Cardiopulmonary bypass (CPB) is associated with defective hemostasias that results in bleeding and the requirement for allogenic blood product transfusions in many patients undergoing cardiac surgery and/or coronary artery bypass graft surgery (CABG). Conservation of blood has become a priority during surgery because of shortages of donor blood, the risks associated with the use of allogenic blood products, and the costs of these products. Further, transfusions expose patients to a variety of potential cellular and humoral antigens, pose risks of disease transmission and immunomodulation, and may alone represent proinflammatory stimuli in the perioperative period. Multiple approaches are important when considering strategies to limit blood transfusions. Strategies to reduce bleeding and transfusion requirements include recognizing risk factors, developing transfusion practices, conservation of red blood cells, new alternatives to red blood cells, altering inflammatory responses, and also potentially improving anticoagulation/reversal. Pharmacologic approaches to reduce bleeding and transfusion requirements in cardiac surgical patients are based on either preventing or reversing the defects associated with the CPB induced coagulopathy, and represent one of the mainstay approaches in cardiac surgery. Strategies to reduce the need for allogeneic blood requirements will be reviewed.

RISK FACTORS

Certain risk factors clearly are important when evaluating patients for bleeding potential. The patient who comes to surgery anemic or with a low preoperative red blood cell mass based on low weight (ie, children) all pose important risk factors for the need of transfused red blood cells. Also, associated diseases and preoperative pharmacologic strategies are important because hemostasis is involved with platelet and coagulation factor interaction, the pre-existing use of antiplatelet agents, especially IIb/IIIa receptor antagonists and clopidogrel (Plavix) are important to consider. Current studies suggest more patients with atherosclerotic vascular disease will be receiving antiplatelet strategies. Further, pre-existing liver disease is important to consider because these patients have complex multifactorial coagulopathies. Also, although widely thought that warfarin pre-exposed the patient to bleeding, more recent data suggests this may not be true. Finally, redo cardiac surgical procedures requiring repeat sternotomies, multiple valve replacements, and other procedures providing long CPB times, may also pose potential risk factors for bleeding.

DEVELOPING TRANSFUSION PRACTICES

Coagulation factor administration in patients with excessive post-CPB bleeding is generally empiric related to turnaround times of laboratory tests and empiric factor administration . Optimal administration of pharmacologic and transfusion-based therapy in patients who exhibit excessive bleeding after cardiac surgery should be considered, unfortunately there are few validated tests to asses platelet function. Point-of-care coagulation monitoring using thromboelastography resulted in fewer transfusions in the postoperative period. The reduction in transfusions may have been due to improved hemostasis in these patients who had earlier and specific identification of the hemostasis abnormality and thus received more appropriate intraoperative transfusion therapy. These data support the use of thromboelastography and/or an algorithm to guide transfusion therapy in complex cardiac surgery, and further support the concept that transfusion algorithms are effective in reducing transfusion requirements.

RED CELL CONSERVATION

Because the pre-existing red blood mass is important, conserving red blood cells is equally important. The use of red blood cell saver techniques for high risk patients is important to consider especially by reprocessing shed blood. Whether in low risk patients this is effective or not still remains to be seen. The use of autologous normovolemic hemodilution is an interesting concept that allows the removal of both red cells and coagulation factors prior to bleeding. This is also done at the time of surgery, and often cannot be preformed in a hemodynamically unstable patient. The role of erythropoietin is interesting, but erythropoietin requires several weeks of pre-existing therapy, requires the need to replete iron, and should be considered in a Jehovah's Witness or other patient who can be operated on electively with the potential for autologous predonation.

RED CELL SUBSTITUTES

Blood substitutes are solutions that can be used in resuscitation emergencies or during surgery when rapid intravascular volume expansion is needed in view of acquired red cell losses. The three main types of products in development are primarily based on cell-free hemoglobin solutions called hemoglobin-based oxygen carrying solutions (HBOCs) or perfluorocarbon emulsions. None of the agents are currently approved for clinical use, but are in different stages of clinical development. Free hemoglobin solutions are subject to more rapid degradation when packaged outside of the red blood cell membrane. Further, the iron moiety of free hemoglobin readily diffuses in the plasma space and effectively scavenges nitric oxide from pulmonary and systemic vascular endothelia, altering both pulmonary and systemic vascular tone.

Four different stroma-free hemoglobin solutions are under development including intramolecularly cross-linked hemoglobin, polymerized hemoglobin, conjugated hemoglobin, and hemoglobin microbubbles, all modified to increase molecular size and decrease renal filtration, prolong intravascular persistence, and to ensure a normal P50 of hemoglobin. Animal, human, or recombinant sources of hemoglobin are used. To stabilize the smaller hemoglobin units obtained from animal or human red cells, these hemoglobin dimers and monomers are modified by either cross-linking, polymerization, or conjugation. Human hemoglobin derived from outdated banked blood is a problematic source due to a shrinking donor pool, better inventory control, and it is unlikely that outdated banked blood could provide enough hemoglobin for commercial purposes. Unfortunately, the half-life of most human-derived hemoglobin solutions is short thus, the need for red cell transfusion may merely be delayed and not eliminated by its use.

Bovine hemoglobin represents an interesting alternative that is currently under development. The P50 of bovine hemoglobin is similar to human hemoglobin and is not controlled by 2,3-DPG but instead by chloride ion which is present in large concentrations of the plasma. The major advantage of bovine hemoglobin is its availability and large quantity. A 500-kg steer has approximately 35 L of blood containing approximately 12 g/dL of hemoglobin for an approximate total body hemoglobin content of 4.2 kg. Further, cow blood is a byproduct of most slaughterhouses and is available as almost an unlimited supply. Despite potential concerns about the possibility of interspecies transmission of infectious disease, hemoglobin can be successfully purified from human RBC units containing the viruses.

Recombinant DNA technology has been used to produce modified human hemoglobin molecules. Unfortunately, it is unclear whether the yield of hemoglobin per unit of microorganism is sufficient to make large scale commercial production of hemoglobin possible. There are also concerns about complete separation of bacterial components from the hemoglobin and waste management of the byproducts of its production 6. Another biotechnologic approach to producing large amounts of hemoglobin involves transgenic manipulation of animals to produce RBCs that contain a substantial proportion of human hemoglobin.

DESMOPRESSIN

Desmopressin acetate (1-deamino-8-D-arginine vasopressin- DDAVP), is a synthetic analogue of vasopressin decreased vasopressor activity. Desmopressin therapy causes a two to twenty fold increase in plasma levels of factor VIII, and stimulates vascular endothelium to release the larger multimers of von Willebrand factor (vWF). Desmopressin also releases tissue plasminogen activator (t-PA), and prostacyclin from vascular endothelium. Although definitive studies are lacking supporting its routine use, patients who might benefit from its use include mild to moderate forms of hemophilia or von Willebrand disease undergoing surgery and uremic platelet dysfunction. Despite initial enthusiasm for desmopressin, only recently has data suggested it may be useful to treat platelet dysfunction after cardiac surgery. Despotis reported a new point-of-care test (hemoSTATUS) to identify patients at risk of excessive bleeding.

LYSINE ANALOGS

Epsilon-aminocaproic acid (EACA, Amicar) and its analogue, tranexamic acid (TA) are derivatives of the amino acid lysine and have been reported in clinical studies of cardiac surgical patients. Both of these drugs inhibit the proteolytic activity of plasmin and the conversion of plasminogen to plasmin by plasminogen activators. Plasmin cleaves fibrinogen and a series of other proteins involved in coagulation. Tranexamic acid is 6-10 times more potent than epsilon-aminocaproic acid. Most of the early studies using antifibrinolytic agents showed decreased mediastinal drainage in patients treated with EACA. However, many of these studies lacked controls, were retrospective, and not blinded. In the literature there have been a small number of thrombotic complications between patients receiving lysine analogs, but the studies were not designed to prospectively capture many of these complications . Although the design of these studies have not been routinely prospective, the incidence of these complications in routine CABG is low, and a small number of patients have been studied. Prospective studies evaluating safety issues including the risk of perioperative MI, graft patency, and renal dysfunction still need to be studied. TA is approved for use in the US to prevent bleeding in patients with hereditary angioedema undergoing teeth extraction. Most studies report lysine analogues in first-time CABG where the risk of bleeding is low, and not in complex cases.

APROTININ

Aprotinin is a serine protease inhibitor isolated from bovine lung that produces antifibrinolytic effects, inhibits contact activation, reduces platelet dysfunction and attenuates the inflammatory response to CPB It is used to reduce blood loss and transfusion requirements in patients with a risk of hemorrhage. Data from clinical trials indicate that aprotinin is generally well tolerated, and the adverse events seen are those expected in patients undergoing OHS and/or CABG with CPB. Hypersensitivity reactions occur in <0.6% of patients receiving aprotinin for the first time, and seem to be greatest within 6 months of reexposure. The results of original reports indicating that aprotinin therapy may increase myocardial infarction rates or mortality have not been supported by more recent studies specifically designed to investigate this outcome. There is little comparative tolerability data between aprotinin and the lysine analogues, aminocaproic acid and tranexamic acid, are available. Aprotinin is often used in patients at high risk of hemorrhage, in those for whom transfusion is unavailable or in patients who refuse allogenic transfusions.

Multiple studies support aprotinin's efficacy and include approximately 45 studies involving 7,000 patients. In redo CABG patients, Cosgrove reported 171 patients who received either high dose aprotinin (Hammersmith dose), low dose aprotinin (half Hammersmith dose), or placebo. They found that low dose aprotinin was as effective as high dose aprotinin in decreasing blood loss and blood transfusion requirements. Despite the efficacy of reducing both the need for allogeneic blood and chest tube drainage, retrospective analysis of the data suggested a higher risk for myocardial infarction and graft closure that was not statistically significant. Despite the question about adequacy of anticoagulation, the study created safety concerns that were addressed to two additional prospective studies reported by Levy in repeat CABG patients, and by Alderman in primary CABG patients.

In patients undergoing repeat coronary artery bypass graft (CABG) surgery, the safety and dose-related efficacy of aprotinin in high risk patients was studied in a prospective, multicenter, placebo-controlled trial in 287 patients were randomly assigned to receive high-dose, low-dose, pump-prime, or placebo. Drug efficacy was determined by the reduction in donor-blood transfusion up to postoperative day 12 and in postoperative thoracic-drainage volume. The percentage of patients requiring donor-red-blood-cell (RBC) transfusions in the high- and low-dose aprotinin groups was reduced compared with the pump-prime-only and placebo groups (high-dose aprotinin, 54%; low-dose aprotinin, 46%; pump-prime only, 72%; and placebo, 75%). There was also a significant difference in total blood-product exposures among treatment groups (high-dose aprotinin, 2.2 +/- 0.4 U; low-dose aprotinin, 3.4 +/- 0.9 U; pump-prime-only, 5.1 +/- 0.9 U; placebo, 10.3 +/- 1.4 U). There were no differences among treatment groups for the incidence of perioperative myocardial infarction (MI). Both high- and low-dose aprotinin significantly reduces the requirement for donor-blood transfusion in repeat CABG patients without increasing the risk for perioperative MI. There was also a statistically significant reduction in strokes in the aprotinin treated patients.

To assess the effects of aprotinin on graft patency, prevalence of myocardial infarction, and blood loss in patients undergoing primary coronary surgery with cardiopulmonary bypass, patients from 13 international sites were randomized to receive intraoperative aprotinin (n = 436) or placebo (n = 434). Graft angiography was obtained a mean of 10.8 days after the operation. Electrocardiograms, cardiac enzymes, and blood loss and replacement were evaluated. In 796 assessable patients, aprotinin reduced thoracic drainage volume by 43% and requirement for red blood cell administration by 49%. Among 703 patients with assessable saphenous vein grafts, occlusions occurred in 15.4% of aprotinin-treated patients and 10.9% of patients receiving placebo. After adjusting risk factors associated with vein graft occlusion, the aprotinin versus placebo risk ratio decreased from 1.7 to 1.05 (90% confidence interval, 0.6 to 1.8). These factors included female gender, lack of prior aspirin therapy, small and poor distal vessel quality, and possibly use of aprotinin-treated blood as excised vein perfusate. At United States sites, patients had characteristics more favorable for graft patency, and occlusions occurred in 9.4% of the aprotinin group and 9.5% of the placebo group (P = .72). At Danish and Israeli sites, where patients had more adverse characteristics, occlusions occurred in 23.0% of aprotinin- and 12.4% of placebo-treated patients (P = .01). Aprotinin did not affect the occurrence of myocardial infarction (aprotinin: 2.9%; placebo: 3.8%) or mortality (aprotinin: 1.4%; placebo: 1.6%). In this study, the probability of early vein graft occlusion was increased by aprotinin, but this outcome was promoted by multiple risk factors for graft occlusion.

STUDIES IN CHILDREN

Aprotinin consistently reduces blood loss and transfusion requirements in adults during and after cardiac surgical procedures, but its effectiveness in children is debated. Miller evaluated the hemostatic and economic effects of aprotinin in children undergoing reoperative cardiac procedures with cardiopulmonary bypass. Control, low-dose aprotinin, and high-dose aprotinin groups were established with 15 children per group. Platelet counts, fibrinogen levels, and thromboelastographic values at baseline and after protamine sulfate administration, number of blood product transfusions, and 6-hour and 24-hour chest tube drainage were used to evaluate the effects of aprotinin on postbypass coagulopathies. Time needed for skin closure after protamine administration and lengths of stay in the intensive care unit and the hospital were recorded prospectively to determine the economic impact of aprotinin. Coagulation tests performed after protamine administration rarely demonstrated fibrinolysis but did show significant decreases in platelet and fibrinogen levels and function. The thromboelastographic variables indicated a preservation of platelet function by aprotinin. Decreased blood product transfusions, shortened skin closure times, and shortened durations of intensive care unit and hospital stays were found in the aprotinin groups, most significantly in the high-dose group with a subsequent average reduction of nearly $3,000 in patient charges. In children undergoing reoperative cardiac surgical procedures, aprotinin is effective in attenuating postbypass

DEEP HYPOTHERMIC CIRCULATORY ARREST (DHCA)

Early experience with aprotinin in deep hypothermic circulatory arrest (DHCA) raised concerns about hazards associated with its use. Based on what little is known about possible mechanistic interactions between hypothermia, stasis, and aprotinin, there is no evidence that aprotinin becomes unusually hazardous in DHCA. Excessive mortality and complication rates have only been reported in clinical series in which the adequacy of heparinization is questionable. Benefits associated with use of aprotinin in DHCA have been inconsistently demonstrated. The only prospective, randomized series showed significant reduction in blood loss and transfusion requirements. Use of aprotinin in DHCA should be based on the same considerations applied in other cardiothoracic procedures.

COMPARISON STUDIES AND META-ANLYSIS

There is little data to compare the efficacy and safety of pharmacological agents available for reducing allogeneic blood administration in cardiac surgical patients. Levi reported a meta-analysis of all randomized, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin). Studies were included if they reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative MI) in addition to perioperative blood loss. In addition, a separate meta-analysis was done for studies concerning complicated cardiac surgery. A total of 72 trials (8409 patients) met the inclusion criteria. Treatment with aprotinin decreased mortality almost two-fold (odds ratio 0.55) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical re-exploration (0.37, and 0.44, respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion. By contrast, the use of desmopressin resulted in a small decrease in perioperative blood loss, but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2.4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results.

SUMMARY

Blood conservation for cardiac surgery requires multiple strategies for reducing bleeding and the need for donor blood products. Of all the strategies, aprotinin has been demonstrated to be highly effective in reducing bleeding and transfusion requirements in high risk patients undergoing repeat median sternotomy or in high risk patients. Results from multicenter studies of aprotinin show there is no greater risk of early graft thrombosis, MI, or renal failure in aprotinin treated patients. Antiinflammatory strategies on the horizon may further add to our pharmacologic armamentarium for cardiac surgery and CPB.

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