sono Massive Hood vanetusion UpToDate” @ Wolters Kluwer Official reprint from UpToDate® eatin] www.uptodate.com ©2014 UpToDate® Massive blood transfusion Author Section Editor Deputy Editor John R Hess, MD, MPH Arthur J Silvergleid, MD Jennifer S Timauer, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2014, | This topic last updated: Apr 24, 2013, INTRODUCTION — Massive transfusion, historically defined as the replacement by transfusion of 10 units of red cells in 24 hours, is a response to massive and uncontrolled hemorhage. With more rapid and effective therapy, definitions such as five units over three hours are more effective in identifying patients needing rapid issue of blood products for serious injuries because of uncontrolled hemorrhage. Such transfusion episodes are associated with a number of hemostatic and metabolic complications [1]. Massive transfusion involves the selection of the appropriate amounts and types of blood components to be administered, and requires consideration of a number of issues including volume status, tissue oxygenation, management of bleeding and coagulation abnormalities, as well as changes in ionized calcium, potassium, and acid-base balance. ‘An overview of the Acute Trauma Life Support approach to massive transfusion with crystalloid fluids and packed red cells is presented here [2,3], as is the “damage control” approach using red cells and plasma in a 1:1 ratio [4]. Other issues related to the use of blood products are discussed separately. (See "Use of blood products in the critically ill” and "Indications and hemoglobin thresholds for red blood cell transfusion in the adult" and "Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters" and "Initial evaluation and management of shock in adult trauma*.) EPIDEMIOLOGY — The most common situation leading to massive transfusion is trauma. Other situations leading to massive transfusion, such as ruptured abdominal aortic aneurism, liver transplant, and obstetric catastrophes are less frequent. In a review of experience in a major trauma center during the year 2000, 8 percent of all admitted patients were given red cells, 3 percent received more than 10 units of red cells during their admission, and 1.7 percent received 10 units in the first 24 hours [5]. More recently, an NIH-sponsored collaboration of trauma centers studying the cytokine response to massive transfusion and other groups reported that the fraction of all patients receiving red cells who go on to receive 10 units of red cells has decreased by 40 percent as more plasma and platelets are given earlier [6]. Taken together, these data suggest that most injured patients never need massive transfusion and can be treated based on physical assessment and laboratory tests, but approximately 1.7 percent of the most severely injured will require more prompt treatment of coagulopathy, which in tum reduces total blood use in some of them. Appropriate care requires knowing both forms of resuscitation and when to use them, (See “Initial evaluation and management of shock in adult trauma".) RED CELL AND VOLUME REPLACEMENT — Correction of the deficit in blood volume with crystalloid volume expanders will generally maintain hemodynamic stability, while transfusion of red cells is used to improve and maintain tissue oxygenation [7,8]. Each unit of packed red blood cells (RBCs) contains approximately 200 mL of red cells and, in an adult, will rise the hematocrit by roughly 3 to 4 percentage points unless there is continued bleeding. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult’,) At rest, oxygen delivery is normally four times oxygen consumption, indicating the presence of an enormous reserve, Thus, if intravascular volume is maintained during bleeding and cardiovascular stalus is not impaired, oxygen delivery will theoretically be adequate until the hematocrit (packed cell volume) falls below 10 percent This is because adequate cardiac output plus increased oxygen extraction can compensate for the decrease in arterial oxygen content. However, increasing cardiac work to increase output requires more oxygen, so the “critical point” where oxygen consumption becomes delivery dependent is higher. epihwwustodate.com cortentsimassive-lood transfusion opicKey=HEMEY2F78618elapsedTimeMs=38scurce=see linkBviow=prinesplayeeM... 1110sono Massive Hood vanetusion ‘The American Society of Anesthesiologists recommends that hemoglobin below 6 g/dL. be avoided in healthy individuals, and notes that higher values are necessary in those with active cardiovascular disease. In healthy medical student volunteers acutely cytapheresed to hemoglobin concentrations of 5.3 g/dL, equivalent to a hematocrit of 16 percent, correct answers to digit-symbol reversal questions and the strength of retinal-evoked potentials were reduced, but promptly improved with retum of their own fresh or stored RBCs [9,10]. ‘Oxygen release by transfused stored RECs is diminished compared with normal RBCs. Storage reduces 2,3- bisphosphoglycerate (2,3-BPG) levels, leading to a leftward shift of the lower end of the oxyhemoglobin dissociation curve (2,3-BPG binds to deoxyhemoglobin). This abnormality, however, has not been shown to be clinically important, as the transfused RBCs regenerate 2,3-8PG to normal levels within 6 to 24 hours after transfusion, and most oxygen delivery occurs from the unaffected upper end of the oxygen binding curve. (See Red blood cell transfusion in adults: Storage, specialized modifications, and infusion parameters", section on '2.3 BPG concentration’) ‘The above considerations, however, represent the optimal clinical response to massive RBC loss with adequate volume replacement. An approach to the use of plasma and RBC transfusions in adult patients suffering from shock due to loss of circulating blood volume secondary to hemorrhage is presented below and separately. (See ‘Trauma patients’ below and “Initial evaluation and management of shock in adult trauma’, section on ‘Transfusion of red blood cells'.) ALTERATIONS IN THE COAGULATION SYSTEM — A patient being massively transfused may have coagulopathy because of activation and consumption of coagulation factors secondary to tissue trauma, such as massive head injury or muscle damage, or have reduced activity of coagulation factors from prolonged shock, hypoxia, hypothermia, or failure to clear activation peptides that act as competitive inhibitors [11]. Such trauma-associated coagulopathy can be diagnosed as acute disseminated intravascular coagulation (acute DIC) when there is microvascular oozing, prolongation of the PT and aPTT in excess of that expected by dilution, together with significant thrombocytopenia, low fibrinogen levels, and increased levels of D-dimer. (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults", section on ‘Acute versus chronic DIC.) Even if coagulopathy diagnostic of acute DIC does not exist and coagulation parameters are normal before blood is replaced, coagulation abnormalities may be induced by the dilutional effects of blood replacement on coagulation proteins and the platelet count [12-14]. This occurs because packed red cell transfusions are essentially devoid of plasma and platelets, which are removed after collection in the blood component manufacturing process. Many patients who suffer massive trauma present to a trauma center with a coagulopathy of trauma that does not meet the diagnostic criteria for acute DIC or dilutional coagulopathy. This coagulopathy is caused by Widespread tissue injury/trauma and shock, and their associated physiologic changes (ie, acidosis, hypothermia, consumption of coagulant proteins, and fibrinolysis) combined with extensive blood loss and the dilutional effects of physiologic vascular refill and fluid replacement therapy [15] Effects of acidosis and hypothermia — Both acidosis and hypothermia interfere with the normal functioning of the coagulation system. As examples: = Acidosis (ie, excess protons) specifically interferes with the assembly of coagulation factor complexes involving calcium and negatively-charged phospholipids. As a result, the activity of the factor XalValprothrombinase complex is reduced by 50, 70, and 80 percent at pHs of 7.2, 7.0, and 6.8, respectively [16]. The resulting delayed production and reduced concentrations of generated thrombin lead to delayed fibrin production, altered fibrin structure, and increased susceptibility to fibrinolysis [17] The interaction of acidosis with coagulopathy to increased trauma mortality has been widely recognized (See "Coaqulopathy associated with trauma’, section on ‘Acidosis'.) + Hypothermia reduces the enzymatic activity of plasma coagulation proteins, but has a greater effect by preventing the activation of platelets via traction on the glycoprotein Ib/IX/V complex by von Willebrand factor [18]. In tests of shear-dependent platelet activation, this pathway stops functioning in 50 percent of individuals at 30° C and is markedly diminished in most of the rest. This profound effect on platelet- epihwwustodte.com cortntsimassive-lood transfusion opicKey=HEMEY2F78618clapsedTimeMs=38scurce=se9_linkBviow=prinesplayeeM... 2110sono Massive Hood vanetusion mediated primary hemostasis means that massive bleeding in conjunction with a core temperature of <30° C is rarely survived [19]. The onset of this effect is seen at core temperatures of 34°C and below. Coagulation proteins — The replacement of blood loss with red cells and a crystalloid volume expander will result in gradual dilution of plasma clotting proteins, leading to prolongation of the prothrombin time (PT) and the activated partial thromboplastin time (aPTT). In an adult, there will be an approximate 10 percent decrease in the concentration of clotting proteins for each 500 mL of blood loss that is replaced, Additional bleeding based solely on dilution can occur when the level of individual coagulation proteins falls to 25 percent of normal. This usually requires 8 to 10 units of red cells in an adult, Thus, the PT, aPTT, and fibrinogen or a viscoelastic test of coagulation (also called point of care testing) (table 4) should be monitored in patients receiving massive blood transfusions of this magnitude. (See "Clinical use of coagulation tests”, section on ‘Evaluation of abnormal clotting times' and "Clinical use of coagulation tests", section on 'Point-of-care testing’) ‘Two to eight units of fresh frozen plasma (FFP) should be given if the values exceed 1.5 times control. Each unit of FFP might be expected to increase the clotting protein levels by 10 percent in an adult, but because of losses in product preparation, storage, and of transfused factors to the interstitial space, typical increments are of the order of 2.5 percent [20]. Cryoprecipitate or, when available, virus inactivated fibrinogen concentrate, may be used when fibrinogen levels are critically low (ie, <100 mg/dL) [2]. (See “Clinical use of plasma components” and "Disorders of fibrinogen’, section on 'Cryoprecipitate and FFP" and "Disorders of fibrinogen’, section on ‘Fibrinogen concentrate.) Platelet count — A similar dilutional effect on the platelet concentration can be seen with massive transfusion [21]. In an adult, each 10 to 12 units of transfused RBCs are associated with a 50 percent fall in the platelet ‘count; thus, significant thrombocytopenia can be seen after 10 to 20 units of blood, with platelet counts below 50,000/microL. For replacement therapy in this setting, six units of whole blood derived platelets or one apheresis concentrate should be given to an adult; each unit should increase the platelet count by 5000/microl. ‘r 30,000/microL for a full six unit adult dose. (See "Clinical and laboratory aspects of platelet transfusion therapy", section on ‘Massive blood loss'.) Monitoring recommendations — In the massively transfused patient, assumptions about possible dilutional effects of RBC transfusion should be confirmed by measurement of the PT, aPTT, and platelet count or a viscoelastic test after the administration of every five to seven units of red cells. Replacement therapy should be based on these parameters rather than on any formula (eg, one unit of fresh frozen plasma (FFP) for every four units of red cells), except in patients with severe trauma and possibly obstetric hemorthage, (See ‘Obstetric hemorrhage’ below.) SPECIAL SCENARIOS Trauma patients — While replacement therapy with plasma, platelets, and red cells should not generally be based upon any set formula, results from a number of observational studies suggest that patients with severe trauma, massive blood replacement, and coagulopathy have improved survival when the ratio of transfused FFP (units) to transfused platelets (units) to red cells (units) approaches 1:1:1 (ie, the “damage control” approach) [22-29]. (See "Clinical and laboratory aspects of platelet transfusion therapy’, section on ‘Massive blood loss" and “Initial evaluation and management of shock in adult trauma’ section on ‘Transfusion of platelets’.) ‘The physiology supporting the 1:1:1 approach derives from the existence of the acute coagulopathy of trauma and the dilute nature of conventional blood products. Patients who present with uncontrolled hemorhage and shock have typically lost 30 to 40 percent of their blood volume. Conventional resuscitation with crystalloid will rapidly lead to greater than 50 percent dilution of coagulation factors and a diminution of thrombin generation. Resuscitation with RBCs in additive solution, plasma, and platelets at 1:1:1 unit ratios means that the actual blood being given has a hematocrit of 29 percent, a coagulation factor concentration of 65 percent of normal, and a platelet count of 88 x 10%/L. Because 10 percent of the RBC and 30 percent of the platelets administered will not circulate, the effective concentrations are hematocrit of 26 percent, plasma coagulation factor concentration of 65 percent, and platelet count of 55x 109/L. Thus, giving blood products, and nothing but epihwarustote.com cortntsimassive- lon ransusion"topcKey=HEME%2F78618clapsedTimeMs=3Bscurce=s69 linkBviow=prinBdisrayeeM 30sono Massive Hood vanetusion blood products, barely keeps levels above conventional transfusion triggers. More of any one product merely dilutes the other two, such that giving two units of RBC for every unit of plasma and platelets (2:1:1) leads to a hematocrit of 40 percent, plasma coagulation factor concentration of 52 percent, and platelet count of 55 x 10°/L; and after storage related losses, a hematocrit of 36 percent, plasma concentration of coagulation factors of 52 percent, and platelet count of 37 x 109/L. Any crystalloid solution administered will further dilute all three blood components. Clinical studies that have shown a benefit for the 1:1:1 approach in massively injured and rapidly bleeding patients include: = A retrospective study of 246 patients who presented to an Army combat support hospital in Iraq has produced some data to evaluate the merits of this regimen [22]. When patients who received massive transfusion were stratified by transfusion therapy regimen, patients who received a high ratio of FFP to red cells (median of 1:1.4) had a survival rate of 81 percent, compared with 66 percent for those with an intermediate ratio (median 1:2.5) and 35 percent for those who received a low ratio of FFP to red cells, (median of 1:8). + Ina retrospective study of 467 massively transfused trauma patients, 30-day survival was increased in patients transfused at a high plasma:RBC ratio (je, 21:2) as well as in those transfused at a high platelet: RBC ratio (ie, 21:2) [23]. The combination of high plasma and high platelet to RBC ratios was associated with decreased truncal hemorrhage and increased six-hour, 24-hour, and 30-day survivals, with no change in deaths due to multiple organ failure, + Ina retrospective study of 694 massively transfused trauma patients who did not receive fresh whole blood, those receiving a high ratio of apheresis platelets (equivalent to six units of pooled platelets) per stored red cell unit (je, ratio 21:8) had a higher 24-hour survival (95 percent) compared with those receiving a medium (je, ratio 1:16 to 1:8, 87 percent) or a low ratio (ie, <1:16, 64 percent) [28]. On multivariate analysis, higher plasma:ted cell ratios and higher apheresis platelets:red cell ratios were both independently associated with improved survival at both 24 hours and 30 days. ‘Such observations have led these and other authors to recommend that patients who have sustained severe traumatic injuries and/or who are likely to require massive transfusion receive a 1:1:1 ratio of FFP to platelets to RBCs at the outset of their resuscitation and transfusion therapy [22:29]. Since there are only a limited number of retrospective studies in patients requiring massive transfusion, the value of this approach is still controversial and remains to be proven. A multicenter, prospective, randomized clinical trial is in progress [30] (See ‘Summary and recommendations’ below and “Initial evaluation and management of shock in adult trauma’, section on ‘Evaluation and management’) For the subset of patients who present with widespread tissue trauma (as in combat injuries) and who present with coagulopathy or the high likelihood of coagulopathy, an approach using plasma as the primary resuscitation fluid has been advocated by the United States military. The treatment of such patients is discussed in depth separately. (See "Coagulopathy associated with trauma’, section on 'Treatment'.) Obstetric hemorrhage — Gravid and parturient women are hypercoagulable with compensatory hyperfibrinolysis. When vascular disruption leads to massive bleeding, those with low fibrinogen are at increased risk for bleeding [34]. (See "Placental abruption: Management", section on ‘Treatment of disseminated intravascular coagulation’ and "Disseminated intravascular coagulation during pregnancy") Liver disease — Liver disease not only leads to the reduced production of normal coagulation factors, but to the production of abnormal factors such as dysfunctional vitamin K-dependent factors and the failure to clear activation fragments of coagulation factors, which can act as competitive inhibitors of coagulation enzymes by ‘occupying binding sites [32]. The presence of such inhibitors of coagulation can reduce the effectiveness of conventional treatment. (See “Coagulation abnormalities in patients with liver disease" ) COMPLICATIONS OF CITRATE INFUSION — Large amounts of citrate are given with massive blood transfusion, since blood is anticoagulated with sodium citrate and citric acid [33]. Metabolic alkalosis and a decline in the plasma free calcium concentration are the two potential complications of citrate infusion and epihwwustodate.com contentsimassive-lood transfusion opicKey=HEMEY2F78618clapsedTimeMs=38scurce=se9 linkBviow=prinisplayeeM... 410sono Massive Hood vanetusion accumulation. Metabolic alkalosis — The pH of a unit of blood at the time of collection is 7.10 when measured at 37°C due to citric acid present in the anticoagulant/preservative in the collection bag. The pH then falls 0.1 pH unit/week due to the production of lactic and pyruvic acids by the red cells, Acidosis does not develop in a massively bleeding patient even if “acidic” blood is infused as long as tissue perfusion is restored and maintained. In this setting, the metabolism of each mmol of citrate generates 3 mEq of bicarbonate (for a total of 23 meq of bicarbonate in each unit of blood). As a result, metabolic alkalosis can occur if the renal ischemia or underlying renal disease prevents the excess bicarbonate from being excreted in the urine. This may be accompanied by hypokalemia as potassium moves into cells in exchange for hydrogen ions that move out of the cells to minimize the degree of extracellular alkalosis [34,35]. (See "Potassium balance in acid-base disorders”) Free hypocalcemia — Citrate binding of ionized calcium can lead to a clinically significant fall in the plasma free calcium concentration. (See "Relation between total and ionized serum calcium concentrations". This change can lead to paresthesias andior cardiac arthythmias in some patients [36]. (See "Clinical manifestations of hypocalcemia’, section on ‘Acute manifestations’. ) Recommendations for citrate infusion — By extrapolation from animal studies, it is possible to calculate the maximum transfusion rate that would permit a normal liver to metabolize excess citrate, thereby avoiding hypocalcemia. The maximum citrate infusion rate should be 0.02 mmol/kg per minute (since this represents the maximum rate of citrate metabolism) and the citrate concentration in whole blood is 15 mmol/L (0,015 mmolimL.). Thus: Maximum citrate infusion rate (mmolikg per min) = (mmol citrate per mL of blood x mi of blood infused per min) + wt (kg) ML of blood infused per min = (0.02 + 0,015) x wt (kg) = 1.33 x wt (kg) For a 50 kg recipient with normal hepatic function and perfusion, the maximum rate of blood transfusion to avoid citrate toxicity is 66.5 mL/min, which is equal to 8.9 units of whole blood per hour (450 mL per unit) and 26.7 units of red cells per hour (approximately 150 mL per unit). Thus, significant hypocalcemia should not develop in this setting except under extreme circumstances. However, the risk is substantially greater in a patient with either preexisting liver disease or ischemia-induced hepatic dysfunction. In such patients, the plasma ionized calcium concentration should be monitored and calcium replaced with either calcium chloride or calcium gluconate if ionized hypocalcemia develops: = If 10 percent calcium gluconate is used, 10 to 20 mL should be given intravenously (into another vein) for each 500 mL of blood infused. = If 10 percent calcium chloride is used, only 2 to § mL per 500 mL of blood should be given. Calcium chloride may be preferable to calcium aluconate in the presence of abnormal liver function, since citrate metabolism is decreased, resulting in slower release of ionized calcium [2]. Care must be taken to avoid administering too much calcium and inducing hypercalcemia, ideally by monitoring the ionized calcium ‘concentration, PREVENTION OF HYPOTHERMIA — A high capacity commercial blood warmer should be used to warm blood components toward body temperature when more than three units are transfused. Rapid transfusion of multiple units of chilled blood may reduce the core temperature abruptly and can lead to cardiac arrhythmias [37]. Six units of RBCs at 4°C will reduce the body temperature of a 70 kg man by 1°C. This heat loss can be additive with the evaporative heat loss associated with an open abdomen or other body cavity which, by itself, can lead to a 1°C decrease in core temperature in 40 minutes. Thus, 10 units of cold blood products and an hour of surgery can lead to a 3°C drop in core temperature and hypothermic coagulopathy. PREVENTION OF HYPERKALEMIA — Infants and patients with renal impairment may develop hyperkalemia because of potassium leakage due to prolonged blood storage or irradiation [37]. (See "Red blood coll transfusion in adults: Storage, specialized modifications, and infusion parameters", section on ‘Potassium epihwwustodate.com contnts/massve-lood transfusion RopicKey=HES .2FT88tBelapsedTimeMs=38scurce=se0 JinkBview=printBdispayedVi... 5110sortiz0t6 Massive ood varstision leakage.) In storage, the supematant of RBCs increases in [K*] by 1 mEq/day, increasing from approximately 3 mEq/L at the time of donation to 45 mEq/L during 42 days of storage. Irradiation can increase this rate to 1.5 mEg/day. Nevertheless, because the volume of suspending solution in a unit of red cells in additive solution is ‘small (150 mL), the actual amount of free K* infused with a unit of RBC is only approximately 7 mEq, and this, is rapidly pumped back into the cells as they warm. As a result, potassium is only a problem when long-stored red cells are infused directly into the central circulation at high concentrations, as occurs with blood-primed cardiopulmonary bypass machines, high volume transfusion devices, or infants transfused through umbilical catheters. In these patients, the following steps can be used to minimize the risk of hyperkalemia + Select only red cells collected less than 5 or 10 days prior to transfusion, = Any unit of red cells can be washed immediately before infusion to remove extracellular potassium. SUMMARY AND RECOMMENDATIONS + The management of the patient who is being massively transfused requires careful and ongoing consideration of a number of complex physiological relationships. There is no clear threshold for hematocrit, platelet count, or coagulation factor deficiency below which blood use is futile. The primary concem is correction of ischemia, which can be accomplished at the outset by aggressive volume expansion to maintain perfusion pressure as blood is being readied for infusion. (See ‘Red cell and volume replacement’ above and "Initial evaluation and management of shock in adult trauma", section on Evaluation and management’) = As volume is replaced, attention must be paid to coagulation parameters, platelet count, and metabolic status. (See ‘Alterations in the coagulation system! above and ‘Complications of citrate infusion’ above.) + The coagulation system should be frequently monitored with measurements of the PT, aPTT, fibrinogen concentration, and platelet count or a viscoelastic measure (also called point of care testing) (table 1), preferably after each five units of blood replaced. If the PT and aPTT exceed 1.5 times the control value, the patient should be transfused with at least two units of fresh frozen plasma. If the platelet count falls below 50,000/microL, six units of random donor platelets, or one unit of apheresis platelets, should be given. (See ‘Alterations in the coagulation system’ above and "Clinical use of coagulation tests", section on ‘Evaluation of abnormal clotting times! and "Clinical use of coagulation tests", section on 'Point-of-care testing.) = The best approach to blood transfusion in trauma is unknown. Transfusions are given based upon the patient's injuries and response to the initial transfusions, with attention being paid to any underlying cardiopulmonary disease. In some cases where there is insufficient time to obtain laboratory values to guide transfusion, it may be necessary to use the “damage control” approach of transfusing red blood cells, platelets, and plasma in a set ratio. (See ‘Trauma patients’ above.) For the subset of patients who present with widespread tissue trauma (as in combat injuries) and who present with coagulopathy or the high likelihood of coagulopathy, an approach using plasma as the primary resuscitation fluid has been advocated by the United States military. The treatment of such patients is discussed in depth separately. (See "Coagulopathy associated with trauma", section on ‘Treatment’ + Management of massive transfusion in other special scenarios (eg, obstetric hemorrhage, liver disease) is discussed separately. (See "“Coaaulation abnormalities in patients with liver disease" and "Placental abruption: Management".) = Ablood warmer should be used whenever more than three units are transfused, Hypothermia should be either avoided or minimized. (See !Prevention of hypothermia’ above.) = Acid-base balance and the plasma ionized calcium and potassium levels should be periodically epihwuustodate.com cortntsimassve-lood transfusion opicKey=HEMEY2F78618elapsedTimeMs=38scurce=see_linkBviow=prinisplayecM... 610sono Massive toad varetusion monitored, particularly in patients with coexistent liver or renal disease or in those with massive hemorhage and low cardiac output [35]. (See ‘Complications of citrate infusion’ above and ‘Prevention of hyperkalemia’ above.) Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Collins JA. Problems associated with the massive transfusion of stored blood. Surgery 1974; 75:274. 2. British Committee for Standards in Haematology, Stainsby D, MacLennan S, et al. Guidelines on the management of massive blood loss. Br J Haematol 2006; 135:634, 3. Committee on Trauma, American College of Surgeons. ATLS: Advanced Trauma Life Support Program for Doctors, 8th ed, American College of Surgeons, Chicago 2008. 4. Holcomb JB, Jenkins D, Rhee P, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007; 62:307. 5. Como JJ, Dutton RP, Scalea TM, et al. Blood transfusion rates in the care of acute trauma. Transfusion 2004; 44:809, 6. Kautza BC, Cohen MJ, Cuschieri J, et al. Changes in massive transfusion over time: an early shift in the right direction? J Trauma Acute Care Surg 2012; 72:106. 7. Stehling L. Fluid replacement in massive transfusion. Massive Transfusion AABB 1994; 1 8. Lundsgaard-Hansen P. Treatment of acute blood loss, Vox Sang 1992; 63:241. 9. Weiskopf RB, Kramer JH, Viele M, et al. Acute severe isovolemic anemia impairs cognitive function and memory in humans. Anesthesiology 2000; 92:1646. 10. Weiskopf RB, Feiner J, Hopf H, et al. Fresh blood and aged stored blood are equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans. Anesthesiology 2006; 104:911 11. Hardy JF, De Moerloose P, Samama M, Groupe d'intérét en Hémostase Périopératoire. Massive transfusion and coagulopathy: pathophysiology and implications for clinical management. Can J Anaesth 2004; 51:293, 12. Miller RD, Robbins TO, Tong MJ, Barton SL. Coagulation defects associated with massive blood transfusions, Ann Surg 1971; 174:794 13. Counts RB, Haisch C, Simon TL, et al. Hemostasis in massively transfused trauma patients. Ann Surg 1979; 190:91 14. Mannucci PM, Federici AB, Sirchia G. Hemostasis testing during massive blood replacement. A study of 172 cases. Vox Sang 1982; 42:113 15, Hess JR. Blood and coagulation support in trauma care, Hematology Am Soc Hematol Educ Program 2007; :187. 16. Meng ZH, Wolberg AS, Monroe DM 3rd, Hoffman M. The effect of temperature and pH on the activity of factor Vila: implications for the efficacy of high-dose factor Vila in hypothermic and acidotic patients. J ‘Trauma 2003; 55:886 17. Cosgriff N, Moore EE, Sauaia A, et al, Predicting life-threatening coagulopathy in the massively transfused trauma patient: hypothermia and acidoses revisited. J Trauma 1997; 42:857. 18. Kermode JC, Zheng Q, Milner EP. Marked temperature dependence of the platelet calcium signal induced by human von Willebrand factor. Blood 1999; 94:199, 19. Jurkovich GJ, Greiser WB, Luterman A, Curreri PW. Hypothermia in trauma victims: an ominous predictor of survival. J Trauma 1987; 27:1019, 20. Stanworth SJ, Walsh TS, Prescott RJ, et al. A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time. Crit Care 2011; 15:R108, 21. Reed RL Jr, Ciavarella D, Heimbach DM, et al. Prophylactic platelet administration during massive transfusion. A prospective, randomized, double-blind clinical study. Ann Surg 1986; 203:48. 22. Borgman MA, Spinella PC, Perkins JG, et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. J Trauma 2007; 63:805. 23, Holcomb JB, Wade CE, Michalek JE, et al, Increased plasma and platelet to red blood cell ratios, epihwwustodate.com contntsimassive- ond ransfsion topicKey=HEME%2F79618elapsedTimeMs=3Bscurcese9_linkBviow=prin&dsplayeeM... 7110sono 24, 31. 32. 33. 37. Massive ood vanstision improves outcome in 466 massively transfused civilian trauma patients. Ann Surg 2008; 248:447 Colton BA, Au BK, Nunez TC, et al. Predefined massive transfusion protocols are associated with a reduction in organ failure and postinjury complications. J Trauma 2009; 66:41 Shaz BH, Dente CJ, Nicholas J, et al, Increased number of coagulation products in relationship to red blood cell products transfused improves mortality in trauma patients. Transfusion 2010; 50:493. Inaba K, Lustenberger T, Rhee P, et al. The impact of platelet transfusion in massively transfused trauma patients. J Am Coll Surg 2010; 211:573. de Biasi AR, Stansbury LG, Dutton RP, et al. Blood product use in trauma resuscitation: plasma deficit versus plasma ratio as predictors of mortality in trauma (CME). Transfusion 2011; 51:1925. Perkins JG, Cap AP, Spinella PC, et al. An evaluation of the impact of apheresis platelets used in the setting of massively transfused trauma patients. J Trauma 2009; 66:S77 Johansson PI, Stensballe J, Rosenberg I, et al. Proactive administration of platelets and plasma for patients with a ruptured abdominal aortic aneurysm: evaluating a change in transfusion practice. Transfusion 2007; 47:593. ClinicalTrials.gov Identifier: NCT01545232. http://clinicaltrials. gov/ct2/show/NCT01545232 (Accessed on February 27, 2013). Simon L, Santi TM, Sacquin P, Hamza J. Pre-anaesthetic assessment of coagulation abnormalities in obstetric patients: usefulness, timing and clinical implications. Br J Anaesth 1997; 78:678 Monroe DM, Hoffman M. The coagulation cascade in cirrhosis. Clin Liver Dis 2009; 13:1 Dzik WH, Kirkley SA. Citrate toxicity during massive blood transfusion. Transfus Med Rev 1988; 2:76. 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; 65:951 Bruining HA, Boelhouwer RU, Ong GK. Unexpected hypopotassemia after multiple blood transfusions during an operation. Neth J Surg 1986; 38:48 Howland WS, Schweizer O, Carlon GC, Goldiner PL. The cardiovascular effects of low levels of ionized calcium during massive transfusion, Surg Gynecol Obstet 1977; 145:581 ‘Smith HM, Farrow SJ, Ackerman JD, et al. Cardiac arrests associated with hyperkalemia during red blood cell transfusion: a case series. Anesth Analg 2008; 106:1062. Topic 7931 Version 17.0 biphwwwustote.comicortenisimassive-lond-ransfsion oicKey=HEME%42F7931&elapsedTimeMs=38scurce=see linkBviewspriniBdspayecM anosono Massive Hood vanetusion GRAPHICS Various types of thromboelastograms Native TEG | Measures clot formation in the absence of a specific activator in either untreated Whole blood or in citrated whole blood after recalcification. Rapid-TEG | Tissue factor is used as the activator inducing clot formation via the extrinsic (rTEG) pathway. Compared with native TEG, rTEG gives a readout of clot characteristics within about 10 minutes. The corresponding RoTEM® test is the EXTEM. Kaolin-TEG | Phospholipid and kaolin are used to induce activation via the intrinsic pathway. ‘The corresponding RoTEM® test is the INTEM, which uses phospholipid and ellagic acid as activators. Heparinase | Simultaneous measurements can be performed comparing heparinase-treated treatment | blood with untreated blood to identify the effects of endogenous heparan sulfates, exogenous heparin and heparinoids. The corresponding RoTEM® assay is the HEPTEM, Platelet —_| Platelet mapping assesses platelet function via the cyclooxygenase and ADP/P2 mapping _| signaling pathways. The decrement in MA can be measured in the presence of platelet antagonists such as acetylsalicylic acid, dipyridamole, and clopidogrel and compared with the untreated MA. Fibrin ‘The RoTEM® FIBTEM test activates the extrinsic pathway in the presence of function | cytochalasin D, which is a cytoskeletal inhibitor of platelet activity. This test testing qualitatively assesses fibrinogen levels since the clot formation in this test is attributable to fibrin polymerization alone. TEG: thromboelastogram; ADP/P2: adenosine diphosphate/P2 receptor; MA: maximal amplitude. Graphic 55087 Version 2.0 epihwwustodte.com contntsimassive-lood transfusion opicKey=HEMEY2F78618clapsedTimeMs=38scurce=see linkBviow=prinesplayecM... 910sono Massive Hood vanetusion Disclosures Disclosures: John R Hess, MD, MPH Nothing to disclose. Arthur J Silvergleid, MD Nothing to disclose. Jennifer $ Timauer, MD Employee of UpToDate, Inc Contributor disclosures are reviewed for conficts of interest by the editorial group. When found, these are addressed by vetting through a mutlevel review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required ofall authors and must conform to UpToDate standards of evidence. 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