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Original Article

Risks associated with bleeding and transfusion: rationale for the optimal management of bleeding after cardiac surgery

Despotis, G.*; Renna, M.; Eby, C.

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European Journal of Anaesthesiology: June 2007 - Volume 24 - Issue - p 15-36

Abstract

Introduction

Adverse outcomes related to excessive bleeding

Patients undergoing surgical procedures are at risk for development of bleeding that results in hemodynamic consequences necessitating volume/vasopressor resuscitation along with transfusion support. Although patients undergoing any type of surgical intervention are at risk for excessive bleeding, generally this problem occurs in certain high risk clinical settings such as trauma, cardiac surgery and liver transplantation. Accordingly, most of the studies which have examined the role of interventions designed to optimize the management of this clinical problem (e.g. point-of-care diagnostics) have been predominately evaluated in the cardiac surgical environment. Therefore, the majority of our discussion will revolve around this clinical setting.

Excessive microvascular bleeding can result in re-exploration which has been shown to be associated with a variety of negative outcomes such as a 3-4 fold increase in mortality, renal failure, sepsis, atrial arrhythmias, prolonged requirement for mechanical ventilatory support and longer length of stay [1-4]. In these analyses, only 50% of patients who have excessive bleeding requiring re-exploration have a surgical source of bleeding which demonstrates the important role of acquired hemostatic abnormalities that result in diffuse, microvascular bleeding. Therefore, failure to find a surgical source of bleeding suggests an acquired hemostatic abnormality causing diffuse, microvascular bleeding. In addition, the analysis by Moulton et al. demonstrated that excessive bleeding per se (without surgical re-exploration) is the most likely cause of increased mortality. Indeed in their series mortality was increased by three-fold when patients who were not re-explored bled more than 2 liters within the first 24 hours after surgery [1]. Excessive bleeding requiring transfusion may also result in other complications such as stroke and may affect long term mortality. In a large, recently published analysis, excessive bleeding requiring more than four units of PRBC transfusion was the strongest (odds ratio=5) independent predictor with respect to perioperative stroke [5]. Similarly, another recent publication by Mangano demonstrated a strong relationship between perioperative platelet transfusion and stroke [6]. In addition, recent studies have demonstrated that long term mortality may be increased in cardiac surgical patients who receive transfusion [7,8]. Patients with excessive bleeding and who require transfusion support may be predisposed to developing stroke due to one or more potential mechanisms such as: ischemic injury as related to bleeding with hypotension/hypoperfusion or anemia, microemboli or microthrombi (i.e., as related to platelet transfusion) or aggravation of ischemic injury by white cell priming lipids within transfusion.

Transfusion-related risks

1. Established transfusion risks

Approximately 14.2 [9] and 1.6 million platelet transfusions (each being a single donor pheresis platelet product or a pool if six whole blood donor platelet concentrates; approximately 85% as single donor platelets) are administered in the United States each year. Transfusion-related serious adverse events were estimated by Walker in the 1980s to occur in 0.5% of transfusions [10] while more recent estimates indicate that they occur in < 0.05% of platelet transfusions. Using early estimates, transfusion-associated adverse events were thought to lead to a short-term (i.e., not including disease transmission-related deaths) mortality of 1 to 1.2 per 100,000 patients or approximately 35 transfusion related deaths/year in the United States. Using more recent estimates, long-term or total (i.e., including disease transmission-related deaths) mortality is probably closer to 1 per every 37,000 platelet or 130,000 red cell units administered or approximately 220 transfusion-related deaths/year in the United States [9,11]. Even these estimates, however, may be underestimating transfusion-related mortality. For example, there were only 21 transfusion-related acute lung injury-related fatalities reported in 2003 [12], while projections based on an incidence of 1:5000 transfusions with a 6% mortality rate indicate that this syndrome can account for at least 300 deaths annually in the United States. Based on application of current estimates to a worst case scenario, transfusion related mortality as related to the three leading causes of death reported to the FDA (e.g. transfusion associated acute lung injury, bacterial sepsis, ABO hemolytic transfusion reactions) [13] and other causes (lipid-enveloped viral transmission, anaphylaxis etc) may approximate 50-100 deaths per million units transfused. However, recent publications suggest that in certain high-risk patient populations, death related to white-cell mediated target organ injury may be exponentially greater (i.e., 10-15,000 deaths per million units) (Fig. 1) [14-17].

Figure 1.
Figure 1.:
Estimates of risk of death per unit transfused for several transfusion related complication categories in patients undergoing cardiac surgery. Misc includes the following transfusion related complication categories: allergic, transfusion associated graft vs. host disease, metabolic (e.g. hyperkalemia, acidosis), or iron overload. WBC-mediated refers to one or more of the following complications: multi-organ system failure, transfusion related immune modulation resulting in perioperative infection, end-organ injury (e.g. myocardium, renal etc). *Denotes that estimates are derived via mathematical modeling. †Denotes that estimates derived from either published studies or via FDA adverse event reporting. ‡Denotes that death rate estimates are derived from randomized, prospective studies that evaluated the potential difference in mortality between patients who received leukoreduced vs. non-leukoreduced red cell units.

2. The leading causes of transfusion-related mortality reported to the FDA

Transfusion-associated respiratory distress can be related to one of the following causes (in order of decreasing frequency): fluid overload (also called transfusion-associated circulatory overload or TACO), allergic reactions, or TRALI. Although the exact incidence of circulatory overload related to transfusion is unknown (e.g., one in every 200-10,000 U) [18] it is more likely to occur in older patients with a history of congestive heart failure. Reported estimates of the frequency of TRALI range from 1:400 to 1:50,000 transfusions (i.e., involving either plasma, platelets or red cells) [19]. This extremely wide estimated range reflects the difficulties in clinical recognition of TRALI with resultant underreporting. Both one-hit (anti-leukocyte antibodies) and two-hit mechanisms have been proposed as the etiology of TRALI. Indeed, as TRALI is a clinical syndrome, more than one mechanism can potentially result in a final common pathway of pulmonary endothelial damage and capillary leak. In the two-hit hypothesis, the first hit involves priming of the pulmonary endothelium via a precipitating event in the recipient (e.g. surgery, infection or hypoperfusion) that activates the endothelium and leads to neutrophil sequestration. The second hit then involves the effects of a biologic response modifier, either anti-HLA antibodies (which are found in 15-26% of units form multiparous donors) or anti-leukocyte antibodies or neutrophil-activating lipid mediators present in transfused units. Any of these potential biologic modifiers can then further attack circulating and pulmonary leukocytes or pulmonary endothelium directly and ultimately stimulate complement activation and pulmonary injury [18]. With ventilatory and hemodynamic supportive management, most patients recover within 48-96 hours, however, mortality rates of 5-25% have been reported [19]. In fact, TRALI has emerged as the leading transfusion-related causes of death (i.e., 15.8-22.3% of total) reported to the FDA from the years 2001-2003 [13]. Although a death rate related to TRALI of 1.5 deaths per million units transfused (i.e., assuming an annual national transfusion of 15 million red cell, platelet and plasma units) can be estimated using FDA reports [13], the death rate may be as high as 500 deaths per million units if it is based on the incidence of TRALI with platelet units as derived from the study by Silliman et al. [20].

The infusion of bacterially contaminated blood is an uncommon cause of febrile transfusion reactions with approximately 1:2000 units contaminated with bacteria. The risk of sepsis is much greater (i.e., 40 fold) from platelets (stored at 20-24 °C) than from RBCs (stored at 4 °C) [9,11]. Overall, infusion of bacterial contaminated blood products can lead to transfusion-related sepsis in 1:25,000 platelet recipients vs. 1:250,000 red cell recipients [21] with an associated mortality rate of 26% [9,11]. This complication accounts for 10.5-17.9% of transfusion-related fatalities previously reported to the FDA [13,22]. It has been estimated that infusion of bacterial contaminated components results in 20 deaths per million units transfused [9]. Bacterial growth increases in components stored at room-temperature especially if the storage interval is greater than five days, which has led to the current FDA limit of 5 days; however, extension to 7 days with use of certain storage media are under investigation. Gram negative septic shock associated with RBC transfusion is related to the effects of endotoxin produced by pathogenic bacteria that grow at 4 °C (e.g. Yersinia enterocolitica) which have been isolated at a frequency of 1:50,000 U [22]. To enhance blood safety, rapid bacterial screening of all platelet products was introduced in the United States in 2004. It is estimated that this step will lead to a major reduction (i.e., potentially 50%) in transfusion-transmitted bacterial infections from platelets.

Current estimates indicate that the wrong unit of blood is administered once every 12,000 units and 1:33,000 units involves ABO incompatibility [23]. Catastrophic, acute hemolytic transfusion reactions are rare with a range of one in every 33,000 to 500,000 U [9,11,22]. However, ABO incompatible transfusions can be fatal in 10% of cases and account for at least (i.e., these events are probably under-reported) 16 deaths every year (i.e., 1:800,000 U transfused or 1.2 deaths per million units transfused) in the United States [11,22]. Delayed hemolytic transfusion reactions which involve non-complement mediated extravascular hemolysis as related to development of an antibody to a non-ABO antigen 1-2 weeks after transfusion are generally well tolerated, however, on occasion they have been reported to cause death.

The risk of transmission of lipid enveloped viruses such as HIV (1:2.1 million units), HTLV- I/II (1:3 million units), Hepatitis B (1:205,000 units) and Hepatitis C (1:1.8 million units) has been steadily decreasing over time [24,25], with utilization of more sensitive immunoassays and the use of nucleic acid amplification testing (NAT) [9,11]. It is currently estimated that the death rate related to transmission of one of the lipid enveloped viruses accounts for 2-3 deaths per million units transfused [9]. Hepatitis D is problematic only when there is ongoing or prior HBV infection whereas transmission of either the enterically-transmitted Hepatitis A or E via transfusion is rare. Other blood-borne, infectious diseases such as syphilis, Epstein-Barr virus, leishmaniasis, Lyme disease, brucellosis, B-19 parvovirus (increased prevalence in hemophiliacs), tick-borne encephalitis virus, Colorado Tick fever virus, and human herpes viruses as well as parasitic diseases (e.g. malaria, babesiosis, toxoplasmosis and Chagas' disease) and possibly variant Creutzfeldt-Jakob disease are rarely (i.e., as compared to transmission rates for the lipid enveloped viruses) transmitted via transfusion in the United States. However, the prevalence of these diseases is relatively high in some areas of the world and with ever increasing international travel and immigration, they can potentially become more significant transfusion risks in the United States. An example is West Nile virus (WNV) which was only identified in the United States in 1999, but led to transplant and transfusion-related viral transmission. Introduction of WNV NAT testing potentially prevented 1500 cases of transfusion-transmitted WNV in 2003 [26].

3. Other Important Red Cell and platelet related complications: Immune modulation, target organ or multi-organ system failure and short vs. long-term survival

Transfusion-associated immune system modulation has been shown to have beneficial (e.g. improved renal allograft survival) effects in certain situations (e.g. improved renal allograft survival) whereas other detrimental effects (e.g. increased cancer reoccurrence, perioperative infections and/or multi-organ system failure) are controversial. Although several studies have demonstrated an independent effect (i.e., using multivariate statistical models) of transfusion on increased perioperative infection rates (i.e., 4-5 fold) in a number of different surgical populations (i.e., trauma, [27,28] spinal [29], colorectal [30-36] and cardiac [37,38]), the exact impact of transfusion-mediated immune-modulation on the incidence of perioperative infection is still controversial [17,39,40].

In addition, several recent studies have demonstrated that transfusion of non-leukoreduced units may potentially increase the incidence of multi-organ system failure (MOSF) in the perioperative setting [41-43]. Although the exact mechanisms of the effect of transfusion on the incidence of this complication have not been clearly elucidated, it is postulated that in patients who are at high-risk (e.g. trauma, long CPB intervals) for developing endothelial dysfunction, either white cell-platelet aggregates, white cell lytic enzymes or other cellular debris cause additional damage to the already dysfunctional endothelium. Support for this mechanism is provided by the findings of van der Watering et al. who demonstrated that non-cardiac mortality as related to other causes like MOSF was reduced by 86% when patients undergoing cardiac surgery received leukoreduced PRBC units [15].

There may be other, incompletely characterized mechanisms related to the number of white cells within the unit or the age of the red cell unit (i.e., which may increase the concentration of cellular debris, lytic enzymes or cytokines) that may account for increased mortality as related to transfusion of red cells in high risk cardiac surgical patients. The reduced safety of red cells in high risk populations is highlighted by several studies which demonstrate an increase in either complications or mortality with increased transfusion of red cell units [14-17,44]. In the first randomized study that evaluated the clinical impact of liberal vs. conservative transfusion strategies in a large series (n = 713) of critically ill intensive care unit patients, Hebert et al. demonstrated a higher complication rate (i.e., myocardial infarction, pulmonary edema and acute lung injury) in patients who received a greater number of red cell units as directed by a liberal transfusion strategy [14]. Although an observed 20% reduction in short-term mortality was not shown to be statistically significant, the lack of significance may have been related to a Type II statistical error (i.e., an additional 1700 patients would have to be enrolled to adequately evaluate the potential for 20% reduction). A similar study was completed by Bracey et al. which evaluated the effect of reducing the red cell transfusion trigger from 9 to 8 g/dl of hemoglobin in a series of cardiac surgical patients (n = 428) [44]. This study demonstrated that sustaining a lower hemoglobin and administration of less red cell units (i.e., treatment group: 0.9 ± 1.5 U vs. control group: 1.4 ± 1.8 U, p = 0.005) did not adversely effect patient outcome (i.e., no statistical difference in morbidity or mortality). Although an observed reduction in mortality by 50% was not statistically different (p = 0.321) between the treatment group (1.4%) and the control group (2.7%), a Type II statistical error cannot be excluded since 5300 patients would be required to adequately power a study to detect a 50% reduction in mortality.

The inherent risks related to administration of red cell units to cardiac surgical patients is also indirectly supported by the reduced mortality observed when patients receive leukoreduced units during or after cardiac surgery in three prospective, randomized studies (Fig. 2) [15-17]. Bilgin et al. [16] observed a 33% reduction in-hospital mortality, while van de Watering et al. [15] observed a 50% reduction in 60 day mortality and Wallis et al. [17] observed a non-significant (p = 0.11) 80% reduction in three-month mortality. However the study published by Wallis may have been inadequately powered to address mortality since enrollment of 1174 patients would be required (i.e., 80% power) to exclude a Type II statistical error. A lower percentage of patients who received leukoreduced units in these trials developed mult-organ system failure which may in part account for the reduced mortality observed (e.g. 86% reduction of MOSF related mortality in the van de Watering study). These findings were also supported by Habib et al. who observed higher renal complication rate in patients who developed intraoperative anemia (mean nadir hematocrit approximately 18%) and who also received red cell units during CPB [45] when compared (i.e., using propensity adjustment) to another cohort who developed the same degree of anemia but who did not receive red cells. Although the study by Fung et al. does not support these findings, unlike the previously cited randomized, prospective studies, the study by Fung et al. was not randomized and used a historical control group [46]. The studies by van de Watering, Bilgin and Wallis highlight the relative importance of the effects of non-leukoreduced red cell units with respect to mortality and specifically reveal that there are inherent risks related to transfusion of non-leukoreduced red cell units to patients undergoing cardiac surgery. In addition, the length of refrigerated storage of transfused red cells may be more relevant to high risk populations like cardiac surgical patients who may be predisposed to end-organ damage or multi-organ system failure [47].

Figure 2.
Figure 2.:
Effect of leukoreduction on mortality after cardiac surgery. This graph summarizes the results from 3 randomized, prospective studies and one non-randomized study using a historical control group (as denoted by £) that examined the impact of use of leukoreduced red cell units. First author and year of publication highlighted within each box at the top of the figure and the number of patients within each study are detailed below the author. Hatched bar represents the mortality in the control (C) series who received non-leukoreduced red cell units. The solid bar represents the mortality in the series of patients who received leukoreduced (LR) red cell units. Asterisks represent p< 0.05 between treatment cohorts. †p = 0.11, to definitively exclude a Type II statistical error 1174 patients would need to be enrolled to detect an 80% decrease in mortality.

The risks related to transfusion of non-leukoreduced red cell units in high-risk scenarios are logarithmically higher than all of the other established and evolving risks of transfusion (Fig. 1). Hopefully, these analyses will lead to a change in practice involving the exclusive issuance of only leukoreduced red cell units to patients undergoing cardiac surgery. Ultimately this can only occur if there are adequate blood bank inventories of leukoreduced red cell units and that cardiac surgical patients are prioritized to receive leukoreduced units.

4. Other clinically significant transfusion-related reactions

Mild allergic symptoms (e.g. rash, hives or itching) occur with 1-3% of transfusions [48], are generally self-limiting and may improve with or be prevented by anti-histamine prophylaxis. More significant allergic transfusion reactions (i.e., anaphylactic) can occur with 0.1-0.3% of units and are most likely related to reactions to other soluble transfusion constituents (e.g. complement or other plasma proteins, drugs or soluble allergens) [48]. Severe anaphylactic reactions, which occur infrequently (i.e., 1:20-50,000), may be accompanied by IgE mediated signs and symptoms involving the respiratory (e.g. dyspnea, bronchospasm), gastrointestinal (e.g. nausea, diarrhea, cramps) or circulatory (e.g. arrhythmias, hypotension, syncope) systems [48]. Although IgA deficiency, which occurs in 1 in every 800 patients of which only 30% have anti-IgA, is an uncommon cause of transfusion-associated anaphylaxis, this diagnosis should be considered in any patient exhibiting anaphylaxis. Laboratory evaluation includes sensitive measurement of serum IgA and if low or absent, testing for IgA antibodies by immunoradiometric assay. In addition to HTR, bacteremia/sepsis and anaphylaxis, other potential causes of hemodynamic perturbations during or after a transfusion include citrate-related hypocalcemia (i.e., with rapid infusion), inadvertent intravenous air embolus, cytokine-mediated effects or activation of bradykinin by leukoreduction filters and inadequate clearance in patients on angiotensin converting enzyme inhibitors (80 reports to the FDA).

5. Relationship between transfusion and long term outcome

Results from one recent study identified the age of transfused red cell units as an independent risk factor for hospital length of stay, adverse renal outcomes and in-hospital mortality [47]. Large database analyses have revealed that transfusion of either platelets [49] or red cell units [50] can potentially increase the risk for stroke and that transfusion in general is associated with reduced short [49] or long-term survival [7,46] after cardiac surgery. Therefore, current and emerging transfusion related risks (Fig. 1) underscore one of the important consequences of excessive bleeding after cardiac surgery and highlight the importance of implementing strategies to minimize blood loss and transfusion by optimizing hemostasis management.

Hemostatic physiology and mechanisms of excessive bleeding

Hemostatic system overview

The hemostatic system limits hemorrhage when vascular integrity is compromised and includes several major components: platelets, von Willebrand factor (vWF), coagulation and fibrinolytic factors and the blood vessel wall. The endothelium normally serves as a protective layer against hemostatic activation. When endothelium is denuded, activated platelets adhere to exposed subendothelium, a reaction largely mediated by vWF, and then aggregate to provide initial hemostasis. Platelets also provide an active phosholipid surface for interaction with coagulation factors. The coagulation system consists of a number of enzyme precursors (zymogens) and co-factors, and is subdivided into three pathways (i.e., intrinsic, extrinsic and common) that ultimately lead to formation of a fibrin clot. Tissue factor activates the extrinsic pathway to form fibrin and leads to thrombin formation which also activates factor XIII, which stabilizes the hemostatic platelet plug. Several important physiologic mechanisms counterbalance the propensity of both platelets (i.e., via PGI2, nitrous oxide) and the coagulation system (e.g., proteins C and S, antithrombin III or antithrombin, heparin-cofactor II and tissue factor pathway inhibitor or TFPI) to form a clot. The fibrinolytic system consists of several plasminogen activators (e.g., tissue plasminogen activator or tPA, urnokinase) that produce plasmin, which lyses fibrin and potentially prevents vasocclusion at the site of vessel injury. The fibrinolytic system is regulated by plasminogen activator inhibitor (PAI1) and α-1-antiplasmin that neutralize tPA and plasmin, respectively.

Mechanisms for excessive perioperative bleeding

Although excessive bleeding during and after surgery may be related to isolated defects within the hemostatic system, excessive bleeding is more likely related to a series of events or ‘multiple hits.’ The incidence of bleeding complications and/or the severity of a specific bleeding event can be related to the number of defects or ‘hits’ as well as the degree or severity of the individual or multiple defects. Potential defects or ‘hits’ that can influence the incidence and severity of bleeding after cardiac surgery include pre-existing inherited or preoperatively acquired (e.g. pharmacologic agents, other co-existing disorders that affect the hemostatic system) defects as well as those acquired defects that are secondary to the use of extracorporeal circulation. Hereditary deficiencies in either coagulation factors or platelets may lead to excessive bleeding, however, these are uncommon causes of bleeding after cardiac surgery relative to the incidence of acquired defects [51-53]. Preexisting preoperative disseminated intravascular coagulation (DIC), significant hepatic or renal impairment, or connective tissue disorders (e.g. Ehlers Danlos) may also precipitate excessive bleeding after surgery.

Specific mechanisms with cardiac surgery

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at increased risk for microvascular bleeding requiring perioperative transfusion of blood components. The pathophysiology of acquired hemostatic system abnormalities as related to use of extracorporeal circulation include: (1) Hemodilution secondary to volume resuscitation or loss (i.e., via bleeding or use of cell salvage) of platelets and coagulation factors. (2) The type of solution used to replenish the intravascular space (e.g. use of large doses of Hespan may lead to specific abnormalities in coagulation factors and platelet adhesion/function). (3) The effects of hypothermia on both plasma coagulation factors and platelet function. (4) Consumption or a ‘DIC-like’ state secondary to tissue injury, contact activation and most importantly, as related to retransfusion of shed pericardial blood. (5) Excessive fibrinolysis as either a primary or more likely a secondary process (i.e., as related to thrombin-mediated activation). (6) Residual heparin or ‘heparin’ rebound.

Exposure of blood to the extracorporeal circuit and hypothermia [54,55] leads to impairment of the hemostatic system and excessive bleeding. Activation of both intrinsic [56] and extrinsic [57,58] pathways results in excessive thrombin [57,59-62] and fibrinolytic [63-69] activity which can lead to consumption of platelets and labile coagulation factors [60,61,70]. The risk of development of excessive, non-surgical bleeding is influenced by the type of procedure [71,72] and the duration of cardiopulmonary bypass (CPB) [1,2,54,73,74] and multiple other patient-related factors (age, gender, body surface area or BSA, co-existing disease, preoperative hematocrit) [74]. These mechanisms ultimately can lead to multiple abnormalities involving either coagulation factors and/or platelet. Although excessive bleeding after cardiac surgery can be related to reduced circulating levels of coagulation factors [72,75-82] and several other abnormalities [83-85] including heparin rebound [86], the effects of hypothermia [54,55] and acidemia [87], platelet-related abnormalities are considered the most important hemostatic abnormality in this setting [73,77,88-91].

Although the use of aspirin and nonsteroidal anti-inflammatory agents can lead to bleeding in a subset of patients who display evidence of an exaggerated response to these agents (i.e., hyper-responders), the majority of patients do not bleeding excessively [92]. Similarly, although patients on warfarin preoperatively may bleed after cardiac surgery two studies demonstrated an inverse relationship between postoperative INR and blood loss which may be secondary to warfarin-mediated hemostatic system preservation during CPB [93,94]. The use of direct (e.g. hirudin [95-97] argatroban [98], bivalirudin) [99], or indirect (low molecular weight heparin compounds [100-103]) inhibitors of thrombin can potentially increase bleeding. More importantly, potent inhibitors of platelet IIb/IIIa (e.g., abciximab [104-108], eptifibatide [109], tirofiban) and the ADP receptors (e.g. chlopidogrel) [110-121] as well as fibrinolytic agents (e.g., recombinant tissue plasminogen activator) [1,2] can potentially increase bleeding and complicate clinical management. The risk of bleeding related to these agents depends on their relative potency, pharmacodynamic half-life, time interval for most recent dose before surgery, and whether or not a reversal agent is available. Although the exact association between these agents and the severity of bleeding or transfusion requirements in patients undergoing cardiac surgical procedures is currently being defined, several reports have demonstrated severe, intractable bleeding with use of either the direct thrombin inhibitors for anticoagulation with cardiopulmonary bypass [95-97,99] or with preoperative use of clopidogrel (Plavix®) [110-121]. In fact, all twelve studies that evaluated the effect of Plavix in the cardiac surgical setting demonstrated a consistent increase in both blood loss and transfusion (e.g. 2-8 fold increase) when patients were receiving this agent preoperatively. In addition, one of the twelve studies demonstrated an increased in-hospital mortality rate when patients received clopidogrel preoperatively [121].

Management of bleeding: indications for hemostatic therapy and dosing

Although numerous pharmacologic and non-pharmacologic strategies are being utilized to prevent excessive bleeding and minimize transfusion requirements, this review will be limited to the optimal management of bleeding after it arises as a clinical problem.

Specific indications and guidelines for hemostatic blood components

Traditional management of excessive bleeding has involved intravenous administration of pharmacologic agents or hemostatic blood components as well as application of topical agents. Replenishment of coagulation factors can be achieved with the use of fresh frozen plasma (FFP). National Institutes of Health (NIH) guidelines for the use of FFP in the perioperative setting have been previously published and recommend use of plasma to restore hemostasis in patients with either acquired or congenital deficiencies [122]. The American Society of Anesthesiologists (ASA) has expanded these recommendations by suggesting that FFP be used in the setting of active bleeding that may be related to substantial reductions in coagulation factor levels (i.e., with PT and aPTT results > 1.5 x the mean of a normal reference population) and that the dose of FFP be adequate to achieve at least 30% factor levels [123]. Approximately 15 ml/kg of FFP will result in a rise in factor values by 30% (i.e., 0.3 U/mL) in the average adult. Cryoprecipitate is generally administered for either hypofibrinoginemia (< 80-100 mg/dl) or dysfibrinoginemia and 10 U of cryoprecipitate will increase fibrinogen by 100 mg/dl; accordingly, administration of 15 ml/kg of FFP will almost increase fibrinogen to the same extent. With non-urgent requirements, Vitamin K can be administered to reverse the effects of warfarin (i.e., reductions in factors II, VII, IX and X as well as protein C and S). Reversal of a coagulopathy due to vitamin K deficiency or antagonism can occur within 6-8 hours when vitamin K is administered intravenously or within 24 hours when administered orally. If prompt resumption of oral anticoagulation with warfarin is anticipated, a minimum amount of Vitamin K should be administered (0.5-2.0 mg) in order to avoid protracted warfarin resistance, which requires a certain amount of time (i.e., 6-8 hours after intravenous administration and 24 hours after oral administration) to achieve effectiveness and the dose administered depends on the subsequent requirement for reinstituting warfarin anticoagulation (i.e., 0.5 mg vs. 10 mg).

Similarly, a NIH consensus panel suggested that platelets can be administered in the following settings: for active bleeding with thrombocytopenia (i.e., < 50,000/μl) or when abnormal platelet function is contributing to bleeding, for prophylaxis with plaletet count < 20,000/μl in patients at high risk or with CNS bleeds, with massive blood transfusion (i.e., > 1-2 blood volumes lost with abnormal bleeding) and that prophylactic administration is contraindicated with cardiac surgery [124]. The ASA modified these recommendations for patients who are actively bleeding: with platelet counts > 100,000/μl platelets are rarely indicated, with platelet counts < 50,000/μl generally needed and that the clinical circumstances should be assessed when platelet counts are between 50-100,000/μl [123]. One apheresis derived platelet unit is equivalent to six random donor platelet units (i.e., containing at least 3 × 1011 platelets) and should result in a one-hour post infusion rise by 30-60,000/μl in platelet count unless there is platelet refractoriness (i.e., as related to rapid antibody mediated clearance secondary to anti-HLA antibodies).

Rationale for targeted therapy

Blood component administration in patients with excessive bleeding after CPB is generally empiric. Thus, transfusion of RBC, platelets and FFP to cardiac surgical patients requiring CPB varies considerably among institutions, in part due to prophylactic administration of FFP and platelets, [125-128] despite evidence that this practice is unwarranted [129,130]. This variability has also been attributed to the empiric use of blood components such as FFP and platelets, which are administered in an attempt to distinguish between excessive microvascular bleeding due to hemostatic system impairment or due to surgical bleeding [122,124]. Although a panel of laboratory-based screening tests can provide a rational basis for diagnosis and treatment of excessive bleeding [131], the clinical utility of laboratory tests is often limited by long turnaround time [85], so that waiting for laboratory coagulation results can potentially prolong operative time and increase blood loss. This has led many investigators to study the role of point-of-care coagulation tests in this setting with respect to optimizing management of the bleeding patient.

Point-of-care tests should help physicians establish more appropriate management of excessive bleeding by targeting blood component therapy according to identified abnormalities in the coagulation system. Secondly, rapid test results may identify patients who could benefit from pharmacologic-based interventions. Thirdly, identification of patients who have a surgical source of bleeding can be expedited if coagulation tests reveal relatively normal results in the setting of excessive bleeding.

Evidence supporting targeted therapy: use of point-of-care tests and standardized transfusion algorithms

Studies that examined the efficacy of use of point-of-care diagnostic tests

Several studies have demonstrated that use of point-of-care (POC) and laboratory based hemostasis tests (i.e. platelet count, PT, aPTT, fibrinogen, thrombelastography, platelet function analyzers) can result in reduced transfusion requirements, shorter operative times and reduced blood loss. The first, prospective, randomized trial compared empiric treatment of microvascular bleeding in cardiac surgical patients to therapy that was administered according to a transfusion algorithm linked to rapid, POC whole blood PT, APTT and platelet results [72]. The algorithm-treated patients (n = 30) received significantly fewer blood products, had shorter operative times and had less blood loss after treatment of excessive microvascular bleeding (MVB) when compared to standard, empiric therapy (n = 36) [72]. In this trial [72], reduced transfusion requirements and blood loss may have occurred as a consequence of prompt, optimal management of bleeding, identification of patients with a surgical source of bleeding and/or a change in the transfusion trigger [132].

The usefulness of preset criterion for transfusion was confirmed in six of seven other recent studies which demonstrated that preset transfusion triggers based on either laboratory [133] and/or POC [117,134,135,135-137] methods can dramatically affect transfusion requirements of patients undergoing cardiac surgery (Fig. 3). The first study compared transfusion rates between 314 consecutive patients managed with preset transfusion criteria when compared to a retrospective group of 947 consecutive patients [133]. A significant decrease in the percentage of patients receiving red cells (26% vs. 41%) and plasma (13% vs. 24%) was observed in the treatment when compared to control patients. In addition, the percentage of patients not receiving allogeneic blood products was significantly greater in the treatment group (69%) when compared to historical controls (48%). Three other algorithms that consist of laboratory-based (e.g. platelet counts and fibrinogen levels) and or point-of-care tests (e.g. whole blood PT/aPTT, thromboelastography-based measurements) have been developed and utilized by Spiess [134], Shore-Lesserson [138] and Nutall [135]. Both the retrospective analysis [134] and two prospective trials [135,138] indicated that use of this approach can significantly reduce transfusion requirements. Four additional randomized trials have also recently examined this issue. Avidan et al. randomly assigned 100 patients to two groups who received therapy based on an algorithm linked to either laboratory or point-of-care based tests for the management of bleeding after cardiac surgery; these two cohorts were also then compared to a retrospective series of 100 patients [137]. Although blood loss was similar between cohorts, a substantially lower percentage of patients treated with the algorithm received platelet (i.e., 75% reduction) and red cell (i.e., 20% reduction) transfusions when compared to the control group. Chen and colleagues randomly assigned 90 patients on Plavix preoperatively to either receive therapy based on an algorithm coupled to point-of-care tests vs. standard therapy [117]. Patients randomly assigned to the algorithm cohort received approximately 85% less platelets and 33% less red cell transfusions. Royston and colleagues randomized 60 patients to receive either standard therapy for the management of bleeding or as directed by a TEG-based algorithm [136]. This resulted in a 75% reduction in the number of platelet and plasma units required to manage excessive bleeding. In contrast, one randomized study involving 58 patients published by Capraro et al. could not demonstrate an impact of implementation of a standardized approach linked to point-of-care diagnostic tests [139]. Overall, data from seven of eight published studies indicate that transfusion can be reduced by on average 50% when a standardized approach is coupled to laboratory or point-of-care diagnostic testing with respect to the management of bleeding after cardiac surgery (Fig. 3).

Figure 3.
Figure 3.:
The impact of use of an algorithm coupled to point-of-care monitoring with respect to mean total donor exposures observed in eight published studies. The first author and year of publication highlighted within each box at the top of the figure whereas the type of study (i.e., study design) and the series enrollment listed below. Hatched bar represents the mean total donor exposures within the control group (C) whereas the solid bar represents the mean total donor exposures within the group of patients who were treated with an algorithm coupled to point-of-care monitoring (M) perioperatively. Asterisks represent p< 0.05 between treatment cohorts.

Mechanisms for efficacy of the use of point-of-care diagnostic tests

The efficacy of point-of-care testing coupled with a standardized approach (i.e., algorithm) to reduce transfusion may be related to several factors. Optimal management of bleeding with the most appropriate and specific therapy may in part account for this efficacy to reduce transfusion [72]. The variability in transfusion rates detailed in Figure 3 support previous studies that have demonstated that there is substantial between-institution variability in transfusion practices [125,128]. Changing or resetting the transfusion trigger has in fact been shown to result from implementation of rapid hemostasis results when coupled to a standardized approach [132]. Finally, if an intervention can facilitate identification of a surgical source of bleeding, it may have a impact on bleeding and related adverse outcomes. The intraoperative period after discontinuation of cardiopulmonary bypass may be provide a critical ‘snapshot’ with respect to identification of a surgical source of bleeding; if there is substantial bleeding in light of relatively normal hemostasis results, this would prompt clinicians to more aggressively search for a source of bleeding. If point of care results are not available, this same patient might be treated empirically and continue to bleed into the postoperative period, at which time substantial derangements in hemostatic test results would be evident and mislead clinicians to continue to manage a coagulation disturbance rather than consider a surgical source. Of the published eight studies, two demonstrated that use of point-of-care diagnostics and an algorithm resulted in reduced re-exploration rates which supports this concept [134,135]. Examples of point-of-care test systems that can potentially be used to optimize perioperative transfusion are listed in Tables 1 and 2. Table 1 lists point-of-care tests or instruments that can be used to evaluate non-platelet related hemostatic system abnormalities whereas Table 2 lists point-of-care tests or instruments that can potentially be used to evaluate platelet function after cardiac surgery.

Table 1
Table 1:
A summary of point-of-care tests/instruments that can be used to assess non-platelet hemostatic abnormalities associated with cardiac surgery.
Table 2
Table 2:
A summary of point-of-care tests/instruments that can be used to assess platelet-related abnormalities associated with cardiac surgery.

Use of point-of-care tests for preemptive therapy

In these studies, investigators utilized hemostatic test results to identify the most accurate hemostatic therapy to be administered with respect to the management of excessive clinical bleeding. However, caution should be exercised with respect to using either point-of-care or laboratory-based test results to direct prophylactic administration of either hemostatic blood components (e.g. platelets, plasma or cryoprecipitate) or pharmacologic agents. Unless there is clear evidence in the literature that a specific test result can consistently and clearly identify patients who are destined to bleed excessively, this approach may lead to inappropriate and/or unwarranted transfusion. This is relevant since many studies have not demonstrated that either laboratory-based or point-of-care test methods (i.e., PT, aPTT, platelet count) can accurately predict which patients are destined to bleed excessively [140,141]. However, both laboratory and point-of-care tests like the PT and aPTT that indirectly evaluate coagulation factor levels can be used to identify patients (i.e., PT or aPTT values with a high positive predictive value) who are likely to have a factor deficiency state (e.g. one or more coagulation factors < 20 or 30% activity after use of cardiopulmonary bypass) and who may benefit from plasma in the setting of a clinical bleeding problem [142].

The role of factor concentrates

Background

Factor concentrates are used to prevent or manage excessive bleeding in patients with congenital (i.e., Hemophilia A and B, von Willebrand Disease) or acquired coagulation factor deficiencies. Factor concentrates can vary in terms of source (e.g. purified from human plasma vs. recombinant), properties (activated vs. non-activated coagulation factors) and content such as isolated (e.g. factor VIII, factor VII) or multiple (e.g. prothrombin concentrate complex or PCC containing factors II, VII, IX and X) coagulation factors.

Factor concentrates are generally administered every 12-24 h depending on extra-intravascular distribution and the half-life of the particular factor being replenished at dose ranges that approximate 50-100 U/kg or 10-120 μg/kg for recombinant activated Factor seven (rFVIIa, NovosevenTM manufactured and marketed by NovoNordisk, Copenhagen, Denmark) and 15-30 U/kg of recombinant Factor XIIIa. Hypothermia and especially severe acidemia should be corrected prior to institution of routine hemostatic therapy and factor concentrates. This concept is supported by recent published evidence which indicates that rFVIIa activity is reduced by 20% with temperatures that approximate 33 degrees and by 90% with a pH of 7.0 [87].

Recombinant activated Factor VII

1. Background and approved indications

Recombinant activated factor VII seems to offer some particular advantages based on it's purity and localized mechanism of action in the setting of bleeding related to an isolated source [143]. Although recombinant activated Factor VIIa currently has FDA approval for the management of bleeding in hemophilia A and B patients with inhibitors to Factor VIII and IX respectively [144] or in patients with congenital Factor VII deficiency, it has been used off-label in a number of differents settings. One recent commercially-derived estimate indicates that the off-label use of rFVIIa has increased in a exponential fashion (300 doses in 1999 to 4500 doses in 2004) [145]. In this time period, important concerns about its safety, efficacy, and costs have also arisen. Currently, the decision whether to use rFVIIa for patients with uncontrolled bleeding continues to be one that must be made by individual physicians, assisted by their hospital pharmacotherapeutics and transfusion committees. An example of policy within our own institution that reflects these interactions has been recently published in Transfusion [146].

Novoseven has been used off-label for the management of bleeding in congenital and acquired hemostatic system disorders [147-149], in patients with impaired liver function [150], with central nervous system and gastrointestinal bleeding, in obstetrics, trauma, congenital or acquired factor VII deficiency patients with von Willebrand Factor (vWF) or platelet defects, neurosurgery, cardiac surgery, liver transplantation [143], the most compelling data for off-label use of rFVIIa have been published by Mayer et al. [151] who demonstrated that rFVIIa was an effective therapy in the management of spontaneous intracranial bleeding (i.e., 38% reduction in mortality). Accordingly, rFVIIa has also been used off-label in the management of excessive, often lifethreatening bleeding after cardiac surgery. The current literature describing the off-label use after cardiac surgery involves predominately of anecdotal experience (i.e., either case reports or case series) with limited data from randomized clinical trials.

2. Off-label use with cardiac surgery

rFVIIa has been utilized with lifethreatening bleeding after cardiac surgery in a total of 415 patients described in 50 reports. These reports have involved both pediatric [98,152-164] and adults patients after cardiac surgery [96,97,99,153,165-169,169-171,171-193] as well as after implantation of ventricular assist [194] or extracorporeal membrane oxygenation (ECMO) devices [159-162,191]. Although the majority of these publications involve isolated case reports, 20 involved case series involving five or more patients [98,152,153,157,163,174,175,177,180-183,186-189,193,195,196] while four involved comparison to historical control groups [182,186,189,193] and one consisted of a small comparison of 20 patients randomly assigned to receive either rFVIIa or placebo on a prophylactic basis [187].

The vast majority of these reports involved use of rFVIIa in the setting of severe, lifethreatening bleeding which was unresponsive to routine hemostatic therapy (i.e., platelets, plasma, cryoprecipitate, DDAVP, aprotinin). These reports consistently demonstrate the efficacy of rFVIIa to achieve hemostasis as demonstrated by markedly reduced transfusion requirements and blood loss (i.e., from 33-99% reduction) even when pre-treatment blood loss approximated 16 liters per hour [171]. Many of the patients treated with rFVIIa were destined to expire based on the severe degree of bleeding that was described prior to intervention which clearly illustrates the life-saving role of rFVIIa.

3. Thrombotic potential and safety

With respect to safety, two isolated case reports [167,191] describe a thrombotic complication and eight published series involving 272 patients which describe the off-label use of rFVIIa reported a relatively high risk-unadjusted complication or death rate [175,180-183,193,197]. Although the complications and high mortality (i.e., 22-75%) reported in some of these series are concerning, the literature does not consistently reflect a high complication or mortality rate with use of rFVIIa after cardiac surgery. Of 415 patients, data from 141 patients (34%) described in seven case series (74 patients) and multiple other isolated case reports (additional 67 patients) consistently support the hemostatic efficacy of rFVIIa while not reporting any untoward effects or an increased mortality related to use of this agent. The discrepancy in adverse outcomes between the various publications may be related to institutional differences with respect to the percentage of patients at high-risk for complications and mortality, the relative severity of the patient's condition at the time of treatment (e.g. severe bleeding, severe hemodynamic compromise and/or hypoperfusion), concomitant use of other agents (e.g. anti-fibrinolytic agents, platelets, FFP, DDAVP) or interventions (e.g. topical hemostatic agents) or other pre-existing patient-related factors that may differ between the published reports. Although randomized controlled studies are needed to clearly define the role of rFVIIa with respect to thrombotic complications, a posthoc analysis was recently performed in the largest single series of patients (n = 114) receiving rFVIIa off-label by Karkouti et al. [193] In their crude (i.e., unadjusted) analysis of adverse events (i.e., stroke, ARF, PE/DVT, death), they observed an increased rate of complications in patients who received rFVIIa. However, no significant increase in these adverse events was observed (adjusted odds ratio= 1.04) when rFVIIa use was adjusted using a multivariate statistical model [193].

Although a previous review which summarized administration of 170,000 doses of rFVIIa reported a low incidence of thrombotic complications (i.e., 1:11,300) [143], most of these cases involved use of this agent for the management of bleeding complications in Hemophilic patients with inhibitors. A summary of reported complications to the FDA (i.e., AERS 1999-2004) as related to the off-label use of rFVIIa was recently published [145]. There were 431 adverse events in the time period from 1999-2004 or 4.3% based on a commercially-derived estimate (i.e., Premier Healthcare Informatics, Preimier Inc, Charlotte, NC) [145] of use during this period which approximates 10,000 exposures. Of these 431 events, 168 of the reports were described as thromboembolic in nature and the overall incidence of thromboembolic events was 1.7%. A causality assessment was obtained in 61% of the described reports of which 81/102 of the thromboembolic complications (80%) were considered to be related to use of rFVIIa. An overall mortality rate of 0.5% (50 of 10,000 estimated exposures) was observed compared to a mortality rate of 30% (50/168) for patients withthromboembolic complications [145]. However, there are several limitations with this type of analysis. Underreporting would tend to underestimate the incidence of adverse events while the estimate of total patients treated with this intervention during this five year period may not be accurate. In addition, the patients who received rFVIIa were probably at a much higher risk for developing thromboembolic complications based on their clinical circumstances (e.g. cardiac assist devices and on-going hemostatic system activation, trauma or cardiac surgical patients with intractable bleeding and with bleeding-related hypoperfusion) as well as the concomitant therapies used to manage bleeding (e.g. antifibrinolytic agents, activated PCC, hemostatic blood components, DDAVP). However, activated factor concentrates should be used with caution in patients with known hypercoagulability (e.g. history of thrombotic complications, established thrombotic disorders like Factor V Leiden, antiphospholipid syndrome etc) or who have excessive bleeding in the setting of DIC or other states of generalized activation of the hemostatic system (e.g. after cardiac surgery, patients on ECMO or ventricular assist devices) based on the potential for development of localized or systemic intravascular thrombosis [167,198].

4. Guidelines for off-label use after cardiac surgery

Accordingly, specific criteria [146] that have been previously suggested include the following: patients with lifethreatening bleeding (e.g. CNS or > 500-1000 mL/h) that have no identifiable surgical source and who are unresponsive to transfusion of hemostatic components (e.g. 1-2 U platelets, 4-8 U FFP, 10-20 U cryoprecipitate) to substantially improve abnormal hemostatic tests or pharmacologic therapy (e.g. DDAVP, epsilon amino caproic acid, tranexamic acid, aprotinin). In addition, other important considerations should include avoidance in patients who either have a documented congenital or acquired hypercoagulable state, administration of lower doses (e.g. rFVIIa 10-30 μg/kg q 15-30 min for a total of 90-180 μg/kg) and confirmation that anticoagulation is therapeutic in patients with ongoing activation states (e.g. ECMO, VADs etc) [146].

5. Summary

Therefore, there are published data that suggest that off-label use of rFVIIa may be useful in certain distinct settings such as first line therapy with intracranial hemorrhage [151] or as rescue therapy for lifethreatening bleeding (i.e., with excessive bleeding that is unresponsive to routine hemostatic therapy) [146,153,171]. This agent may also be extremely useful in bleeding patients for whom no blood is available due to multiple allo-antibodies or who refuse blood or for whom component therapy or when platelets may not be effective (e.g. platelet refractoriness that is unresponsive to HLA matched platelets) [199] or unavailable (e.g. contamination of the national supply with Avian influenza). Until additional safety studies are completed, this agent should be used sparingly and cautiously in non-lifethreatening settings or as a prophylactic measure especially in patients who are at increased risk for thrombotic complications. Many of these conclusions can be applied to recombinant activated Factor XIII (rFXIIIa) which is currently undergoing safety analyses [200,201]. The potential usefulness of rFXIIIa is supported by two small trials that showed reduced blood loss after cardiac surgery when patients received this agent [202,203] which supports the findings or earlier studies which demonstrated an inverse relationship between Factor XIII levels and blood loss [204-206].

Pharmacologic augmentation of the hemostatic system

Off-label use of desmopressin

Desmopressin or DDAVP (1-deamino-8D-arginine vasopressin), a synthetic analog of arginine vasopressin, which has been used off-label to manage excessive bleeding with some efficacy in various settings (i.e., for uremic-induced platelet dysfunction or hereditary platelet disorders [207], Type 1 von Willebrand disease and acquired platelet abnormalities after cardiac surgery) [140], is generally administered at a dose of 0.3-0.4 μg /kg over 30 min to minimize hypotension related to release of prostacyclin via endothelial cells. DDAVP results in shortened bleeding time results [208] most likely due to a marked increase in plasma levels of large molecular weight von Willebrand factor multimers [209] that are directly released by endothelial cells or in response to secretion of PAF by monocytes [210]. In an early randomized, prospective, double-blind study, DDAVP (0.3 μg/kg IV infusion) administered immediately after protamine significantly reduced mean intra-, and early postoperative blood loss, without any untoward effects [211]. However, in several subsequent studies a consistent beneficial of prophylactic administration of desmopressin could not be shown, as positive studies [212-217] were slightly outnumbered by negative studies [218,218-223].

Published studies have revealed that certain patient subsets at high risk for excessive bleeding as identified by tests of hemostatic function may benefit from desmopressin [217,224]. The first study by Czer et al. demonstrated that desmopressin is beneficial when administered to patients with excessive bleeding and prolonged bleeding times [217]. Mongon et al. studied the use of the thromboelastograph (TEG) for risk stratification of patients when evaluating post-CPB coagulation status [224]. Patients were also randomly assigned to receive either normal saline (placebo) or 0.3 mcg/kg of DDAVP. A post-hoc analysis divided the patients into normal or abnormal TEG groups based on TEG maximum amplitude (MA) measurements. The mediastinal chest tube drainage in the placebo-treated, abnormal MA (< 50 mm) patients was substantially greater when compared with normal (> 50 mm) MA patients, indicating that TEG could identify patients at risk for excessive bleeding. These findings indicate that DDAVP may improve reduce blood loss in patients who have abnormal TEG and who are at risk for increased blood loss.

Another recent prospective, blinded, placebo-controlled trial utilized the hemoSTATUS platelet function method (i.e., clot ratio values derived from platelet-activating factor mediated acceleration of clot times). After exclusion of 30 patients who required intraoperative management of microvascular bleeding with hemostatic blood products and 72 patients with normal clot ratio values, 101 patients with abnormal clot ratio values (i.e. %maximal <60 in channel 5) after administration of protamine were randomly assigned to either placebo (n = 51) or DDAVP (n = 50) treatment arms. Desmopressin-treated patients had a 50% reduction in red cell (1.1 vs. 2.2 U), 95% reduction in platelet (0.1 vs. 1.9 U) and 87% reduction in fresh frozen plasma (0.1 vs. 0.8 U) units transfused with an overall 69% reduction in total donor exposures (1.6 vs. 5.2 U) when compared to placebo patients. When compared to placebo-treated patients, patients who received Desmopressin also had a 39% (182 vs. 297 mL), 42% (299 vs. 513 mL) and 39% (624 vs. 1028 mL) reduction in blood loss in the first 4, 8 and 24 postoperative hours, respectively [140].

Since our review is focused on the optimal management of bleeding after cardiac surgery, we will not address the use of agents that can be used prophylactically to prevent bleeding after cardiac surgery. Although agents that have either direct anti-fibrinolytic actions (e.g. epsilon amino caproic acid or tranexamic acid) or broad spectrum activities (i.e., aprotinin) are used prophylactically to prevent excessive bleeding and transfusion, these agents have also been used as a treatment modality for excessive bleeding after cardiac surgery. The direct antifibrinolytic agents have been used empirically to manage excessive bleeding in hemophilia patients with refractory bleeding. In addition, four small studies have shown that aprotinin may also reduce bleeding when administered either after surgery [225] or as treatment therapy administered intravenously [226,227] or topically [228] rather than on a prophylactic basis.

Use of topical hemostatic agents

A wide variety of topical hemostatic agents are available for use during cardiac operations [229,230], however there is almost no evidence to support the routine use of these agents for blood conservation [230]. The only evidence is in the form of anecdotal or non-controlled reports with little indication of benefit [229,230]. Although bovine thrombin is a component of several topical hemostatic agent preparations (e.g. fibrin glue, Tisseal, Gelfoam) used during cardiac operations, this agent may induce an immunologic response that may result in lifethreatening bleeding on either initial (i.e., within 7-14 days of first exposure) or re-exposure as related to neutralizing antibodies to factor V and II [231]. Use of topical bovine thrombin cannot be recommended because of the potentially harmful immunologic reactions that may occur with this drug. However, a new recombinant preparation of human thrombin has been developed and is being investigated. Use of this agent may potentially reduce the incidence of immunologic reactions. Fibrin glue preparations, with or without the addition of bovine thrombin, have been used extensively in complex operations involving the aorta. Autologous platelet-rich-plasma when combined with calcium and thrombin have been used to restore hemostasis and enhance wound healing. In addition, utilization of new electrocautery (e.g. argon) devices, scalpels (i.e., ultrasonic or microwave) or water jet dissector devices may enhance hemostasis [229].

Summary

Although the incidence and pathophysiology of many transfusion-related complications are well-documented, unresolved questions persist. Transfusion Medicine initiatives are being implemented to reduce the incidence of complications (e.g. chemical inactivation of pathogens, white cell depletion etc), however, the literature is describing new potential problems related to transfusion (e.g. TRALI, immune-modulation, MOSF etc) in addition to identification of new potential pathogens (e.g. variant CJD, SARS, Avian Influenza Viruses). In addition, blood shortages may limit our ability to adequately manage our anemic and bleeding patients. Excessive bleeding after cardiac surgery can result in increased morbidity and mortality related to transfusion and hypoperfusion-related complications as well as injury to critical organ systems.

Use of point-of-care (POC) tests of hemostatic function can facilitate the optimal management of excessive bleeding and reduce transfusion. Accordingly, point-of-care tests that assess platelet function may also identify patients at risk for acquired, platelet-related bleeding that may attenuated with pharmacologic agents. In addition, rapid acquisition of coagulation data can also allow physicians to better differentiate between microvascular bleeding and surgical bleeding. An ideal algorithm would encompass test systems that evaluate heparin activity, fibrinolysis, coagulation factor levels, qualitative and quantitative platelet abnormalities.

Recombinant FVIIa has the potential to reduce transfusion and transfusion-related sequelae and may be life-saving in certain circumstances. However, randomized, controlled trials are warranted to assess both the efficacy and, more importantly, the safety of this intervention in cardiac surgical patients prior to its use as a first line therapy for bleeding or for bleeding prophylaxis. We must continue to carefully investigate the role of new interventions since the ability to reduce use of blood products, to decrease operative time and/or re-exploration rates has important implications for disease prevention and overall patient safety, blood inventory and associated costs as well as overall health care costs.

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                      Keywords:

                      Bleeding; Transfusion; Cardiac surgery; Blood; Blood components; Blood risks; Point-of-care diagnostic tests; Factor concentrates

                      © 2007 European Society of Anaesthesiology