When is transfusion therapy indicated in critical illness and when is it not?

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81 When Is Transfusion Therapy Indicated in Critical Illness and When Is It Not? Babak Sarani and Cheralyn J. Hendrix

INTRODUCTION Transfusion of blood products is one of the most common therapies ordered in the intensive care unit (ICU). It is estimated that 4 million patients are transfused 8–12 million units of packed red blood cells (PRBC) annually in the United States alone and that the majority of transfusions occur in either surgical or critically ill patients. Several studies in various countries have documented that the incidence of PRBC transfusion in the ICU varies between 20 and 50%.1–5 In addition to anemia approximately 40% of critically ill patients have a low platelet count or elevation in their coagulation parameters at some point during their ICU stay. Most of these hematological derangements, however, are asymptomatic, and numerous studies have shown that outcomes are either not changed or worsened following transfusion to normalize these values. While there are some well-designed trials that may be used to formulate guidelines regarding transfusion of PRBC in critically ill patients, there are no good studies that can be used to determine which patients will likely benefit from platelet or plasma transfusion in the ICU. This chapter reviews the available evidence on best transfusion practices in the ICU, including a review of the use of recombinant factor VIIa and four-factor prothrombin complex concentrate (PCC).

BASIS FOR TRANSFUSION OF BLOOD PRODUCTS—BENEFITS AND RISKS Outcomes related to transfusion practices are only now being studied in well-designed prospective trials. Although there are many trials related to transfusion of PRBC, there is a dearth of information related to practice patterns and outcomes from the use of non-RBC products in patients who are not actively hemorrhaging.

Packed Red Blood Cell Transfusion The normal blood volume is 7–8% of ideal body weight. This corresponds to a hemoglobin (Hb) level of 14–16 g/dL 584

and hematocrit level of 40–45%. Transfusion of RBCs can restore both circulating blood volume and oxygen-carrying capacity. The body has many adaptive responses to increase oxygen delivery in the face of anemia (Box 81.1). Clinically, the easiest initial maneuver to increase oxygen delivery is to increase the oxygen saturation or Hb concentration because increasing cardiac output can increase myocardial oxygen demand and may precipitate ischemia in patients with coronary artery disease.6 Historically, the ideal Hb / hematocrit values in hospitalized patients were considered to be 10 g/dL or 30%. The basis for this claim lies partially on rheological principles, which suggest that there is an optimal balance between oxygencarrying capacity (where high is better) and viscosity (where low is better). Such a balance would minimize cardiac work and maintain peripheral oxygen delivery. As recently as the 1990s, this recommendation was supported by two large retrospective studies in Jehovah’s Witness populations that showed a significant increase in perioperative mortality if the preopera­ tive Hb was 6 g/dL as opposed to 12 g/dL (odds ratio of 2.5 for each gram that the postoperative Hb was ,8 g/dL; Table 81.1).7,8 The risk of death was highest in patients with known cardiovascular disease. Trials in postoperative patients have called into question the validity of these retrospective studies and suggest that transfusion thresholds should be individualized based on the documentation of end-organ hypoxia. Two randomized studies of post-cardiac surgery patients found no difference in morbidity in those randomized to a liberal vs. restrictive transfusion strategy.9,10 However, the study by Hajjar et al.9 found a dose-dependent increase in morbidity following transfusion, whereas the study by Murphy et al.10 found an increase in mortality but no change in morbidity in those randomized to the restrictive transfusion arm of the study. Reasons for these findings are uncertain considering that the mean difference in the Hb level between the two arms was only 1 g/dL. Thus although a restrictive strategy for blood transfusion following cardiac surgery may be desirable, the

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BOX 81.1  Physiologic Mechanisms to

Increase Oxygen Delivery in Anemia.

Mechanisms that increase arterial oxygen content -Increased production of erythropoietin leading to increased hemoglobin synthesis and concentration -Rightward shift of hemoglobin saturation curve due to increased 2,3-diphosphoglycerate permitting increased oxygen “off-loading” at capillary Po2 Mechanisms that increase cardiac output -Increased heart rate -Increased myocardial contractility -Decreased blood viscosity leading to decreased peripheral vascular resistance (afterload)

TABLE 81.1  Postoperative Outcomes

of Anemic Jehovah’s Witnesses. Preoperative Hemoglobin Level (g/dL)

Mortality (%)

,6

61.5

6.1–8

33

8.1–10

0

.10

7.1

From Carson JL, Poses RM, Spence RK, Bonavita G. Severity of anaemia and operative mortality and morbidity. Lancet. 1988;1(8588): 727–729.

actual Hb trigger has yet to be determined. Similarly, another randomized study of elderly patients undergoing total hip arthroplasty found no difference in morbidity or mortality in those randomized to Hb transfusion threshold of 10 g/dL vs. 8 g/dL,11 whereas a retrospective study in a similar patient population found a significant increase in perioperative morbidity and no change in mortality.12 In a single prospective, randomized, blinded study, blood transfusion used as part of a sepsis bundle was found to improve survival in patients with septic shock whose hemodynamic parameters did not correct with intravenous fluids.13 However, because the interventions in this study were delivered as a bundle, it was not possible to determine the relative impact of transfusion on outcomes. Subsequently, an adequately-powered, randomized, prospective study of critically ill patients with septic shock found no difference in mortality or need for ongoing critical care interventions, such as mechanical ventilation, vasopressor use, or renal replacement therapy, between patients assigned to transfusion at Hb trigger of 7 g/dL vs. 9 g/dL.14 Moreover, there was no change in the results in the subgroups of patients aged .70 years nor in those with known cardiovascular disease, though patients with acute coronary syndrome were excluded from this study. “Three small RCTs failed to demonstrate a benefit from PRBC transfusion, in terms of oxygen delivery or uptake, in septic critically ill patients.”15–17

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Many studies have addressed the role of PRBC transfusion in asymptomatic, hemodynamically stable, nonbleeding, anemic, critically ill patients. A single, randomized, blinded, prospective study in 1999, along with several subsequent observational studies, found that patients who are transfused above the Hb value of 7 g/dL have either the same or better outcomes than those who are transfused the Hb value of 10 g/dL.3–5 These findings are consistent with other studies and one metaanalysis that also documented an increased risk of infection following PRBC transfusion.3,5,18–25 Other studies have documented an increased risk of death following RBC transfusion.3,5 Based on these data, current guidelines regarding PRBC transfusion in critically ill but asymptomatic and resuscitated patients call for the Hb transfusion trigger of 7 g/dL (Boxes 81.2 and 81.3).26 There are no randomized studies evaluating a threshold for PRBC transfusion in patients with unstable angina or acute coronary syndrome (ACS). However, a large, post hoc analysis from the combined patient pool of three studies that were originally designed to evaluate the efficacy of antiplatelet agents in those with myocardial ischemia found a significant increase in the hazard ratio in patients who were transfused to a hematocrit .25%.27 This finding has been corroborated in multiple other retrospective studies.28–30 Conversely, a recent, retrospective analysis of a highly selected cohort of patients with ACS suggested a decrease in mortality for those transfused for a Hb trigger of 9 g/dL.31 However, the authors caution that the cohort enrolled in the study was not representative of typical patients with ACS; therefore, the results of the trial may not be generalizable to the overall population of patients with ACS. Thus, although there are insufficient data upon which to strongly recommend a transfusion threshold below the Hb level of 10 g/dL in this cohort, transfusion to the Hb level of 8–10 g/dL may

BOX 81.2  Thresholds for Transfusion

in Stable Anemic Patients Without Risk for Potential Acute Blood Loss or Acute Surgical Stress. Hemoglobin ,8–10 g/dL Acute myocardial infarction or acute coronary syndrome Hemoglobin #7 g/dL All other patients

BOX 81.3  Thresholds for Transfusion

in Stable Patients at High Risk for Acute Blood Loss. Hemoglobin #10 g/dL Known disorders of hemostasis or red blood cell dyscrasia (e.g., sickle cell anemia) All with anticipated estimated blood loss 1000 mL Hemoglobin #7 g/dL All other patients

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be reasonable in most patients. Furthermore, the need for transfusion to a higher Hb level may be more appropriately reserved for patients with the evidence of ongoing end-organ ischemia. Transfusion of blood products carries many risks. These include transmission of blood-borne pathogens, transfusionassociated circulatory overload (TACO), transfusion-related acute lung injury (TRALI), and transfusion-related immunomodulation (TRIM). Clinically significant transfusion reaction is rare under current guidelines and is most commonly due to clerical error. Interestingly, this adverse event is rarely observed in exsanguinating patients. This is likely due to alterations in the immune system resulting from severe injury necessitating massive transfusion.32 TRALI and TRIM are most likely variants of the same disorder—an exaggerated inflammatory response and altered or deranged immune system due to transfusion of foreign protein—and may explain the increased risk for infection.33 TRALI may result from local (pulmonary) inflammation, whereas TRIM may represent systemic immune derangement. Both entities are likely underreported due to a lack of unique diagnostic criteria and adequately-designed studies aimed at addressing their incidence. TRALI is defined as noncardiogenic pulmonary edema that occurs within 4–6 hours of transfusion. It has a reported incidence of 1:5000 to 1:10,000 transfusions34 and is most common following plasma transfusion. TRIM is best exemplified by reports showing the association between PRBC transfusion and infection19,20,22,23,35,36 and reports documenting a chimeric state where donor epitopes can be expressed by cells of transfused trauma patients years after the transfusion itself.37–39 Mechanisms underlying TRIM are only now being elucidated. Cotransfusion of soluble proteins, such as human leukocyte antigen or fibrinogen/fibrin degradation products, or cotransfusion of disrupted white blood cell products have been proposed as possible explanations.33

Plasma Transfusion The plasma portion of donated whole blood contains most of the necessary clotting factors of the coagulation cascade. Although there are decreased concentrations of factors V, VII, and VIII, as a result of degradation and fibrinogen (factor I) due to dilution, spontaneous hemorrhage rarely occurs with factor concentrations .25%.40,41 Plasma is dosed as 10–15 mL/kg (ideal body weight) and generally, 4 units will result in 40–60% factor recovery.41 It is important to note that transfusion of 5 units of random donor platelets or 1 unit of single donor platelets also results in the transfusion of 1 unit-equivalent of plasma since platelets are suspended in plasma.40 Plasma is commonly used in the ICU to rapidly treat coagulopathy with concomitant hemorrhage or in anticipation of an invasive procedure in a patient with coagulopathy. Warfarin is a commonly used oral anticoagulant to prevent thromboembolic disease from various causes. A retrospective study found that each 30-minute delay in the administration of the first unit of plasma decreases the odds of correction of warfarin-induced coagulopathy by 20% in patients with intracerebral bleeding, underscoring the need for

rapid and accurate reversal of the drug in hemorrhaging patients.42 Because the speed with which plasma can be administered is limited by its supply and the time required to thaw and prepare the product, the use of PCCs to quickly restore clotting ability is becoming increasingly common. PCCs provide a concentrated source of three or four vitamin K-dependent coagulation factors. PCCs are stored in a lyophilized state and only require reconstitution. A type/ screen is not needed, the product does not need to be thawed, and the total volume of drug to be administered is ,100 mL, thus making administration significantly faster and eliminating the risk of TACO. Multiple international organizations, including the American College of Chest Physicians, recommend a combination of PCC and vitamin K for emergency anticoagulation reversal.43 A 2013 study by Sarode et al.44 evaluated the efficacy and safety of PCC compared with plasma in patients on vitamin K antagonists presenting with major bleeding. Rapid international normalized ratio (INR) reduction was achieved in 62% of patients receiving PCC vs. 10% of patients receiving. The safety profile was similar between groups.44 There is wide variability in the manner in which physicians utilize fresh frozen plasma (FFP) in nonbleeding patients with coagulopathy.45 Many physicians use FFP prophylactically to reverse coagulopathy in nonbleeding patients despite published guidelines recommending against this, along with an unknown risk-benefit ratio.46,47 Others cite mild coagulopathy as a reason to use FFP as a volume expander in nonbleeding, volume-depleted patients.48 To date, there are no guidelines universally agreed upon for the use of FFP in nonbleeding patients. Suggested indications and dosing are shown in Box 81.4. Historically, plasma transfusion was associated with a high incidence of TRALI. However, this risk has diminished to the point where TRALI is now rarely associated with plasma transfusion because most transfused plasma is collected from men and women who are either nulliparous or have had very few babies. The proposed mechanism to account for this phenomenon is a decrease in the variability of plasma proteins found in these individuals compared with multiparous women. This hypothesis is supported by a randomized, blinded, crossover study that found that the

BOX 81.4  Indications for Transfusion

of Plasma.

Emergency reversal of warfarin-induced coagulopathya Replacement of isolated coagulation protein deficiency Massive transfusion Disseminated intravascular coagulation with serious active bleeding Liver disease with clinical bleeding and evidence of coagulation defect Thrombotic thrombocytopenic purpura Replacement of clotting factors after apheresis therapy Consider prothrombin complex concentrate in lieu of plasma.

a

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risk of TRALI is higher following plasma transfusion obtained from multiparous women.49 Transfusion of plasma may be associated with TRIM. A retrospective study identified a three-fold higher relative risk of infection in critically ill surgical patients who received FFP, a finding that is consistent with the risk of infection following PRBC transfusion.50 This study has not been repeated because the donor pool for procurement of plasma was altered to try to exclude multiparous women. Finally, hemolytic transfusion reactions also are possible following plasma transfusion as plasma contains variable titers of anti-A and anti-B antibody. Single-center studies have suggested that the use of PCC may be effective in treating non-vitamin K antagonist-related coagulopathy, reducing the need for plasma transfusion. One study involving severely injured patients found that use of PCC plus plasma (compared with plasma alone) was associated with a significant reduction in the time required to lower the INR below 1.5 as well as the need for both RBC and plasma transfusion.51 There was no difference in thromboembolic event risk. Another study found that the INR could be lowered significantly in patients who were coagulopathic due to either sepsis or liver failure.52 However, both of these studies require validation in larger, appropriately-designed studies.

Cryoprecipitate Transfusion Cryoprecipitate is the precipitated fraction obtained from thawing FFP at 4°C. This method of isolation means that cryoprecipitate is pooled from the FFP obtained from multiple donors. Cryoprecipitate is rich is factor VIII, von Willebrand factor, factor XIII, and fibronectin. Most importantly, it contains concentrated fibrinogen and thus the main indication for its use is the treatment of coagulopathy due to hypofibrinogenemia.47 It may therefore be useful in the management of disseminated intravascular coagulation (DIC) with hemorrhage and in the reversal of thrombolytic agents (Box 81.5). While an adequate dose of plasma can replete fibrinogen, hypofibrinogenemia can be reversed more quickly using cryoprecipitate or, better, fibrinogen concentrate. Cryoprecipitate is dosed as a 10-pack transfusion; each 10-pack raises the fibrinogen level 75%.41 Bleeding patients with known von Willebrand deficiency also should receive cryoprecipitate to optimize platelet function, while nonbleeding patients with this disorder can be treated with desmopressin.

BOX 81.5  Indications for Transfusion

of Cryoprecipitate.

Hemophilia A (factor VIII deficiency) von Willebrand’s disease Fibrinogen deficiency Dysfibrinogenemia Factor XIII deficiency Uremic platelet dysfunction

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Risks associated with transfusion of cryoprecipitate are the same as those reported for the other blood components. However, the incidence of TRALI and TRIM is probably lower than that associated with plasma transfusion because the total volume of cryoprecipitate transfused is much less than that of plasma, thereby minimizing the recipient’s exposure to foreign protein antigen. The risk of transmission of blood-borne pathogens, however, may be higher due to the pooled nature of this product. There are no well-designed studies assessing outcomes or adverse events related to transfusion of cryoprecipitate.

Platelet Transfusion Platelet transfusion is less common than RBC or plasma transfusion. The most common indication for platelet transfusion is decreased production followed by the increased destruction of cells.40 In the critically ill population, where DIC is more prevalent, increased consumption of platelets can also lead to thrombocytopenia. Although the absolute platelet count may not correlate with function and ability to form a stable clot, it is generally accepted that spontaneous bleeding can occur with platelet counts ,10,000 cells/µL.53 Although not validated in studies, many clinicians recommend that a minimum platelet count of 50,000 cells/µL should be maintained, if possible, for patients at significant risk of bleeding (e.g., trauma postoperative patients, or those about to undergo an invasive procedure associated with a significant risk of hemorrhage), and a target of 80,000–100,000 cells/µL is recommended for patients who are actively bleeding or at risk for intracranial hemorrhage.40,54 However, the authors stress that there is no evidence-based basis for this practice, and it is very likely that platelet number and physiologic impact on clot formation/stability do not have a linear relationship. Despite the fact that the platelet count can be determined easily and quickly, there is no simple method for testing platelet function. A possible exception is thromboelastography (TEG), a method of assessing clot formation and lysis. Limited evidence from observational and retrospective data suggests that TEG is able to detect platelet dysfunction following trauma.55–57 However, these studies also demonstrate a high rate of inhibition of both the arachidonic acid and adenosine diphosphate pathways in the platelet following even minor injury or relatively mild critical illness. Thus, in contrast to serum coagulation parameters, there are no studies that can be used to direct platelet transfusion in critically ill patients. The critical care practitioner should be aware of the high incidence of platelet dysfunction in the critically ill patient and base the decision to transfuse platelets on the clinical scenario at hand. There are no studies that can be used to recommend timing and volume of platelet transfusion in nonbleeding, critically ill patients. Further, although there are no studies to determine the impact that use of aspirin or nonsteroidal antiinflammatory agents have on hemorrhage following injury, a review of the literature suggests that use of aspirin may worsen intracranial hemorrhage following traumatic brain

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injury.58–60 An open-label, ex-vivo study in volunteers showed that platelet transfusion can reverse the platelet dysfunction caused by clopidrogel.61 Two studies demonstrate that platelet transfusion is effective in reversing the degree of platelet inhibition caused by aspirin or clopidogrel, although the studies were not appropriately designed to describe a dose-response curve.57,62 The authors recommended utilizing serial TEG measurements to determine the efficacy after each platelet transfusion.

MASSIVE EXSANGUINATION AND TRANSFUSION Patients requiring massive transfusion are a unique cohort in whom aggressive transfusion is needed for hemodynamic support and reversal of coagulopathy (Table 81.2). The most commonly utilized definition of massive transfusion is the administration of 10 units of PRBC within 24 hours. This does not address the coagulopathy that also exists in these patients and fuels the process underlying the hemorrhage.63 Non-controlled and retrospective studies suggest that aggressive transfusion using plasma:RBC ratios that approach 1:1 within a pre-defined massive transfusion protocol may result in earlier arrest of hemorrhage, as well as a mortality benefit.64–66 The PROMMTT trial prospectively evaluated 1245 trauma patients who received at least one unit of RBCs within 6 hours of admission. Increased ratios of plasma:RBCs and platelets:RBCs were independently associated with a decrease in 6-hour mortality. Patients with ratios less than 1:2 were 3–4 times more likely to die than patients with ratios of 1:1 or higher.67 The PROPPR trial found no difference in mortality, but a decrease in hemorrhage and transfusion need in trauma patients who received a 1:1 vs. 1:2 transfusion strategy.68 Until similar studies are carried out in the non-trauma population, it may be prudent to treat exsanguinating, critically ill patients with

TABLE 81.2  Transfusion Guidelines for

Patients who are Acutely Bleeding. Clinical Situation

Recommended Response

Rapid acute hemorrhage without immediate control, estimated blood loss .30–40%, or presence of symptoms of severe blood loss

Transfuse PRBC. Initiate massive transfusion protocol with 1:1 RBC:FFP transfusion.a

Estimated blood loss ,25–30% without uncontrolled hemorrhage

Crystalloid resuscitation, proceed to blood transfusion if hemorrhage is not quickly arrested

Presence of comorbid factors

Consider transfusion with lesser degrees of blood loss

May require uncrossmatched or type-specific blood. FFP, fresh frozen plasma; PRBC, packed red blood cells. a

BOX 81.6  Causes of Abnormal Bleeding

in Surgery and Trauma.

Release of tissue thromboplastin Massive transfusion Autotransfusion Disseminated intravascular coagulation Platelet dysfunction Hypothermia

aggressive transfusion of plasma and platelets in addition to RBCs while also preventing hypothermia, acidosis, and other causes of on-going coagulopathy.69 Common causes of abnormal bleeding in critically ill patients are noted in Box 81.6.

RECOMBINANT FACTOR VIIA Mechanism of Action and Clinical Use Recombinant factor VIIa is approved for use in hemophiliacs with antibodies to factor VIII or IX. However, many case reports and small series found that it may also have a role in arresting hemorrhage from other causes. Recombinant factor VIIa works by binding to exposed tissue factor in an area of endothelial injury, thereby activating platelets and platelet plug formation. Factor VIIa then stimulates the coagulation cascade by activating thrombin on the platelet plug. Fibrinolysis is inhibited through factor VIIamediated activation of thrombin activatable fibrinolysis inhibitor. Factor VIIa has been shown to reduce hemorrhage following injury. Two parallel, randomized, blinded, placebocontrolled studies found that the drug was associated with a 50% relative reduction in severity of hemorrhage in bluntly injured patients but did not have a transfusion-sparing effect in victims of penetrating trauma.70 However, the potential transfusion-sparing effect was only seen at very high doses, a difference that has substantial cost implications. The only large, randomized, blinded, placebo-controlled study on the use of factor VIIa in injured patients (CONTROL trial) was stopped early for futility when the control arm was noted to have a substantially lower mortality than anticipated.71 Given the drug’s cost, lack of mortality benefit, its association with thrombotic events (see later), and the availability of PCC, factor VIIa is no longer routinely used in trauma or critically ill patients.

Adverse Events Associated with Recombinant Factor VIIa Factor VIIa has been associated with thromboembolic complications, particularly when used off-label. Reports from the Food and Drug Administration suggest that the incidence of thromboembolic disease is 0.02% in hemophiliacs, but the incidence of myocardial infarction, stroke, or pulmonary embolism may be as high as 8% when the agent is used in other populations.72 Moreover, there is an almost equal incidence of

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arterial and venous thrombi following administration of the drug. However, the CONTROL trial did not find any difference in complications between trauma patients who did and did not receive factor VIIa.71

TRANEXAMIC ACID Mechanism of Action and Clinical Use Tranexamic acid (TXA) is a synthetic lysine derivative that inhibits fibrinolysis by binding to and inhibiting plasminogen. A review of 53 studies incorporating 3836 persons undergoing elective surgery found that administration of this agent resulted in a 39% reduction in blood transfusion. CRASH-2, a multinational, randomized, blinded, placebocontrolled study, that included 270 hospitals and enrolled over 20,000 injured patients, found that administration of TXA within 8 hours of injury resulted in a statistically significant 1.5% decrease in the risk of death from any cause.73 Further analysis suggested that the biggest reduction was in hemorrhage-related death. Subgroup analysis found that this benefit was confined to patients who received tranexamic acid within 3 hours of injury.74 Persons who were treated with the medication 3–8 hours following injury actually had a higher mortality than the placebo group. The study has been criticized for enrolling patients who were actually hemorrhaging as well as those perceived to be at risk of hemorrhage based on the judgment of the bedside clinician. Furthermore, although the study found a significant decrease in the probability of hemorrhage-related death, there was no difference in the amount of blood transfused in surviving patients. The MaTTERS and MaTTERS II trials are retrospective studies of the same patient cohort and evaluated the benefits of TXA in soldiers wounded in battle.75,76 Similar to the CRASH-2 trial, these studies also found a significant decrease in hemorrhage-related mortality, but the study cohort consisted solely of patients requiring a massive transfusion. Maximal benefit from administration of TXA was found in patients who received both a 1:1:1 ratio of PRBC:FFP as well as cryoprecipitate. The risk of venous thromboembolic disease was 2–3%. The number needed to treat to prevent one hemorrhage-related death in the MaTTERS study was 7. Reports have been published suggesting an increase in mortality associated with TXA administration in patients who do not have fibrinolysis evident on TEG, a condition referred to as “fibrinolysis shut down.”77–79 These studies suggest that TXA administration to persons with an LY30 value ,0.8% is associated with an increase in mortality, whereas TXA administration to persons with an LY30 value .3% is associated with a reduction in death risk. As such, until randomized trials validating these findings are published, it may be prudent to check the degree of thrombolysis present prior to administrating this agent, if possible. Lastly, these findings have not been validated in noninjured patients, and the risk/benefit analysis of TXA as a treatment for sepsis or other related causes of thrombolysis remains uncertain.

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CONCLUSION There remains a paucity of high-level evidence to guide transfusion practice in the ICU. Studies to date argue for a restrictive policy of PRBC transfusion in critically ill patients who are not hemorrhaging and are not manifesting signs of end-organ ischemia. Similarly, patients who have other asymptomatic derangements in coagulation should not be transfused unless an invasive procedure, with propensity for hemorrhage, is planned. The use of PCC may be superior to the use of FFP in this setting. Patients who require ongoing transfusion support should be aggressively treated with transfusion of PRBC, plasma, and platelets. Further studies are needed to better evaluate pharmacologic adjuncts and laboratory-guided transfusion therapy, particularly viscoelastogram-guided therapy, in hemorrhaging patients. AUTHORS’ RECOMMENDATIONS Red blood cell transfusion • Used to augment the oxygen-carrying capacity of blood • Evidence-based transfusion trigger in critically ill, resuscitated patients is Hb 7 g/dL • Transfusion trigger in patients with end-organ dysfunction or shock remains uncertain. Common practice uses Hb 9–10 g/dL as a trigger for transfusion if the patient fails crystalloid resuscitation • Complication of transfusion can be grouped into: transfusion reaction (clerical), volume overload (TACO), and immune dysfunction (TRALI and TRIM) Plasma transfusion • Used to reverse diffuse coagulopathy • Dosed as 10–15 mL/kg • Has the highest association with TRALI • Consider treating vitamin K-dependent coagulopathy with PCC. Cryoprecipitate transfusion • Contains factor VIII, von Willebrand factor, factor XIII, and fibronectin • Used to treat DIC or to reverse thrombolytic-induced hemorrhage (i.e., hypofibrinogenemia) Platelet transfusion • May be used to reverse clopidrogrel (and possibly aspirin)-induced thrombocytopathy • Platelet count of 50,000–100,000 cells/dL are needed for operation, depending on the nature of the procedure planned • Other than TEG, there is no readily available test to clinically evaluate platelet function • Platelet dysfunction is common in critically ill or injured patients. Platelet transfusion should be carried out in the appropriate clinical setting and not solely to reverse this dysfunction Massive transfusion • Retrospective studies suggest that a ratio approaching 1:1:1 of RBC:FFP:platelet may decrease net transfusion needs • TXA acid may be associated with a survival benefit in hemorrhaging patients who have demonstrable thrombolysis but may also be associated with a rise in mortality in persons who do not

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74. Roberts I, Shakur H, Afolabi A, et al. The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096-1101, 1101. e1-2. 75. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147: 113-119. 76. Morrison JJ, Ross JD, Dubose JJ, Jansen JO, Midwinter MJ, Rasmussen TE. Association of cryoprecipitate and tranexamic acid with improved survival following wartime injury: findings from the MATTERs II Study. JAMA Surg. 2013;148:218-225.

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e1 Abstract: Transfusion therapy is ubiquitous in the intensive care unit, both as a means to optimize oxygen delivery as well as to maintain or restore appropriate coagulation. Coagulopathy and platelet dysfunction are reportedly common in severely injured or critically ill patients. The need to prioritize plasma transfusion in patients with trauma is established, and this practice has been extrapolated in noninjured, critically ill, bleeding patients as well. However, there are many risks associated with transfusion therapy, most of which can be broadly categorized as transfusion-related risks, such as volume

overload, acute lung injury, and immunomodulation. More recently, pharmacologic agents, including recombinant factor VIIa, tranexamic acid, and prothrombin complex concentrates, are being used for reversal of coagulopathy in bleeding patients. Each of these agents is associated with a variable degree of risk of thromboembolism. It remains to be determined if the use of these agents can partly or fully supplant the need for plasma transfusion. Keywords: anemia, coagulopathy, hemorrhage, platelet dysfunction, thrombocytopathy