Massive Transfusion in Trauma

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1 Page 1 Massive Transfusion in Trauma Robert S. Harris, M.D. Atlanta, Georgia Definitions and Demographics Hemorrhage is the second most common cause of death following injury and trauma, and is responsible for 20-40% of deaths. For those patients who survive, a distinct minority (1-3%) is massively transfused. Although many definitions of massive transfusion have been discussed in the literature, massive transfusion is most commonly defined as replacement of at least one blood volume or transfusion of ten or more packed red blood cells (RBCs) within 24 hours. Other definitions include the acute administration of 4 units of blood with the anticipation of continuing hemorrhage, or replacement of 50% of blood volume within 2 hours. Major risk factors for massive transfusion (85% predictable with ROC curves) include hypotension (systolic blood pressure less than 110 mm Hg), tachycardia (heart rate greater than 105 beats per minute), anemia (hematocrit less than 32%) and acidemia (ph less than 7.25). A physical exam and point of care testing or arterial blood gas sample can inexpensively aid providers in predicting who will require a massive transfusion. Survival rates are improving in patients following massive transfusion. Traditionally, in the whole blood era, survival rates of 0-10% were common, even after only units of whole blood. These poor outcomes were likely due to exhaustion of platelets, which are non-functional in refrigerated blood after 24 hours, and secondary to diminished clotting factor activity over the storage period. Today, survival rates of 80% and 40-50% have been achieved following transfusion of 10 units of RBCs, and 40 units of RBCs, respectively. Patients have survived traumatic insults requiring more than 150 units of RBCs. Reasons for improved survival rates include damage control surgical techniques, better rewarming techniques, and two significant changes in transfusion management: blood component therapy and massive transfusion protocols (MTP). Management Goals 1. Fluid Resuscitation The first goal of resuscitation in the massively transfused trauma patient is not RBC transfusion but is in fact fluid resuscitation with crystalloids, if blood is not immediately available. Restoration of circulating blood volume is of primary and paramount importance, as the subsequent risk of coagulopathy is proportionate to the degree and antecedent time of hypoperfusion or shock. Isotonic crystalloids remain the preferred fluid, despite fifty years of debate in the literature. Patients have survived traumatic injuries with hemoglobin levels as low as 1.7 g/dl, provided that euvolemia was maintained. Although there is no universal agreement in the literature, most individual studies and a dozen meta-analyses have failed to show a difference between crystalloids and colloids. At least 3-5 times the estimated blood loss (EBL) is generally required. Hemodilution with crystalloid up to 30-40% levels does not significantly contribute to coagulopathy, due to a greater dilution of antithrombin than other clotting factor levels. Colloids, even at low levels of hemodilution (above 10-20%), decrease factor VIII, von Willebrand factor and platelet function. Minimizing crystalloid administration in some cases, particularly blunt abdominal trauma, has been beneficial and is known as delayed resuscitation or permissive hypotension. Survival can be improved in this select population by avoiding excessive fluid administration prior to surgical control of bleeding. Excessive crystalloid administration in these cases can cause dilutional coagulopathy, increased perfusion pressure and clot disruption. Regardless of fluid choice, it is vital to warm all fluids, RBCs and fresh frozen plasma (FFP), as administration of one liter of crystalloid at operating room temperatures or one unit of RBCs at refrigerated temperatures can drop a patient s core temperature by 0.25ºC. Platelets and cryoprecipitate should not be warmed during transfusion.

2 Page 2 2. Restoration of Oxygen-Carrying Capacity The second goal when caring for a massively transfused trauma patient is restoration of oxygen carrying capacity via administration of RBCs. Blood loss during hemorrhage can be difficult to quantify, as it may have occurred prehospitalization. Additionally, hemoglobin levels may not change with acute hemorrhage until volume status has been replete. Healthy patients can lose up to 30% of their estimated blood volume (EBV) prior to vital sign changes. There is no universal trigger for transfusion in these patients. The American College of Surgeons Guidelines address volume status rather than oxygen-carrying capacity, and the American Society of Anesthesiologists (ASA) Guidelines on the subject apply to elective surgical patients. With respect to the latter organization s targets between 6 and 10 g/dl, I recommend the upper limit of 10 g/dl as an initial target for several reasons. First, the red cell storage lesion decreases oxygen transport and delivery. This defect refers to metabolic changes that occur in RBCs stored up to 42 days, and includes such perturbations as decreased 2,3 diphosphoglycerate, which is responsible for a leftward shift in the oxyhemoglobin dissociation curve and therefore decreased oxygen delivery to the tissues. Decreased ATP levels can also lead to decreased flexibility of the RBCs and decreased flow through capillary beds. A second reason that a higher hemoglobin level is desirable is the salubrious effects of RBCs on hemostasis. There are rheological effects of RBCs that foster platelet margination, and ADP release assists with platelet aggregation. Human and animal studies show an inverse relationship between bleeding time and hematocrit, with benefits seen up to a hematocrit of 35%. A third reason for my bias toward a higher transfusion trigger relates to red cell count versus function and viability. Based on studies during the ACD storage period, up to 25% of the RBCs were non-viable (not capable of carrying oxygen) after 28 days of storage. After ten or more units of older, transfused RBCs, it is possible that a hemoglobin level of 10 g/dl may not have the oxygen carrying capacity that it appears. During massive transfusion cases, often blood components are required prior to the completion of compatibility testing. Providers should be familiar with the risks of transfusing uncrossmatched blood. As soon as possible, a blood sample should be sent to the blood bank for a type and screen. This permits the avoidance of over-reliance upon universal donor products such as type O RBCs and type AB plasma. Only 4% of the population is type AB, and therefore universal donor plasma can be exhausted. Group O, Rh negative, uncrossmatched blood is the safest to administer if immediately required and if no sample has been sent to the blood bank. However, this is generally reserved for females of childbearing age, due to the subsequent risk of hemolytic disease of the fetus and newborn if alloimmunization to the Rh D antigen occurred. Approximately 0.3% of the population (1% in patients previously transfused or pregnant) will have an RBC alloantibody, but intravascular hemolytic or other immediate transfusion reactions are rare with uncrossmatched blood. Group O, Rh-positive uncrossmatched blood is preferred in the emergency setting for males and postmenopausal females. There is a similarly low risk of hemolytic reactions; the Rh D antigen requires alloimmunization from prior transfusion or pregnancy. Furthermore, 90% of the population is Rh D positive. The risk of alloimmunization to the Rh D antigen, normally 80% in healthy volunteer studies and 20% in cancer patients, is between 1-5% in massive transfusion recipients. Type-specific, uncrossmatched blood is preferred in these patients if time permits. This preserves type O RBCs and type AB plasma. Due to clerical error, type-specific blood may be less safe than type O uncrossmatched blood. Clerical errors are estimated to occur in 1:100,000 transfusions, with 60% of them occurring within the blood bank. However, even in the emergency setting, transfusion administration policies should not be compromised. Verification of patient ABO type (if available) and unit type by at least two individuals should be performed. A potential controversy exists when a patient has received some uncrossmatched type O blood in an emergency setting, and subsequently after a type and screen is performed (usually within minutes), the patient s (if applicable) non-type O blood is delivered to the operating room. Should one stay with the type-o blood, or switch back to the patient s native blood type? Due to the small amount of plasma present in type O RBCs (which contains anti-a and anti-b antibodies), it is possible to cause a hemolytic reaction by subsequently administering type A, B or AB RBCs. Recent case reports demonstrate the potential for a hemolytic transfusion reaction after as little as 2 units

3 Page 3 of type O RBCs; hence this lecturer s bias is to stay with type O uncrossmatched blood if even only one unit has been given. Type-specific plasma products can be administered once a blood type has been established. 3. Prevention, Mitigation and Treatment of Coagulopathy The third goal of managing the massive transfusion patient is the prevention, mitigation and treatment of coagulopathy. Before examining specifics, it is important to remember that the coagulopathy that may accompany massive bleeding and transfusion may be multifactorial. The etiology will likely depend upon the antecedent events. The physiology is certainly different in an elective surgical case than a trauma case that may involve hypothermia, coagulation factor and platelet consumption, and metabolic changes due to hypotension, acidosis and shock. One should realize that there is a relatively low correlation between hemodilution, clotting factor levels, laboratory tests and clinical bleeding. I will demonstrate guidelines for management based upon the literature, but in the end each patient is different. Traditionally, the risk was weighing delayed intervention and the administration of unnecessary blood products. a) Platelets From a strict dilutional standpoint, thrombocytopenia occurs after replacement of blood volumes, or units of RBCs. There is a lax correlation between levels of hemodilution and platelet counts, as sequestered platelets can be released from the spleen, lung and bone marrow. Most studies demonstrate that platelet counts are greater than expected for a given level of hemodilution. Typical correlation coefficients comparing platelet counts to dilution are in the 50% range. Target platelet counts in this patient population range between 50,000 for minor trauma to 100,000 for major trauma. Most platelets (75%) are collected by apheresis from a single donor, and a patient s platelet count should increase by 30,000-60,000/µl following transfusion of one apheresis platelet concentrate. A similar increase in platelet counts can be seen following transfusion of whole blood derived platelets (random donor), composed of 4-6 platelet concentrates. The recovery rate of 5 day-old platelets is roughly 50%, and it may take up to four hours for platelets to become fully functional after administration. In the whole blood era, thrombocytopenia was the earliest perturbation seen in coagulopathic patients, as there were few to no viable platelets available in refrigerated, banked whole blood. Today, it is a late finding, as component therapy has supplanted whole blood therapy. b) Fibrinogen Hypofibrinogenemia is perhaps the earliest disturbance seen in the coagulopathy of massive transfusion. In contrast to the kinetics of platelets, fibrinogen depletes rapidly and in a very predictable fashion (correlation coefficient of 90%) in bleeding patients, both from dilution and consumption. In addition, fibrinogen becomes dysfunctional in hypothermic and acidotic patients. Target levels of fibrinogen are in excess of 100 mg/dl. This critical level is generally reached after one blood volume or 8-10 units of RBCs. It is important to remember to measure fibrinogen levels in patients; lack of fibrinogen despite adequate clotting factor levels may be responsible for a prolonged prothrombin time (PT) and/or activated partial thromboplastin time (APTT). Cryoprecipitate is the treatment of choice for fibrinogen replacement. Cryoprecipitate is typically pooled, and each pool should raise the fibrinogen level by 50 mg/dl. Fibrinogen is concentrated five-fold in cryoprecipitate with respect to plasma. Cryoprecipitate can take time to thaw and pool if pre-pooled product is not available, so early anticipation and planning for its need is critical. Cryoprecipitate must be transfused within 6 hours if given in a single unit, and within 4 hours if pooled in order to avoid wastage.

4 Page 4 c) Coagulation Factors Coagulation factor deficiencies are seen around the same dilution levels of those associated with hypofibrinogenemia. Although only 20-30% of normal clotting factor levels are typically required for hemostasis, this limit is reached after replacement of approximately one blood volume, or 8-10 units of RBCs. The aforementioned limits account only for dilution; consumption would merit earlier intervention. Fresh frozen plasma is the treatment of choice for clotting factor deficiency; a dose of ml/kg of body weight should increase clotting factor levels by 20-30%. Plasma requires a minute thaw time in the blood bank. New regulations allow plasma to be thawed for up to 5 days and labeled as thawed plasma. Although there is decreased factor activity in thawed plasma, this is not typically clinically significant, and is acceptable given the additional benefits of increased availability and decreased wastage. d) Adjuvant Therapy In 2011, there are few existing alternatives or complements to allogeneic blood during massive transfusion traumatic cases. Intraoperative cell salvage, also known as cell saver, is impractical (staffing and personnel limitations) and incomplete (offers only RBC replacement) therapy. Additionally, the majority of major trauma cases would be considered dirty wounds, and most surgeons do not seem to find the risk worth the moderate benefit that cell saver would provide. One therapy that is being used with increasing frequency in trauma cases is recombinant factor VIIa (rfviia, NovoSeven RT). Although approved in 1999 for the treatment of congenital and acquired hemophilia with factor inhibitors or congenital factor VII deficiency, up to 90% of its usage has been reported to be off-label. A majority of that usage is occurring in major trauma, cardiac, liver and neurosurgical cases. Recombinant factor VIIa works physiologically by enhancing clot formation in the presence of tissue factor expressed on injured vascular endothelium. It also acts pharmacologically by binding directly to activated platelets, increasing thrombin burst, and promoting the formation of a stable hemostatic plug. There are limited prospective data with respect to massive transfusion and trauma populations, although case reports suggest that it is helpful in select cases. Treatment based on a standard 4 mg dose in massive transfusion costs approximately $4,000, so it is important to realize that the drug will be ineffective under certain conditions. Predictors of futility of treatment include acidosis (ph < 7.2), hypothermia (less than 35ºC) or prolonged PT. The risk of a thromboembolic event following rfviia in studies is estimated as 2.5-5%. New Developments in Massive Transfusion 1. Acute Coagulopathy of Trauma A new paradigm of coagulopathy immediately following injury has recently been described; it is called acute traumatic coagulopathy (ATC), acute coagulopathy of trauma-shock (AcoTS), or early trauma-induced coagulopathy (ETIC). This newly recognized entity has been identified in approximately 25% of trauma patients, and is defined as prolonged clotting times (PT and/or APTT) on hospital arrival. It is a primary coagulopathy and is characterized by systemic anticoagulation in the presence of shock, hypoperfusion and tissue injury. It is not strictly due to consumption of platelets and fibrinogen, is independent of head injury, and is not secondary to acidosis and hypothermia. ATC can be predicted by the duration of antecedent hypotension/shock, injury severity score (ISS) and acidosis (base deficit). Patients presenting with ETIC have a 4-fold increase in 30-day mortality when compared with patients presenting with normal coagulation parameters. Even when controlling for ISS, it is clear that ATC increases mortality. Initial investigation postulates that the pathophysiology of ATC involves a) tissue hypoperfusion that leads to activation of protein C and systemic anticoagulation and b) fibrinolysis from the activated protein C inhibition of plasminogen activator inhibitor-1.

5 Page 5 2. Pre-determined blood product administration / massive transfusion protocols (MTP) Traditionally, resuscitation of the massive transfusion patient was based on formula replacement, or was reactive based upon laboratory results that weren t necessarily in real-time. Frequently, blood banks could not keep up with the demands with respect to thaw times of various blood products. Based on military data, practice has changed in civilian trauma centers from formula-based therapy to those involving pre-determined protocols (hospital-specific). The goal of MTP is essentially to recapitulate whole blood transfusion, thus preventing or mitigating dilutional coagulopathy or ATC. Other logistical benefits include a standardization of care, a reduction in transfusion errors, better cooperation with the transfusion medicine service to anticipate product needs, and the ability of the blood bank to quickly provide products. Although the ratios of products differ by institution, the benefits from outcome studies demonstrate that MTP improves patient survival rates, decreases overall blood usage and decreases transfusion costs. Below is a table demonstrating the ratio of product administration for the massive transfusion protocol at Grady Memorial Hospital in Atlanta, GA. PACKAGE PRBCs Plasma Platelets Cryoprecipitate 1 6 units 6 units (AB) 1 apheresis 2 6 units 6 units 10 units (pooled) 3 6 units 6 units 1 apheresis 4 6 units 6 units 10 units (pooled) 5 6 units 6 units 1 apheresis 6 6 units 6 units 10 units (pooled) rfviia (initial dose of 4 mg) may be requested after the third package if there is active non-surgical bleeding, and repeated dosages may be given if bleeding continues unabated. Metabolic Complications of Massive Transfusion 1. Hyperkalemia Hyperkalemia can occur during massive transfusion, but it is generally due to prolonged RBC storage. Due to the decreased level of ATP in stored, refrigerated blood, the extracellular potassium levels of banked blood can rise. While a general rule of thumb states that potassium levels of 1 meq/l per day of storage are present in banked blood, levels greater than 100 meq/l have been reported. Concomitant acidosis, tissue injury and hypocalcemia can exacerbate hypokalemia and its adverse effects on the myocardium. After transfusion, ATP levels return to normal, and the excessive potassium is usually rapidly redistributed. The rate of transfusion is an important variable. Sequelae are most often seen in neonates or patients with renal failure or acquired renal injuries. 2. Acid-Base changes The ph of banked blood after 3 weeks of storage is around 6.5; after 6 weeks of storage it approaches 3. During a massive transfusion, despite the acid load, metabolic acidosis from banked blood is not common. The citrate present as a preservative in banked blood is rapidly metabolized in the liver to bicarbonate and buffers the acid. Assuming adequate hepatic perfusion and function, banked blood should not be the primary culprit of continuing metabolic acidosis. Attention in these cases should be given to the sequelae of prolonged or uncontrolled hemorrhage, or to missed injuries and ongoing regional ischemia. Empiric sodium bicarbonate administration is generally not required in these cases.

6 Page 6 3. Hypocalcemia As mentioned above, the citrate in banked blood offers the salutary effect of neutralizing the acid load associated with massive transfusion. However, the citrate also binds ionized calcium. The liver can generally metabolize the citrate present in one unit of banked blood in five minutes. With rapid infuser systems, possible hepatic dysfunction or injury, and increased citrate loads today (plasma citrate is greater than that in RBC units), hypocalcemia is extremely common in massively transfused patients. Hypotension can be present with ionized calcium levels as high as mmol/l. Cardiac arrest can occur with calcium levels as high as 0.6 mmol/l. Coagulopathy generally occurs with a calcium level less than 0.55 mmol/l. 4. Hypomagnesemia The citrate in banked blood binds calcium and magnesium with equal affinity. Manifestations of hypomagnesemia in massively transfused trauma patients include dysrhythmias refractory to conventional therapies and hypotension despite adequate calcium replacement. If not diagnosed in a timely fashion, the sine qua non, torsade de pointes, can be seen. 5. Changes in hemoglobin-oxygen affinity Banked blood contains very low levels of 2,3-diphosphoglycerate (2,3-DPG). Blood stored as little as 14 days at refrigerated temperature has only 0-10% of normal 2,3-DPG levels. As a result, the oxyhemoglobin dissociation curve is shifted to the left with older blood, implying a higher affinity of the hemoglobin for oxygen. The resultant tissue oxygen delivery suffers, and repletion of 2,3-DPG levels takes several hours to commence and up to 48 hours to complete. 6. Hypothermia Hypothermia, either antecedent to patient presentation or from failure to warm RBCs and plasma, is common in trauma patients. Hypothermia can contribute to coagulopathy in massively transfused patients. Hypothermia does not alter clotting factor levels, but kinetic slowing or enzymatic inhibition is present at temperatures below 34-35ºC. It is important to realize that blood samples are heated to 37ºC prior to analysis for coagulation studies. Hence, if a patient is suffering from micro vascular bleeding and coagulation tests are normal, rewarming the patient may be all that is required to correct the coagulopathy. Additional changes from hypothermia include the stimulation of fibrinolysis and inhibition of platelet function. Platelet morphology and counts can be adversely affected by hypothermia as well, but these are reversible with rewarming. References 1. Hauser CJ et al. Results of the CONTROL trial: efficacy and safety of recombinant activated factor VII in the management of refractory traumatic hemorrhage. Journal of Trauma 2010;69: Hsia CC et al. Recombinant activated factor VII in the treatment of non-hemophilia patients: physician under-reporting of thromboembolic adverse events. Transfusion Medicine 2009;19: McLaughlin DF et al. Effect of plasma and red blood cell transfusions on survival in patients with combat related traumatic injuries. Journal of Trauma 2008;64:S57-S Kashuk JL et al. Post-injury life threatening coagulopathy: is 1:1 fresh frozen plasma: packed red blood cells the answer? Journal of Trauma 2008;65: Hess JR et al. The coagulopathy of trauma: a review of mechanisms. Journal of Trauma 2008;65: Como JJ et al. Blood transfusion rates in the care of acute trauma. Transfusion 2004;44:

7 Page 7 7. Cotton BA et al. The cellular, metabolic, and systemic consequences of aggressive fluid resuscitation strategies. Shock 2006;26: Ruttman TG et al. Effects on coagulation of intravenous crystalloid or colloid in patients undergoing peripheral vascular surgery. British Journal of Anaesthesia 2002;89: Erber WN et al. Massive blood transfusion in the elective surgical setting. Transfusion and Apheresis Science 2002;27: Hiippala S. Replacement of massive blood loss. Vox Sanguinis 1998;74: Brummel-Ziedens K et al. The resuscitative fluid you choose may potentiate bleeding. Journal of Trauma 2006;61: Andrews DA et al. Role of red blood cells in thrombosis. Current Opinion in Hematology 1999;6: Dutton RP et al. Safety of uncrossmatched type-o red cells for resuscitation from hemorrhagic shock. Journal of Trauma 2005;59: Stainsby D. Errors in transfusion medicine. Anesthesiology Clinics of North America 2005;23: Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients. Transfusion Medicine Reviews 2004;18: Miller RD et al. Coagulation defects associated with massive blood transfusions. Annals of Surgery 1971;174: Leslie SD et al. Laboratory hemostatic abnormalities in massively transfused patients given red blood cells and crystalloid. American Journal of Clinical Pathology 1991;96: Murray DJ et al. Coagulation changes during packed red cell replacement of major blood loss. Anesthesiology 1988;69: MacLaren R et al. A multi-center assessment of recombinant factor VIIa off-label usage: clinical experiences and associated outcomes. Transfusion 2005;45: Dutton RP et al. Scientific and logistical challenges in designing the CONTROL trial: recombinant factor VIIa in severe trauma patients with refractory bleeding. Clinical Trials 2009;6: Stein DM et al. Determinants of futility of administration of recombinant factor VIIa in trauma. Journal of Trauma 2005;59: Hirshberg A et al. Minimizing dilutional coagulopathy in exsanguinating hemorrhage: a computer simulation. Journal of Trauma 2003;54: Kashuk JL et al. Post-injury life-threatening coagulopathy: is 1:1 fresh frozen plasma: packed red blood cells the answer? Journal of Trauma 2008;65: McLeod J et al. Early coagulopathy predicts mortality in trauma. Journal of Trauma 2003;55: Hewson JR et al. Coagulopathy related to dilution and hypotension during massive transfusion. Critical Care Medicine 1985;13: Brohi K et al. Acute traumatic coagulopathy. Journal of Trauma 2003;54: Niles SE et al. Increasing mortality associated with the early coagulopathy of trauma in combat casualties. Journal of Trauma 2008;64: Cosgriff N et al. Predicting life-threatening coagulopathy in the massively transfused patient: hypothermia and acidosis revisited. Journal of Trauma 1997;42: Brohi K et al. Acute coagulopathy of trauma: mechanism, identification and effect. Current Opinion in Critical Care 2007;13: O Keeffe T et al. A massive transfusion protocol to decrease blood component use and costs. Archives of Surgery 2008;143: Johansson PI et al. Transfusion practice in massively bleeding patients: time for a change? Vox Sanguinis 2005;89: Borgman MA et al. The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat support hospital. Journal of Trauma 2007;63: Stinger HK et al. The ratio of fibrinogen to red cells transfused affects survival in casualties receiving massive transfusions at an army combat support hospital. Journal of Trauma 2008;64:S79-S85.

8 Page Holcomb JB et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Annals of Surgery 2008;248: Dente CJ et al. Improvements in early mortality and coagulopathy are sustained better in patients with blunt trauma after institution of a massive transfusion protocol in a civilian level I trauma center. Journal of Trauma 2009;66: Linko K et al. Electrolyte and acid-base disturbances caused by blood transfusions. Acta Anaesthesiologica Scandinavica 1986;30: Smth HM et al. Anesthesia & Analgesia 2008;106: Ruttman TG et al. The coagulation changes induced by rapid in vivo crystalloid infusions are attenuated when magnesium is kept at the upper limit of normal. Anesthesia & Analgesia 2007;104: Diaz J et al. Serum ionized magnesium monitoring during orthotopic liver transplantation. Transplantation 1996;61: Meikle A et al. Management of prolonged QT interval during a massive transfusion: calcium, magnesium or both? Canadian Journal of Anaesthesia 2000;47: Watts DD et al. Hypothermic coagulopathy in trauma: effect of varying levels of hypothermia on enzyme speed, platelet function and fibrinolytic activity. Journal of Trauma 1998;44: Ciavarella D et al. Clotting factor levels and the risk of diffuse microvascular bleeding in the massively transfused patient. British Journal of Haematology 1987;67:

9 Disclosure This speaker has indicated that he or she has no significant financial relationship with the manufacturer of a commercial product or provider of a commercial service that may be discussed in this presentation.