Michael P. Jones and John E. Arbo
The use of blood product transfusion in the critically ill is commonplace, with more than 40% of all ICU admissions receiving some form of transfusion therapy.1 Patients with acute hemorrhage from trauma or gastrointestinal bleed, with severe coagulopathy, sepsis, and toxicologic syndromes may all require blood product administration. While blood products may confer benefit to the critically ill patient, the emergency physician and intensivist must also consider the potential risks of transfusion—which are numerous—when choosing to employ this therapy. This chapter reviews the indications and associated complications of the most commonly transfused blood products, namely packed red blood cells (PRBCs) and whole-blood derivatives such as fresh frozen plasma (FFP), cryoprecipitate, and platelets. Use of the synthetic antifibrinolytic tranexamic acid is also discussed.
INDICATIONS FOR BLOOD PRODUCT TRANSFUSION
Packed Red Blood Cells
The use of red blood cells in the critically ill patient has evolved in recent years. Prior to the Transfusion Requirements in Critical Care (TRICC) trial, PRBCs transfusion was used aggressively in patients with a hemoglobin (Hgb) concentration below 10 g/dL; this cutoff was based largely on physiologic and clinical assumptions and lacked significant evidentiary support.2 The results of the TRICC trial and subsequent follow-up studies suggested a more restrictive threshold of 7 g/dL for PRBC transfusion. The TRICC trial was a multicenter randomized controlled trial (RCT) of 838 patients admitted to the ICU (without evidence of active bleeding) and randomized to a restrictive (Hgb goal 7–9) or liberal (Hgb goal 10–12) transfusion strategy. Enrolled patients were euvolemic and had Hgb levels of <9 within 72 hours. The primary outcome, 30-day mortality, was similar in the two groups; however, the restrictive group's 30-day mortality was significantly lower among a subset of less acutely ill patients (APACHE II scores = <20, 8.7% vs. 16.1%) as well as among patients older than 55 years. There was also a significant reduction in in-hospital mortality for the restrictive group (22.2% vs. 28.1%).
Exceptions to the restrictive transfusion strategy recommendation include patients with acute hemorrhage and hemodynamic instability; and septic patients with evidence of inadequate tissue oxygen delivery (guided by trauma and sepsis literature respectively). The optimal transfusion threshold for patients with acute myocardial ischemia or unstable angina is unknown, as these patients have typically been excluded from these trials.3 In a subgroup analysis of the TRICC trial, however, patients with active ischemic cardiac disease had better outcomes when a transfusion threshold of <10 g/dL was used.
Plasma Products: Fresh Frozen Plasma and Cryoprecipitate
Plasma products, including FFP and cryoprecipitate, represent the liquid portion of human blood that remains after cellular components such as red and white blood cells have been removed. Guidelines for plasma use in critically ill patients are poorly established due to a paucity of data. Based on clinical experience and biologic rationale, plasma transfusion is generally recommended in patients with inadequate hemostasis, particularly in those with known or suspected coagulation abnormalities. The current accepted indication for plasma is: any abnormality on coagulation tests (prothrombin time, international normalized ratio (INR), or partial thromboplastin time) in patients slated for invasive procedures carrying a high risk of bleeding complications; and severe coagulation abnormality in patents slated for invasive procedures carrying a low risk of bleeding complications.4 Additionally, any patient with abnormal coagulation tests and life-threatening bleeding should receive FFP.
Fresh frozen plasma (FFP) is a plasma product that contains all coagulation factors in normal concentrations. In the average patient, 1 unit of FFP will raise coagulation factors by 5% to 8% and fibrinogen by 13 mg/dL. FFP is used to reverse severe coagulopathy or excessive anticoagulation resulting from warfarin use in patients with active bleeding or in need of immediate invasive procedures.5FFP is not effective at reversing minor elevations in the INR (1.3 to 1.8).6
Cryoprecipitate, also derived from plasma, contains fibrinogen, von Willebrand factor, factor VIII, and factor XIII. It is packaged in six concentrated units, each unit taken from a separate donor. Cryoprecipitate is indicated for patients with severe hypofibrinogenemia (<100 mg/dL) immediately prior to any invasive procedure. Its chief advantage is that it provides these factors in substantially less volume than an equivalent transfusion of FFP. Cryoprecipitate is not commonly used in patients with von Willebrand disease or hemophilia A (factor VIII deficiency), as other therapies, such as desmopressin (DDAVP) and concentrated factor VII, are more specifically targeted to these conditions.
Platelet transfusion in the critically ill may be used to help stop or prevent bleeding in patients with thrombocytopenia. Current guidelines recommend platelet transfusions in patients with platelet counts <10,000/μL for the prevention of spontaneous bleeding; in patients with counts <50,000/μL with active bleeding or requiring invasive procedures; and in those with counts <100,000/μL with central nervous system (CNS) injury, major trauma, or requiring neurosurgical intervention.7,8
Tranexamic acid is a synthetic derivative of the amino acid lysine and an antifibrinolytic that inhibits the activation of plasminogen to plasmin. It is commonly used in surgeries with high risk of blood loss. Several recent studies have advocated its use in acute care settings; data suggest that when given to trauma patients within 3 hours of acute injury, tranexamic acid confers a mortality benefit.9–11 In the CRASH-2 study—an RCT of 20,211 adult trauma patients with, or at risk of, significant bleeding—patients received either tranexamic acid (loading dose 1 g over 10 minutes and then infusion of 1 g over 8 hours) or matching placebo. Tranexamic acid was associated with a 1.5% absolute reduction in mortality (14.5% vs. 16%) compared to placebo. A separately published but prespecified subgroup analysis demonstrated that early administration of tranexamic acid (within 1 hour of injury) was associated with greater reductions in death due to bleeding, while delayed administration (>3 hours from injury) was associated with increased bleeding deaths. All-cause mortality was reduced in the <1 hour and 1–3 hour strata, but not in the >3 hour stratum. Further studies are needed to clarify these results, as this trial did not specifically measure innate fibrinolytic activity of participants and lacked complete data in the subgroup of all-cause mortality.
Transfusion in Massive Hemorrhage
Several recent and ongoing studies advocate for a more balanced approach to the ratio of blood product transfusion in the acutely hemorrhaging patient, specifically in cases of hemorrhage due to trauma. Hemorrhaging patients lose red cells, platelets, and coagulation factors, so replacement with PRBCs alone can lead to a dilution of platelets and coagulation factors, blunting the effects of the clotting cascade. A more appropriate strategy in these patients is to replace red blood cells, platelets, and plasma simultaneously. The exact ratio of these products is the subject of ongoing clinical trials, but data suggest a ratio of 1:1:1 confers a survival benefit at 24 hours and 30 days (Table 30.1).12–14
TABLE 30.1 Summary of Indications for Blood Product Transfusion
Blood product transfusion is not without risk; however, adverse reactions with significant morbidity and mortality have steadily declined, due in large part to advances in screening techniques for infectious disease.15 Transmission of serious infectious disease, once the most common cause of blood transfusion mortality, has been supplanted in frequency by transfusion-related acute lung injury (TRALI), transfusion-related circulatory overload (TACO), and transfusion-associated immunologic complications.
Transfusion-transmitted infections have a variety of bacterial and viral etiologies. Platelet transfusions carry the highest risk of bacterial contamination because they are stored at room temperature. If bacteremia—which may present with typical findings of fever, rigors, tachycardia, and hypotension—is suspected, the transfusion should be stopped, and the patient and blood products broadly cultured and evaluated for an immunologic-related transfusion reaction (discussed below). HIV infection from blood transfusions has steadily declined, mostly because of donor behavior screening and sophisticated testing of blood products for HIV antibody and nucleic acid. However, HIV contamination may occur if the donor is tested during the window period of infection or is infected with a variant strain that eludes current assays. The risk of HIV transmission from transfusion is estimated to be 1 in 1.4 million units.16
Transmission of the hepatitis C virus via blood transfusion once accounted for 0.5% to 10% of HCV infections; now, with increasingly sensitive blood donor screening assays (including nucleic acid testing) and with behavioral screening, the transmission rate from transfusion is estimated to be 1 per 2 million units.17
Transfusion-Related Acute Lung Injury
Transfusion Related Acute Lung Injury (TRALI) is a rare but serious complication of blood transfusion. The diagnosis of TRALI is made in patients receiving transfusions who develop hypoxemia, fever, and bilateral infiltrate on chest radiograph within 2 to 6 hours of blood product transfusion. The condition must be determined not to be the result of circulatory overload or preexisting acute lung injury. TRALI is considered a form of acute respiratory distress syndrome (ARDS), caused when HLA antibodies in the donor serum trigger activation of the complement system and result in lung injury. Aggressive respiratory support is warranted in these patients and may include noninvasive positive pressure ventilation; most patients eventually require intubation and mechanical ventilation.18,19 With appropriate supportive care, complete recovery is usually made within 24 to 48 hours.
Transfusion-Associated Circulatory Overload
Transfusion-Associated Circulatory Overload (TACO) occurs following large-volume blood transfusion and is more common in the elderly, children, and those with preexisting cardiac dysfunction. Clinical presentation is similar to TRALI and includes acute dyspnea and hypoxemia, but TACO is uniquely accompanied by hypertension, which can help distinguish the two entities. Additionally, B-type natriuretic peptide levels are likely to be elevated in TACO. Prevention is paramount and includes slow transfusion rates and smaller volumes of transfusion. TACO should be treated similarly to cardiogenic pulmonary edema, with noninvasive ventilatory support and diuresis.20
Immunologic complications of blood transfusion include acute and delayed hemolytic reactions, febrile nonhemolytic transfusion reactions (FNHTR), transfusion-associated graft versus host disease (TA-GvHD) and allergic reactions.
Hemolytic reactions are rare, and occur in <0.01% of transfusions. These reactions, caused most often by ABO-incompatible blood, may be immediate or delayed. Immediate reaction is characterized by fevers, hypotension, pain, and oliguria; delayed reactions by fever, Coombs-positive hemolytic anemia, jaundice, and lack of expected rise in Hgb levels. Treatment includes immediate cessation of transfusion, aggressive hydration, supportive care, and blood bank notification.
FNHTRs, caused by the presence of leukocyte debris and cytokines in the donated blood, are more common and occur in up to 7% of red blood cell transfusions.21 Patients will present with a spectrum of symptoms including fevers, pain at the infusion site, hypotension, mental status changes, and bleeding diathesis. Laboratory tests used to differentiate hemolytic reaction from nonhemolytic reaction include a peripheral blood smear, haptoglobin, and Coombs' testing. Mainstays of therapy include acetaminophen and diphenhydramine. In patients who have had FNHTRs, future transfusions require use of leukoreduced blood specimens.
TA-GvHD is a rare and commonly fatal complication of blood transfusion.22 TA-GvHD results when donor lymphocytes mount an immune response to the blood recipient's antigen presenting tissues. TA-GvHD is typically limited to immunosuppressed patients (e.g., Hodgkin disease and leukemia, but notably not with HIV), and presents with dysfunction of the liver, skin, and bone marrow 4 to 30 days following blood transfusion. Since no effective therapy exists, prevention in susceptible patients—achieved by use of leukoreduced or irradiated blood products—is essential.17
Allergic reactions are also common in blood product transfusion and do not require previous sensitization to blood products. Like all allergic reactions, they range from urticaria to bronchospasm to anaphylaxis, and should be treated with the immediate cessation of transfusion and antihistamines, steroids, volume replacement, and, when necessary, epinephrine.
Citrate toxicity may occur following large-volume blood transfusion. Citrate is an anticoagulant added to preserved PRBCs in order to chelate calcium and prevent clotting. Large-volume infusions can cause a metabolic alkalosis from citrate metabolism, as well as a reduction in ionized calcium resulting from calcium complex formation. Symptoms of severe hypocalcemia include tetany, cardiac dysrhythmias, and hypotension, and require treatment with calcium gluconate or calcium chloride. Importantly, if required, calcium therapy should be administered in a separate vein from the transfusion line to prevent clotting.
Transfusion therapy, while commonplace in the critically ill population, is not without its accompanying risks. Adherence to established guidelines for transfusion enables appropriate patient care and minimization of adverse outcome.
1.Corwin HL, Gettinger A, Pearl RG, et al. The CRIT Study: anemia and blood transfusion in the critically ill—current clinical practice in the United States. Crit Care Med. 2004;32:39.
2.Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409.
3.Napolitano LM, Kurek S, Luchette FA, et al. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009;37:3124.
4.Yang L, Stanworth S, Hopewell S, et al. Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. Transfusion. 2012;52:1673.
5.Gajic O, Dzik WH, Toy P. Fresh frozen plasma and platelet transfusion for nonbleeding patients in the intensive care unit: benefit or harm? Crit Care Med. 2006;34:S170.
6.Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion. 2006;46:1279–1285.
7.Fresh-Frozen Plasma, Cryoprecipitate, and Platelets Administration Practice Guidelines Development Task Force of the College of American Pathologists. Practice parameter for the use of fresh-frozen plasma, cryoprecipitate, and platelets. JAMA. 1994;271:777.
8.Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007:172–178.
9.Shakur H, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage. Lancet. 2010;376(9734):23–32.
10.Roberts I, 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(9771):1096–1010.
11.Morrison JJ, et al. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147(2):113–119.
12.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.
13.Holcomb JB, Wade CE, Michalek JE, et al. Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients. Ann Surg. 2008;248:447.
14.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.
15.Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113:3406.
16.Zou S, Dorsey KA, Notari EP, et al. Prevalence, incidence, and residual risk of human immunodeficiency virus and hepatitis C virus infections among United States blood donors since the introduction of nucleic acid testing. Transfusion. 2010;50:1495.
17.www.cdc.gov/hepatitis/HCV/index.htm. Accessed September 16, 2013.
18.Kleinman S, Caulfield T, Chan P, et al. Toward an understanding of transfusion-related acute lung injury: statement of a consensus panel. Transfusion. 2004;44:1774.
19.Toy P, Popovsky MA, Abraham E, et al. Transfusion-related acute lung injury: definition and review. Crit Care Med. 2005;33:721.
20.Li G, Rachmale S, Kojicic M, et al. Incidence and transfusion risk factors for transfusion-associated circulatory overload among medical intensive care unit patients. Transfusion. 2011;51:338.
21.Raghavan M, Marik PE. Anemia, allogenic blood transfusion, and immunomodulation in the critically ill. Chest. 2005;127:295.
22.Fast LD. Developments in the prevention of transfusion-associated graft-versus-host disease. Br J Haematol. 2012;158(5):583–588.