 92 Levy JH. Antifibrinolytic therapy: new data and new concepts. Lancet 2010; 376 (9734) 3-4
• 93 Bolliger D, Görlinger K, Tanaka KA. Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology 2010; 113 (5) 1205-1219
• 94 Hirshberg A, Dugas M, Banez EI, Scott BG, Wall Jr MJ, Mattox KL. Minimizing dilutional coagulopathy in exsanguinating hemorrhage: a computer simulation. J Trauma 2003; 54 (3) 454-463
• 95 Gonzalez EA, Moore FA, Holcomb JB , et al. Fresh frozen plasma should be given earlier to patients requiring massive transfusion. J Trauma 2007; 62 (1) 112-119
• 96 Davenport R, Curry N, Manson J , et al. Hemostatic effects of fresh frozen plasma may be maximal at red cell ratios of 1:2. J Trauma 2011; 70 (1) 90-95 , discussion 95–96
• 97 Stinger HK, Spinella PC, Perkins JG , et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. J Trauma 2008; 64 (2) (Suppl) S79-S85 , discussion S85
• 98 MacLennan S, Williamson LM. Risks of fresh frozen plasma and platelets. J Trauma 2006; 60 (6) (Suppl) S46-S50
• 99 O'Shaughnessy DF, Atterbury C, Bolton Maggs P , et al; British Committee for Standards in Haematology, Blood Transfusion Task Force. Guidelines for the use of fresh-frozen plasma, cryoprecipitate and cryosupernatant. Br J Haematol 2004; 126 (1) 11-28
• 100 Practice Guidelines for blood component therapy: A report by the American Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996; 84 (3) 732-747
• 101 Lippi G, Favaloro EJ. Recombinants in thrombosis and hemostasis: from basic research to clinical therapy. Semin Thromb Hemost 2010; 36 (5) 471-476
• 102 Franchini M, Montagnana M, Targher G, Zaffanello M, Lippi G. The use of recombinant factor VIIa in liver diseases. Blood Coagul Fibrinolysis 2008; 19 (5) 341-348
• 103 Franchini M, Franchi M, Bergamini V , et al. The use of recombinant activated FVII in postpartum hemorrhage. Clin Obstet Gynecol 2010; 53 (1) 219-227
• 104 Franchini M, Targher G, Lippi G. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 2011; 364 (6) 575 , author reply 575–576
• 105 Franchini M, Lippi G. Recombinant activated factor VII: mechanisms of action and current indications. Semin Thromb Hemost 2010; 36 (5) 485-492
• 106 Dutton RP, McCunn M, Hyder M , et al. Factor VIIa for correction of traumatic coagulopathy. J Trauma 2004; 57 (4) 709-718 , discussion 718–719
• 107 Boffard KD, Riou B, Warren B , et al; NovoSeven Trauma Study Group. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma 2005; 59 (1) 8-15 , discussion 15–18
• 108 Dutton RP, Parr M, Tortella BJ , et al; CONTROL Study Group. Recombinant activated factor VII safety in trauma patients: results from the CONTROL trial. J Trauma 2011; 71 (1) 12-19
• 109 Wafaisade A, Lefering R, Maegele M , et al; TraumaRegister der Deutschen Gesellschaft für Unfallchirurgie. Recombinant factor VIIa for the treatment of exsanguinating trauma patients: a matched-pair analysis from the Trauma Registry of the German Society for Trauma Surgery. Unfallchirurg 2012; (e-pub ahead of print). DOI: 10.1007/s00113-011-2146-z
• 110 Morel N, Chabarttier C, Merson L , et al. Advantage of using a recombinant activated factor VII in traumatic haemorrhagic shock: The Bordeaux experience. J Emerg Trauma Shock 2012; 5 (2) 143-148
• 111 Koh YR, Cho SJ, Yeom SR , et al. Evaluation of recombinant factor VIIa treatment for massive hemorrhage in patients with multiple traumas. Ann Lab Med 2012; 32 (2) 145-152
• 112 Simpson E, Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev 2012; 3: CD005011
• 113 Shibeko AM, Woodle SA, Lee TK, Ovanesov MV. Unifying the mechanism of recombinant FVIIa action: dose dependence is regulated differently by tissue factor and phospholipids. Blood 2012; 120 (4) 891-899
• 114 Tobin JM, Varon AJ. Update in trauma anesthesiology: perioperative resuscitation management. Anesth Analg 2012; (e-pub ahead of print). DOI: 10.1213/ANE.0b013e3182639f20.
• 115 Davidson GH, Hamlat CA, Rivara FP, Koepsell TD, Jurkovich GJ, Arbabi S. Long-term survival of adult trauma patients. JAMA 2011; 305 (10) 1001-1007