Transfusion therapy is necessary and can be lifesaving in surgical patients. However, despite being the standard of care for blood loss and anemia, it has never undergone the rigorous, randomized testing required of a new therapeutic agent, including assessment of adverse events and risk assessment. Since the outbreak of acquired immunodeficiency syndrome (AIDS) in the 1980s, it has become apparent that the full extent of the risk of allogeneic transfusion therapy is unknown. In the 2000s, the British National CJD Surveillance Unit identified 48 individuals who received a blood component from 15 donors who later developed variant Creutzfeldt-Jakob disease (vCJD). One of these individuals developed symptoms 6.5 years after a transfusion of packed red blood cells (PRBCs) from an asymptomatic donor and died of vCJD in December 2003. A decade later, investigators in Brazil described two patients who tested positive for Zika virus after receiving platelet transfusions. The donor was asymptomatic at the time of donation, but later was confirmed to be infected with Zika virus after developing rash, retro-orbital pain, and bilateral knee pain. Considering these risks, it becomes apparent that alternatives to transfusion must be developed in combination with blood conservation measures. The goal of these measures should be to limit transfusion to clinical scenarios in which allogeneic blood product administration is clearly necessary to maintain adequate oxygen delivery and reduce mortality.
Patient Blood Management and Preoperative Evaluation
Patient blood management (PBM) is a process designed to optimize the risk-to-benefit ratio of allogeneic blood component administration and improve patient outcomes. According to the Society for the Advancement of Blood Management, the four pillars of PBM include interdisciplinary blood conservation strategies, management of anemia, optimization of perioperative coagulation, and patient-centered decision making. PBM requires an integrated program of preparation, reduction of blood loss, and elimination of unnecessary allogeneic transfusion. Although the benefit to patient outcome and cost reduction has been documented in the literature, implementation of an effective PBM program is challenging. In order to realize the benefits of PBM, infrastructure necessary for the diagnosis and treatment of anemia in the preoperative period prior to major elective surgery is essential.
When the concept of PBM is simplified, the major components of the program are geared toward preventing clinically significant levels of anemia in the perioperative period. While autologous predonation of PRBC has been recommended in the past for noncardiac surgical procedures with significant intraoperative blood loss such as total joint replacement and spine surgery, the cost and questionable efficacy of this technique has resulted in decreased utilization. Autologous predonation can result in lower hemoglobin at the time of surgery, off-setting any potential benefit. Predonation is also subject to the risk of clerical error and results in significant wastage of predonated units.
Preoperative anemia is an independent risk factor for mortality in both cardiac surgery and major noncardiac surgery. Without adequate red blood cell mass prior to a major operation, intraoperative blood conservation strategies are limited and allogeneic blood transfusion is almost assured. In a national audit of patients undergoing elective orthopedic surgery in the United States, 35% of patients had hemoglobin levels < 13 g/dL at the time of preadmission testing with one-third of these patients testing positive for iron deficiency. Treatment of reversible causes of anemia requires assessment up to 28 days prior to surgery with delay of elective cases for anemia treatment in order to optimize outcome. Without the ability to input, assess, and treat patients more than 7 days prior to major surgery, an opportunity to avoid unnecessary transfusion and limit cost is missed. In conjunction with plans for early input into enhanced recovery pathway programs as part of an expanded Preoperative Evaluation Clinic, anemia detection and treatment as well as preparation for intraoperative and postoperative PBM are recommended. If done comprehensively, cost-savings from this approach will be realized for the institution, patients will avoid allogeneic transfusion, and excess utilization of the blood supply will be curtailed.
Preoperative Assessment of Bleeding Risk
Common Disease States Associated with Excessive Bleeding
Patients with hepatic failure have an increased risk of perioperative hemorrhage as a result of factor deficiency and portal venous obstruction. In the event of portal venous obstruction, development of esophageal varices and potential venous engorgement around the operative field can produce enhanced blood loss. Deficiencies of liver-dependent factors, including factors II, VII, IX, and X, result in a coagulopathy most frequently characterized by prolongation of the prothrombin time (PT). Vitamin K may be indicated in the preoperative period if malnutrition is a component of the coagulopathy in a patient with liver failure. On the other hand, factor deficiency resulting from inadequate hepatic synthesis is likely to be unresponsive to vitamin K, and direct repletion of clotting factors with fresh frozen plasma (FFP) or prothrombin complex concentrate may be necessary to prevent life-threatening hemorrhage. However, patients with hepatic insufficiency also have anticoagulant deficiency and conventional repletion of factors can easily lead to overcorrection and thrombotic complications.
Accelerated fibrinolysis probably also plays a role in the coagulopathy seen in patients with liver failure. This acceleration is evidenced by D-dimer levels that are normal or slightly elevated in severe liver disease. One mechanism for the increased fibrinolysis in patients with chronic liver failure is the reduced clearance of tissue plasminogen activator (t-PA). Another potential mechanism is related to decreased synthesis of hepatic regulating plasma proteins. Alpha-2-antiplasmin is a hepatically synthesized enzyme that may be deficient in liver failure resulting in increased plasmin activity. Alpha-2-antiplasmin inhibits plasmin-mediated fibrinolysis by rapidly inactivating circulating plasmin and by crosslinking to fibrin, making clots that are resistant to plasmin degradation. Although plasminogen (the precursor to plasmin) and alpha-2-antiplasmin are both synthesized in the liver, alpha-2-antiplasmin is present in lower concentrations than plasminogen and may be depleted even when plasminogen is not. Another liver-synthesized molecule, fibrinogen, may also become depleted in liver failure and may merit measurement. Despite that, pure fibrinogen deficiency is uncommon.
Platelet count is often low in liver failure as a result of either splenic sequestration or increased consumption. Nevertheless, the hemostatic effect of platelets may still be clinically near-normal because of elevated levels of von Willebrand Factor (vWF). The synthesis of ADAMTS13, a vWF-cleaving protease, is decreased in liver failure thus leading to higher than normal vWF activity and platelet adhesion.
The most common blood clotting abnormality in uremic renal failure is platelet dysfunction. The defect is a function of uremia and is not intrinsic to the platelets. Therefore, transfusion of allogeneic platelets is not indicated except for patients with documented low platelet counts. Primary treatment for uremic platelet dysfunction is treatment of the underlying renal failure, with dialysis if necessary. Desmopressin (DDAVP; 1-deamino-8-D-arginine vasopressin) may help platelet function by stimulating endothelial cell release of vWF. A one-time dose of 0.3 μg/kg delivered intravenously may be indicated to help offset life-threatening hemorrhage while efforts are made to correct the underlying uremia.
Clotting Factor Deficiency
Deficiency of individual clotting factors can be the result of inherited defects such as those found in hemophilia A (factor VIII) and hemophilia B (factor IX). Deficiency can also result from acquired deficiencies, such as the abnormal platelet consumption occasionally observed in patients after cardiopulmonary bypass. A history of excessive bleeding with prior surgical or dental procedures or development of hemarthrosis should raise awareness of a possible bleeding diathesis. Treatment of specific clotting factor deficiencies requires identification and replacement of the missing factors. Both factor VIII and factor IX are available as recombinant products that are effective but expensive. In general, more than 40% of normal clotting factor activity is required to prevent bleeding and higher levels may be necessary to stop active bleeding.
Patients with vitamin K deficiency or those who have experienced a warfarin overdose usually respond to vitamin K administration within 12 to 24 hours. Intramuscular, subcutaneous, or intravenous administration of 10 mg of vitamin K often corrects the prothrombin time to an International Normalized Ratio (INR) of less than 1.3. Smaller doses of 1 to 2 mg allow partial correction in the absence of active bleeding for patients who need reinstitution of warfarin. Acute treatment of life-threatening hemorrhage from vitamin K deficiency or warfarin overdose may be treated with prothrombin complex concentrate (PCC).
Deficiency of platelet number or function has multiple potential etiologies, many of which require interventions other than transfusion. Primary bone marrow failure or drug-induced bone marrow suppression can cause a deficiency in platelet production. Conversely, immune-mediated mechanisms, mechanical destruction, or drugs can cause a deficiency because of increased platelet consumption. Idiopathic thrombocytopenic purpura (ITP) is caused by presence of a platelet antibody of unknown etiology. This condition does not respond well to transfusion and is treated with steroids and/or large doses of intravenous immune globulin when there is life-threatening bleeding. Patients with chronic ITP may be treated with immune suppression or splenectomy. Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by a pentad of fever, thrombocytopenia, microangiopathic hemolytic anemia, central nervous system dysfunction, and renal failure. TTP is most likely the result of an inborn or acquired deficiency of a plasma protease that normally cleaves vWF multimers. Presumably, when vWF multimers are not cleaved they promote spontaneous aggregation of platelets in the circulation, producing thrombi rich in platelets and vWF, with a resultant consumptive deficiency. Patients with TTP usually maintain a normal fibrinogen level and a normal disseminated intravascular coagulation (DIC) screen. This condition must be treated aggressively with plasmapheresis or plasma exchange; patients have an 80% chance of survival if treated early and aggressively. Awareness and identification of this condition in the perioperative period is essential, given the increased usage of drugs known to be offending agents. Important drugs that can cause acquired TTP include ticlopidine, quinine, clopidogrel, and calcineurin inhibitors such as cyclosporine A.
In addition to the disruptive processing of vWF seen with TTP, deficient production and function of vWF, as seen with von Willebrand disease (vWD), also lead to excessive bleeding perioperatively. Although not an intrinsic platelet disorder, vWD leads to a reduction in the adhesion and aggregation of platelets. This condition is frequently diagnosed in patients with a history of abnormal bleeding associated with surgical and dental procedures, who often present with an elevated PTT. Appropriate therapy of this condition requires identification of the disease type through an activity assay in conjunction with input from a hematology specialist. Patients with type 1 vWD are most effectively treated by the administration of DDAVP in a dose of 0.3 μg/kg. This therapy is most useful in patients who have vWF that is stored and can be released. Other types of vWD respond to administration of cryoprecipitate that is rich in vWF. Cryoprecipitate is rich in the “labile” clotting factors VIII, XIII, and vWF and is also a concentrated source of fibrinogen for patients with fibrinogen deficiency who are unable to tolerate large volumes of FFP. Cryoprecipitate is prepared by flash-freezing plasma and thawing it at 1°C to 6°C. The cold insoluble portion of the thawed plasma is expressed off the top, collected into separate collection bags, and refrozen to become the cryoprecipitate product.
Heparin-induced thrombocytopenia (HIT) is a spectrum of diseases resulting from the formation of antibodies against platelet factor 4 (PF4) and heparin complexes in response to heparin therapy. The incidence of HIT has been reported to be as low as < 1% while other studies have report rates approaching 5%. Heparin administration may lead to a modest decline in platelet count a couple of days after exposure, but this phenomenon is attributed to a nonimmune interaction between heparin and platelets and is not considered true HIT. HIT typically leads to thrombocytopenia 5 days after heparin exposure, which is the time required to form PF4/heparin complex antibodies. However, HIT can develop immediately in patients with recent heparin exposure and preexisting PF4/heparin antibodies. These preexisting antibodies are not permanent, and a study has shown that serum levels become undetectable at a median of 50 to 85 days. Life-threatening HIT is characterized by bleeding associated with a low platelet count or “white clot” thrombosis caused by abnormal platelet aggregation. Because of the frequency with which heparin is used in the hospitalized patient population, vigilance for the formation of this potentially lethal adverse drug reaction must be maintained. Diagnosis is made by the detection of antibodies and clinical findings indicating HIT.
The 4Ts scoring system is a method using clinical parameters ( t hrombocytopenia, t iming of platelet decrease, t hrombosis, and o t her causes of thrombocytopenia) to assess the probability of HIT. A low probability 4Ts score has a very robust negative predictive value; however, an intermediate or high probability 4Ts score only has modest positive predictive value. A 4Ts score of at least intermediate probability should be followed by a PF4-heparin enzyme-linked immunosorbent assay (ELISA) test. This test takes only a couple of hours to complete and has high sensitivity to rule out HIT, but also has a high incidence of false-positive results and low specificity. After a positive PF4-heparin ELISA test, a serotonin-release assay (SRA) should be performed, which is the gold standard. One downside of the SRA is it must be performed at a specialized laboratory and thus takes several days to obtain the results.
Because the PF4/heparin ELISA is relatively nonspecific and SRA results are frequently not immediately available, initiation of therapy may need to proceed on the basis of clinical suspicion while awaiting definitive diagnosis. If HIT is suspected, heparin therapy must be discontinued and other agents used for anticoagulation. Direct thrombin inhibitors, including argatroban and bivalirudin, are acceptable alternatives to heparin therapy but lack the safety benefit of reversibility with protamine. Bivalirudin has been successfully used for patients with HIT on cardiopulmonary bypass. However, because no reversal agent exists for bivalirudin, postoperative bleeding after cardiac surgery is frequently excessive until the bivalirudin is cleared. For patients with a vague history of heparin-induced thrombocytopenia without life-threatening bleeding or thrombotic complications, the use of heparin for anticoagulation during cardiopulmonary bypass may still be the safest therapy. If antiplatelet antibody titers are not detectable with screening, bolus-dose heparin therapy prior to bypass with prompt reversal at the end of bypass may be indicated. The advice of a consulting hematologist is recommended to assist with the risk-to-benefit analysis of short-term heparin exposure in a patient with a history of HIT. Low molecular weight heparin can also stimulate antiplatelet antibodies and should not be used for patients with suspicion of HIT. If long-term anticoagulation is required for a patient with HIT, administration of therapeutic warfarin therapy is recommended. However, warfarin should be started and adjusted to therapeutic levels while other forms of anticoagulation are in place and already at therapeutic levels. Warfarin has the potential to inhibit production of the antithrombotic, vitamin K–dependent factors protein C and protein S prior to therapeutic depression of factors II, VII, IX, and X.
Tirofiban, a glycoprotein IIb/IIIa antagonist, has been used successfully to inhibit platelet aggregation from HIT during cardiopulmonary bypass. Koster et al. have published a protocol where a bolus of tirofiban 10 μg/kg was administered 10 minutes prior to cardiopulmonary bypass cannulation followed by an infusion of 0.15 μg/kg/min. Heparin was given in a standard fashion with an activated clotting time goal of > 480 seconds. The tirofiban infusion was stopped 1 hour prior to coming off cardiopulmonary bypass. After arrival in the intensive care unit, a recombinant hirudin infusion was started for thromboprophylaxis.
As an alternative to medical management, plasmapheresis has been used to remove heparin/PF4 antibodies from circulation and allow heparin administration safely for cardiopulmonary bypass. Welsby et al. have described their experience with 11 patients undergoing plasmapheresis prior to cardiothoracic surgery. Nine patients had a pre- and postprocedure PF4-heparin ELISA test, where six had negative postprocedure ELISA results and the remaining three patients had titer reductions between 48% and 78%. One patient underwent a second round of plasmapheresis postoperatively for a possible acute, humoral rejection after heart transplantation. None of the patients in this study developed postoperative HIT.
The management of HIT is quite diverse. Confirmation tests include the fast turnaround PF4-heparin ELISA, which has high sensitivity but low specificity, and the SRA, which is a send-out test, but has much higher specificity. The treatment plan could include waiting for the heparin/PF antibody to be naturally eliminated, using heparin alternatives such as direct thrombin inhibitors, administering platelet inhibitors, and performing plasmapheresis. The likelihood of HIT, with the timing and urgency of surgery and the availability of resources at the clinician’s institution, must all be assessed prior to moving forward with the best plan for each patient.
Patients often require surgery while on therapeutic doses of anticoagulants to manage chronic conditions such as prosthetic mechanical valves, ventricular assist devices, and atrial fibrillation. The management of warfarin, a commonly used vitamin K antagonist, for elective surgery involves stopping the medication 5 days prior to the procedure. Patients who are considered high-risk for thrombus formation should discontinue warfarin 5 days prior and bridge with an alternative anticoagulant such as heparin or enoxaparin. In the case of emergency surgery, warfarin reversal can be accomplished in several ways: vitamin K, FFP, or PCC. Vitamin K induces the synthesis of factors II, VII, IX, and X and is best given intravenously and not orally in the perioperative setting. Intravenous vitamin K has been described to take more than 12 hours to bring down a supratherapeutic INR to ≤ 2.0 in the majority of patients. Therefore vitamin K alone is not a suitable method to normalize INR for emergency surgery.
FFP can be used to reverse the effect of warfarin by increasing coagulation factor activity. However, the number of units of FFP needed to lower the INR to a clinically reasonable level is quite significant. Such a large-volume transfusion puts the patient at increased risk of transfusion-related acute lung injury, transfusion-associated circulatory overload, and increased infection risk. Moreover, it is difficult to achieve an INR < 1.5 with FFP alone, because at this point the additional coagulation factors given through continued FFP transfusion become diluted by the volume of the plasma product. Current guidelines do not promote FFP as the preferred agent for emergency warfarin reversal.
PCCs contain vitamin K–dependent factors II, VII, IX, and X, and are considered first-line therapy, with concurrent administration of IV vitamin K, for emergency warfarin reversal. In the United States, the most common PCC formulation is the 4-factor Kcentra, which is also known as Beriplex P/N (CSL Behring). In addition to the above-mentioned vitamin K–dependent factors, Kcentra provides the anticoagulant proteins C and S, antithrombin, and heparin. Advantages of PCCs over FFP for emergency warfarin reversal include decreased risk of pathogen transmission, lower volume administration, and greater predictability in reestablishing a normal coagulation state. Because of its dependability in producing a procoagulant state, PCCs also increase the risk of unwanted thromboembolism, which needs to be balanced with its benefits. In addition, British guidelines state that “PCC should not be used to enable elective or non-urgent surgery.”
Oral anticoagulants that are not vitamin K antagonists include factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors such as dabigatran. In a double-blind parallel group study, the factor Xa inhibitor rivaroxaban was administered for 3 days to volunteers followed by 4-factor PCCs, tranexamic acid (TXA), or saline. The study found that PCCs partially reversed the prothrombin time and there was no reversal detected in the TXA group. They also looked at bleeding time and volume, which showed no difference between the PCC, TXA, or saline groups. Another crossover study had volunteers take either rivaroxaban or the direct thrombin inhibitor dabigatran, followed by 4-factor PCC (Cofact, Sanquin). They found that in the rivaroxaban group, PCCs normalized thrombin generation, but failed to do so in the dabigatran group. Emerging studies continue to support the notion that PCCs are a reasonable yet off-label option to normalize the anticoagulant effect of factor Xa inhibitors, but not for direct thrombin inhibitors. It is hypothesized that direct thrombin inhibitors act too downstream of the coagulation cascade for PCCs to have a meaningful effect.
Instead of PCCs, idarucizumab is the agent of choice for dabigatran reversal. The REVERSE study recently published on the safety and efficacy of idarucizumab. It was a prospective multicenter study that followed approximately 500 patients who either had uncontrolled bleeding or were in need of an urgent procedure. The majority of these patients either had intracranial or gastrointestinal bleeding. They were administered a 5-g dose of idarucizumab, which resulted in a complete reversal in 98% of patients with duration of anticoagulation reached 24 hours after the initial dose. Adverse events such as thrombosis occurred at a lower rate than that of PCCs.
Andexanet alfa was developed as a reversal agent to factor Xa inhibitors. The ANNEXA-4 study enrolled 354 patients who suffered bleeding while on a factor Xa inhibitor. They were given andexanet alfa and their antifactor Xa activity levels were followed; in addition, they were clinically assessed for hemostatic efficacy at 12 hours after their andexanet alfa dose. The investigators found that 82% of patients had good to excellent clinical hemostasis after andexanet alfa administration. However, they concluded that a drop in antifactor Xa activity level was not a predictor of clinically significant hemostasis. Andexanet alfa also reverses anticoagulation induced by heparin and enoxaparin. The mechanism of this reversal is andexanet binding to heparin-activated antithrombin’s anticoagulation complex; the reversal is not andexanet inhibiting free heparin or enoxaparin from binding to antithrombin.
Tranexamic acid (TXA) and aminocaproic acid (EACA) are synthetic derivatives of lysine that downregulate fibrinolysis by inhibiting plasmin production. In 2010, the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage (CRASH-2) trial described the analysis of 20,211 trauma patients who were randomized to tranexamic acid or placebo within 8 hours. The primary outcome of death at 4 weeks after traumatic injury was significantly decreased in the TXA group at 14.5% versus placebo 16.0% (RR 0.91, 95% CI 0.85–0.97, P = 0.0035). The causes of death were divided into the following groups: bleeding, vascular occlusion, multiorgan failure, head injury, and other causes. Among these groups, only death by bleeding was significantly reduced with TXA 4.9% versus placebo 5.7% (RR 0.85, 95% CI 0.76–0.96, P = 0.0077). This study could not identify the reason or mechanism behind TXA reducing all-cause mortality and death by bleeding. It may be presumed that the reason is TXA’s ability to reduce fibrinolysis; however, blood transfusions were not significantly different between the TXA and placebo groups ( P = 0.21). Extended analysis performed on the CRASH-2 data found that administration of TXA less than 3 hours after injury was most effective and that later administration was either ineffective or possibly harmful.
Two years later, the Military Application of Tranexamic Acid in Trauma Emergency Resuscitation Study (MATTERS) examined 896 patients who received at least 1 unit of PRBC. This study was retrospective and observational and found a 6.5% absolute risk reduction for death in the TXA group versus the control non-TXA group. Additionally, in patients who underwent a massive transfusion, this study revealed a 13.7% absolute risk reduction for death in the TXA group versus the non-TXA group. These findings were interesting given the TXA group had higher Injury Severity Scores and incidences of severe extremity injuries compared with the non-TXA group. The study also found a statistically significant decrease in hypocoagulable state in the TXA group over controls, but higher rates of deep vein thrombosis and pulmonary embolism.
Both CRASH-2 and MATTERs trials demonstrated the benefit of antifibrinolytics administration in trauma patients, but also indicated signs of possible harm. Although the CRASH-2 trial did not show a significant difference in vascular occlusive events with TXA administration, the MATTERs trial revealed increased deep vein thrombosis and pulmonary embolism. Additionally, the extended analysis of CRASH-2 showed harm when TXA was given too late. Such concern has led to the investigation of a phenomenon called fibrinolysis shutdown, defined as state of resistance to tissue plasminogen activator. Moore et al. describe a three-group spectrum of fibrinolysis intensity: hyperfibrinolysis, physiologic fibrinolysis, and fibrinolysis shutdown. In their study of 180 patients, they found that hyperfibrinolysis patients required more PRBC and FFP, and there was a higher incidence of massive transfusion. Mortality was the lowest in the physiologic fibrinolysis group with hyperfibrinolysis and fibrinolysis shutdown having higher mortality. The most frequent cause of death in the hyperfibrinolysis group was acute blood loss, while for the fibrinolysis shutdown group, multiple organ failure presumably from ischemia was the leading cause of death. Because this study showed significant harm when patients received an excess of antifibrinolytics leading to fibrinolysis shutdown, the practice of routine administration of antifibrinolytics has been put into question. Current trends advocate a more targeted use of antifibrinolytics based on laboratory studies to maximize benefits and to mitigate risks.
Intraoperative Blood Management
Appropriate triggers for transfusion of allogeneic red blood cells in the perioperative period have been the subject of extensive academic debate. According to the guidelines for transfusion in the perioperative period published jointly by the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists in 2011, transfusion of allogeneic packed red blood cells is indicated for patients with a hemoglobin level < 6 g/dL or for patients with a hemoglobin level between 6 and 10 g/dL with evidence of tissue ischemia. While not controversial, the wide range of hemoglobin over which red blood cells were indicated in the presence of tissue ischemia provided little solid clinical guidance for most patients undergoing heart surgery. The benefit of increasing oxygen carrying capacity with allogeneic red blood cell transfusion versus the risk of an allogeneic red blood cell transplantation remained largely up to provider experience and practice patterns. Individual patient characteristics that elevate risk of tissue ischemia such as preexisting vascular insufficiency must also be considered when selecting a hemoglobin level for red blood cell transfusion. Regarding the effect of age of stored blood, the most recent guideline reports that comparative outcomes of transfusing old versus new blood products are equivocal.
The level of hemoglobin at which allogeneic red blood cell transfusion is necessary while a patient is anesthetized, paralyzed, and cooled on cardiopulmonary bypass is significantly lower than in the postoperative period. In an analysis of 10,179 consecutive patients with normal preoperative hemoglobin who underwent cardiac surgery with cardiopulmonary bypass, Karkouti et al. found that a composite outcome of death, stroke, and renal failure did not significantly rise until hemoglobin fell to less than 50% of the patient’s baseline. This data suggest that the percentage fall in hemoglobin level is a better trigger for red blood cell transfusion than an absolute hemoglobin level while on cardiopulmonary bypass.
In randomized trial testing the noninferiority of a restrictive red blood cell transfusion strategy compared with a liberal strategy for patients undergoing cardiac surgery utilizing cardiopulmonary bypass with a moderate to high risk of mortality, investigators in the Transfusion Requirements in Cardiac Surgery (TRICS) III trial concluded that an intraoperative hemoglobin threshold of 7.5 g/dL was not inferior to a higher threshold of 9.5 g/dL in the intraoperative and ICU period or 8.5 g/dL on the non-ICU ward. According to guidelines for management of bleeding in cardiac surgery patients published in 2019, the Society of Cardiovascular Anesthesiologists Task Force agreed that a hemoglobin transfusion threshold of 7.5 g/dL is “clinically reasonable and practical” for cardiac surgical patients. Noninferiority of a threshold lower than 7.5 g/dL following separation from cardiopulmonary bypass has not been sufficiently tested.
The most effective means of limiting allogeneic blood transfusion is preservation of the patient’s own red blood cell mass. Techniques such as limitation of unnecessary intravenous fluid administration and reduction in cardiopulmonary pump prime volumes limit dilution of red blood cells, platelets, and clotting factors.
Cell salvage involves suction of shed blood from the operative field, which is then washed and resuspended in crystalloid for reinfusion. Cell salvage is currently widely used in cardiac surgery and represents a low-risk method of recovering red blood cells from the surgical field when not on cardiopulmonary bypass as well as from the residual cardiopulmonary bypass circuit following separation from bypass. During this process, platelets and plasma proteins are removed, but fresh autologous red blood cells are preserved.
Meta-analysis performed at the end of the 1990s strongly supported the use of perioperative cell salvage in orthopedic surgery but was equivocal with regard to the efficacy in cardiac surgery. In a 2009 meta-analysis of cell salvage use in cardiac surgery, data from 2282 patients enrolled in randomized clinical trials were combined for analysis. Using cell salvage, exposure to allogeneic red blood cells was significantly reduced as was exposure to any allogeneic blood product. The volume of allogeneic blood products transfused per patient was also significantly reduced by 256 mL (95% CI: -416 to -95 mL, P = 0.002).
A subanalysis of the Wang et al. study suggested that cell salvage was only beneficial when used for shed blood or residual cardiopulmonary bypass circuit blood. Therefore cell salvage appears to be beneficial for the recovery of red blood cells during the portions of cardiac surgery when not on cardiopulmonary bypass, making the technique complimentary to acute normovolemic hemodilution.
Acute Normovolemic Hemodilution (ANH)
According to the 2011 Society of Thoracic Surgeons (STS) and Society of Cardiovascular Anesthesiologists (SCA) Blood Conservation Clinical Practice Guidelines, “Acute normovolemic hemodilution may be considered for blood conservation but its usefulness is not well established. It could be used as part of a multipronged approach to blood conservation. (Level of evidence B).” While this technique has been used for many years, definitive evidence of efficacy is lacking. As with many clinical interventions designed to reduce transfusion, randomized controlled trials are limited. Because allogeneic blood component transfusion is considered to be a standard of care, transfusion research trials are complicated by the inability to remove investigator bias and withhold transfusion in the treatment group deemed necessary by the clinical team. Opponents of ANH will argue that the procedure is time-consuming, distracting, risky, and ineffective. Proponents will argue that in select populations where transfusion is likely, but limited to a need for 1–2 units of PRBCs, the procedure allows avoidance of low-volume transfusion. It is also believed to be inexpensive, safe when performed by a trained team in the operating room, and well accepted by patients.
Particularly in the arena of cardiac surgery with cardiopulmonary bypass, the risk-to-benefit ratio of ANH would seem to be the most favorable for this technique. Whole blood passed through the cardiopulmonary bypass machine has a reduced clotting factor activity, a reduced platelet count, and measurable thrombasthenia. By setting aside units of whole blood for reinfusion following cardiopulmonary bypass, not only will RBC mass be preserved, but each unit of whole blood will provide one unit of fresh RBCs, one unit of fresh plasma, and a single donor unit of autologous platelets, potentially improving post-bypass hemostasis.
Following the HIV crisis in the 1980s, significant emphasis was placed on blood conservation research. Meta-analysis performed at the end of the 1990s suggested that ANH reduced the likelihood of exposure to allogeneic blood. However, simply by using a perioperative transfusion protocol guiding decision-making, the beneficial effect of ANH was eliminated. This analysis was also criticized for including studies from the 1970s that drove the study conclusions. In 2001, Richard Weiskopf performed a mathematical analysis to estimate the effect of ANH on red blood cell mass preservation. Using elegant mathematical calculations, he concluded that ANH would indeed preserve RBC mass, but only if the surgical blood loss exceeded 50% of the blood volume. He also calculated that it would take a blood loss of 70% of the blood volume to save 1 unit of packed RBCs from being transfused. In practice, this would require an ANH harvest volume of 4 units of whole blood and a blood loss approaching 2 L to preserve only 1 unit of RBCs based solely upon RBC mass preservation. A subsequent meta-analysis in 2004 compared ANH with other blood conservation techniques. Although hemodiluted patients were transfused between 1 and 2 units less and had significantly less intraoperative bleeding, the risk of allogeneic blood exposure was not significantly different and the authors concluded that the safety of the procedure is unproven and widespread use of ANH could not be supported. As a result, enthusiasm in the medical community waned for this technique.
In 2015, Zhou et al. performed a subsequent meta-analysis of 3819 patients in 63 studies comparing ANH with controls in all types of surgery. A significant reduction in the volume of allogeneic RBC transfusion was identified and a reduction in risk of allogeneic exposure. However, because of heterogeneity in the studies and a concern for publication bias, the authors concluded that the true efficacy of ANH is unproven. Critique of this study cited the inclusion of small trials, absence of consistent transfusion protocols, and variation in surgical type and ANH technique as significant limitations making the study inconclusive.
Combining knowledge gained from decades of studies regarding the need for large volume blood loss and the need for a controlled environment to realize benefit and minimize risk from ANH, cardiac surgical patients undergoing cardiopulmonary bypass would seem to be the best candidates for ANH. When the volume of the cardiopulmonary bypass circuit is combined with surgical blood loss, the total temporary blood loss approaches 2 L. With the controlled environment allowing time for gradual blood harvest under general anesthesia, large harvest volumes up to 4 units of whole blood are possible, making the total blood loss during cardiopulmonary bypass mathematically favorable for significant preservation of RBC mass. Setting aside fresh whole blood that is not exposed to the cardiopulmonary bypass circuit would prevent decrement in clotting factor activity as well as platelet number and function in the whole blood. Infusion of fresh whole blood following separation from cardiopulmonary bypass would then enhance coagulation and improve hemostasis.
Recent analyses limited to cardiac surgery with cardiopulmonary bypass have yielded findings supporting ANH. In a database study from the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative, 13,354 patients undergoing on-pump coronary artery and valve surgery from 26 hospitals were analyzed. ANH patients had a lower adjusted relative risk of allogeneic RBC transfusion that improved with larger harvest volumes. ANH patients also displayed a significantly lower risk of plasma and platelet transfusion, risk-adjusted 30-day mortality, and acute kidney injury. As a database study, selection bias could not be excluded.
Subsequent meta-analysis including only randomized, controlled trials of ANH in cardiac surgery also revealed a signal favorable for the use of ANH. Twenty-nine trials involving 2439 patients were included with findings of significantly less allogeneic RBC transfusions in the ANH group and a significantly higher allogeneic blood avoidance rate with ANH. ANH patients also had less postoperative blood loss. As with all conclusions provided from a meta-analysis, the combination of data from a large number of different clinical trials with variation in technique, endpoints, and quality can potentially limit the validity of the findings. In a commentary of the Barile et al. study, it was noted that the primary outcome was reported as a standardized mean difference, instead of an absolute reduction in RBCs transfused, and that assessment of patient outcome was also lacking in the study. The significant differences identified also resulted largely from older studies, suggesting that other blood management techniques have eliminated the benefit of ANH in recent years.
In a recent single-center study by Henderson et al., 84 patients having undergone coronary artery bypass grafting (CABG), aortic valve repair or replacement (AVR), or CABG/AVR surgery with cardiopulmonary bypass and ANH with a harvest volume of at least 2 units of whole blood (900 mL) were propensity-matched for likelihood to receive allogeneic transfusion with 84 patients undergoing the same procedure with a harvest volume of 0–899 mL of whole blood. Patients were excluded for age > 80 years or < 40 years, body mass index > 45, preoperative warfarin, P2Y12 inhibitor or direct oral anticoagulant (DOAC) therapy, cardiopulmonary bypass time > 4 hours or < 40 minutes, emergency surgery, hematocrit < 27%, or platelet count < 100 × 10 9 /L. Multifaceted blood conservation strategies were used in both groups. There was no difference in adverse events between groups. The rate-ratios for allogeneic transfusion were significantly lower for patients undergoing high-volume ANH for both RBC and non-RBC transfusion compared with patients receiving either low-volume or no ANH. This study strongly suggests that the use of high-volume ANH in this select patient population is beneficial for reduction of allogeneic transfusion.
The patient population refusing allogeneic transfusion under any circumstance represents a group of patients for whom all available means of blood conservation are maximized around the time of cardiac surgery in order to offer the best chance for survival. Pattakos et al. published a comparison of outcomes between 322 patients refusing transfusion and 322 propensity-matched controls. Postoperative myocardial infarction, reoperation for bleeding, prolonged ventilation, length of ICU stay, and length of hospital stay were all reduced in the cohort of patients refusing transfusion. One-year survival approached significant improvement ( P = 0.07) in the refusal cohort. In a series of 45 consecutive patients undergoing cardiac surgery and refusing allogeneic transfusion, large-volume hemodilution was used for 37 of the 45 patients (not used for critical aortic stenosis or off-pump CABG) as part of a comprehensive patient blood management program. In the case series, 90-day mortality was zero and hemoglobin levels were maintained above 10 g/dL except while on cardiopulmonary bypass.
Given the evidence to date, use of large-volume ANH for selected patients undergoing cardiac surgery with cardiopulmonary bypass should be considered as part of a comprehensive patient blood management strategy. Study of this technique in a large randomized, controlled trial is warranted.