Management of Postoperative Bleeding in Cardiac Surgery: Using Evidence-Based Practice Guidelines in Clinical Practice CME


Complete author affiliations and disclosures are at the end of this activity.


Release Date: July 31, 2007

Patient History and Introduction

 

 

RC is an 80-year-old woman with a history of coronary artery disease, type 2 diabetes mellitus, and hypertension who is admitted to the hospital for evaluation of unstable chest pain. Cardiac catheterization was performed, revealing a 90% occluding lesion in the left anterior descending (LAD) coronary artery and diffuse disease in the left circumflex artery. In anticipation of an angioplasty, she was given a 600-mg loading dose of clopidogrel prior to the cardiac catheterization. Based on her ongoing chest pain and the lesion found at catheterization, she is scheduled for urgent coronary artery bypass graft (CABG) surgery.

Pertinent physical examination and laboratory results prior to CABG are as follows:

The patient was taking the following medications prior to admission:


It is projected that by 2010, a cost of $500 per unit of blood product will be commonplace (Spiess, 2004b).

Recent data indicate that the cost of a unit of blood in the United States ranges from approximately $50 for a unit of fresh frozen plasma (FFP) to $475 for a unit of platelets (Morgan, 2005; Spiess, 2004b). Other additional costs include laboratory/institutional expenses, storage, testing, and administration (Morgan, 2005).

Anemia is common in patients in intensive care units and in those who undergo major surgical procedures, and is associated with increased mortality (Vincent, 2006). More than 11 million units of blood are transfused in the United States each year, with 10% to 20% associated with CABG surgery (Green, 2004). Interestingly, patients undergoing cardiac procedures (15% to 20%) consume more than 80% of the blood products transfused during cardiac surgery (Figure 1).

 
Figure 1. Pareto diagram of the distribution of nonautologous blood units transfused in 4445 cardiac surgical patients over a 4-year period; 86% of the units transfused are consumed by 20% of the patients who receive more than 10 donor units per operation. From Ferraris, Int J Angiology., 2005.

Despite the fact that transfusion is a common medical intervention, the practice is supported by limited scientific evidence (Spiess, 2004a; Spiess, 2005). A survey of 24 hospitals by Stover and colleagues showed that transfusion rates varied from 27% to 92% (Figure 2) (Stover, 2000). Arbitrary transfusion triggers such as the "10/30 rule" (ie, transfusion of RBCs indicated for hemoglobin concentration < 10 g/dL or hematocrit of 30%) are commonly applied (Madjdpour, 2006).

 
Figure 2. Variability in transfusion rates. From Stover, J Cardiothorac Vasc Anesth., 2000.

In the United States, there are several layers of safeguard systems for blood collection, and largely this system has proved effective (Klein, 2000). However, transfusion of blood products can be associated with an increased incidence of nosocomial infections, pneumonia, respiratory distress syndrome, myocardial infarction, renal failure, and stroke (Hebert, 1997; Spiess, 2004a; Leal-Noval, 2001; Carson, 1999; Vincent, 2002; Hill, 2003; Rao, 2004; Habib, 2003, 2005; Taylor, 2006; Silliman, 2006; Fields, 2006). Interestingly, many of these outcomes also appear to be related to an increasing number of units of blood transfused, leading to a higher risk of adverse outcomes. Similar results have been seen in many patient populations including the critically ill, trauma patients, and those undergoing surgical procedures (eg, CABG, orthopedic surgery, esophagectomy) (Koch, 2006; Hill, 2003; Fields, 2006). The risks associated with blood transfusion are summarized in Table 1 (Ferraris, 2007).

Table 1. Risks of Transfusion

Infectious
   Human immunodeficiency virus
   Hepatitis B
   Hepatitis C
   Bacterial infection
Immunologic reactions
   Febrile nonhemolytic transfusion
   Anaphylactic transfusion
   ABO mismatch
   Hemolysis
   Death
   Leukocyte-related target organ injury
   Transfusion-related acute lung injury
   Post-transfusion purpura
Transfusion services error
   Donor screening error (malaria, Trypanosoma cruzi, babesiosis, Creutzfeld-Jakob disease)
   Transfusion services error
From Ferraris, Ann Thorac Surg., 2007.

These data are supported by the Transfusion Requirements in Critical Care (TRICC), which is the only prospective, randomized, multicenter trial to compare outcomes in 2 groups of critically ill patients. The incidences of pulmonary edema, acute respiratory distress syndrome, infection, myocardial infarction, and mortality were lower in the restrictive treatment group than in the group in which the decision to administer the agent was made based on a liberal set of criteria for administration, consistent with clinical practice (Hebert, 1997).

A retrospective study of 10,289 patients in the US Social Security Death Index between January 1995 and June 2002 evaluated the effect of demographics, comorbidities, and operative factors on survival in transfused patients (Koch, 2006). Survival among transfused patients was found to be significantly reduced when compared with nontransfused patients. Transfusion of RBCs was associated with a risk-adjusted reduction in survival for both the early (up until 6 months postoperatively) (0.34 ± 0.02, P < .0001) and late phases (up to 10 years) (0.074 ± 0.016, P < .0001). One factor that may affect mortality risk is immunomodulation and immunosuppression due to allogeneic transfusion, which can increase the risk of postoperative bacterial infection (Utter, 2004; Spiess, 2002, 2004a; Vamvakas, 2000).

In summary, to ensure optimal patient outcomes and an adequate supply of blood, it is critical that transfusion procedures are evaluated by applying the tenets of evidence-based medicine (Ferraris, 2007). A subset of patients undergoing CABG surgery who are at increased risk for transfusion can be identified. The Society of Thoracic Surgeons (STS) and the Society of Cardiovascular Anesthesiologists (SCA) have performed a rigorous review of the available evidence and have developed guidelines to allocate this valuable resource and improve patient outcomes (Ferraris, 2007).

The aim of the STS/SCA blood conservation guidelines is "...to provide clinically useful guidelines, based on available evidence, to aid cardiothoracic surgeons and anesthesiologists in their decisions about blood conservation and transfusion" (Ferraris, 2007).

The authors note in the guidelines: "Evidence-based guidelines are an attempt to reconcile often conflicting lines of evidence, giving greater weight to evidence derived from more methodologically rigorous studies and those for which the overall weight of evidence is most convincing. They must be viewed as guidelines and recommendations, not absolutes." The authors searched multiple sources for available evidence about use of blood transfusions and blood conservation before, during, and after cardiac operations. In formulating the recommendations, science was the focus and cost analysis was not a primary consideration (Ferraris, 2007).

Evidence suggests that blood conservation interventions and blood transfusion decisions vary widely among different healthcare providers, including hospitals and individual practitioners (Ferraris, 2007). By adhering to guideline-recommended interventions, this variability in practice can be limited, thereby improving patient outcomes and reducing healthcare costs.

The STS/SCA guidelines define a class I recommendation as having a benefit greater than risk, and the procedure/treatment should be performed/ administered. A class IIb recommendation has a benefit greater than or equal to risk; additional studies with broad objectives are needed, additional registry data would be helpful, and it is not unreasonable to perform procedure/administer treatment (Ferraris, 2007).

A class IIa recommendation has a benefit greater than risk; however, additional studies with focused objectives are needed. Therefore, it is reasonable to perform procedure/administer treatment.

Table 2 describes the methods used to quantify the types of evidence available and the classification system (same as the system used by the Joint Task Force for Guidelines of the American College of Cardiology [ACC] and the American Heart Association [AHA]) used to summarize recommendations about clinically important questions (http://circ.ahajournals.org/manual/manual_IIstep6.shtml).

Table 2. Classification Scheme Used to Summarize Clinical Recommendations

  Class I Class IIa Class IIb Class III
Estimate of certainty (precision) of treatment effect Benefit >>> Risk
Procedure/treatment SHOULD be performed/administered
Benefit >> Risk: additional studies with focused objectives needed

IT IS REASONABLE to perform procedure/administer treatment
Benefit ≥ Risk: additional studies with broad objectives needed; additional registry data would be helpful

IT IS NOT UNREASONABLE to perform procedure/administer treatment
Risk ≥ Benefit: no additional studies needed

Procedure/treatment should NOT be performed/administered AS IT IS NOT HELPFUL AND MAY BE HARMFUL
 
Level A

Multiple (3-5) population risk strata evaluated

General consistency of direction and magnitude of effect
Recommendation that procedure or treatment is useful/effective

Sufficient evidence from multiple randomized trials or meta-analyses
Recommendation in favor of treatment or procedure being useful/effective

Some conflicting evidence from multiple randomized trials or meta-analyses
Recommendation's usefulness/efficacy less well established

Great conflicting evidence from multiple randomized trials or meta-analyses
Recommendation that procedure or treatment not useful/effective and may be harmful

Sufficient evidence from multiple randomized trials or meta-analyses
 
Level B

Limited (2-3) population risk strata evaluated
Recommendation that procedure or treatment is useful/effective

Limited evidence from single randomized trial or nonrandomized studies
Recommendation in favor of treatment or procedure being useful/effective

Some conflicting evidence from single randomized trial or nonrandomized studies
Recommendation's usefulness/efficacy less well established

Greater conflicting evidence from single randomized trial or nonrandomized studies
Recommendation that procedure or treatment not useful/effective and may be harmful

Limited evidence from single randomized trial or nonrandomized studies
 
Level C

Very limited (1-2) population risk strata evaluated
Recommendation that procedure or treatment is useful/effective

Only expert opinion, case studies, or standard-of-care
Recommendation in favor of treatment or procedure being useful/effective

Only diverging expert opinion, case studies, or standard of care
Recommendation's usefulness/efficacy less well established

Only expert opinion, case studies, or standard-of-care
Recommendation that procedure or treatment not useful/effective and may be harmful

Only expert opinion, case studies, or standard of care
From Ferraris, Ann Thorac Surg., 2007.

Based on review of the STS/SCA guideline committee, 6 patient-related variables stand out as important indicators of the risk for bleeding or blood transfusion during or after cardiac operations:

RC has 5 of these 6 factors: advanced age, low preoperative red blood cell volume, preoperative antiplatelet or antithrombotic drugs, reoperative or complex procedures, and noncardiac comorbidities.

According to the STS guidelines, any of these risk factors should alert the clinician regarding bleeding risk and should trigger blood conservation measures for specific risks. Certain clinical situations will need special interventions and should serve as "red flags" for surgeons. Examples include patients with acquired or congenital coagulopathies, patients scheduled for complex procedures (eg, combined valve/coronary revascularization, aortic dissection with deep hypothermic circulatory arrest), sepsis with thrombocytopenia, repeat cardiac procedures, and patients of the Jehovah's Witness religion (Ferraris, 2007).

More than 50% of patients undergoing cardiac procedures do not receive allogeneic blood transfusion. Patients who receive more than 10 donor units of blood products are in the 90th percentile of the patient transfusion profile (Ferraris, 2007).

There is consistently a high-risk subset of patients who require large amounts of blood products during their cardiac procedures. It is reasonable to identify these patients and target transfusion guidelines to this population as they are the most likely to benefit. As noted in the STS/SCA guidelines: "By identifying these high-risk patients and altering transfusion practices in this group, the variability in transfusion practices is expected to trend toward standard levels and ultimately conserve valuable resources."

The specific STS/SCA guideline recommendations regarding multivariate predictors and observational variables associated with blood transfusion are as follows:

Class I:

Preoperative identification of high-risk patients (advanced age, preoperative anemia, small body size, non-CABG or urgent operation, preoperative antithrombotic drugs, acquired or congenital coagulation/clotting abnormalities, and multiple patient comorbidities) should be performed and all available preoperative and perioperative measures of blood conservation should be undertaken in this group since they account for the majority of blood products transfused (Level of Evidence A).

Class IIa:

Patients who have thrombocytopenia less than 50,000/mm2, who are hyper-responsive to aspirin or other anti-platelet drugs as manifested by abnormal platelet function tests or prolonged bleeding time, or who have known qualitative platelet defects represent a high risk group for bleeding. Maximum blood conservation interventions during cardiac procedures are reasonable in these high-risk patients (Level of Evidence B).

Table 3 summarizes the clinical data on which these recommendations are based.

Table 3. Risk Factors Associated with Increased Bleeding or Blood Transfusion During or After Cardiac Operations

Risk Factor
Patient-Related Variables
Advanced age or age > 70 years
Preoperative anemia
Female gender
Body size or body surface area
Preoperative antithrombotic therapy
   High intensity (abciximab, clopidogrel, direct thrombin inhibitors, low molecular weight heparin, long-acting direct thrombin inhibitors, thrombolytic therapy)
   Low intensity (aspirin, dipyridamole, eptifibatide, tirofiban)Preoperative coagulopathy
   Hereditary coagulopathy or platelet defect (von Willebrand's disease, Hermansky-Pudlak, Bernard-Soulier, Scott, Werlhof, Glanzmann's, hemophilia A or B, clotting factor deficiencies, etc)
   Acquired coagulopathy or platelet abnormality (nonspecific platelet defect measured by template bleeding time or PFA-100, chronic lymphocytic leukemia, cirrhosis, lupus anticoagulant, drug-related polycythmia vera, myelodysplastic syndrome, idiopathic thrombocytopenic purpura, beta thalassemia, etc)
Cardiogenic shock, congestive heart failure, or poor left ventricular function
Renal insufficiency
Insulin-dependent adult-onset diabetes mellitus
Peripheral vascular disease
Preoperative sepsis
Liver failure or hypoalbuminemia

Procedure-Related Variables
Prolonged cardiopulmonary bypass time
Reoperation
Type of operation (other [aortic, complex, etc] > valve/CABG > valve > CABG)
Increased protamine dose after cardiopulmonary bypass
Increased cell-saver volume
Intraoperative autologous donation
Need for transfusion while on cardiopulmonary bypass
Use of polymerized starch for volume expansion

Process-Related Variables
Lack of transfusion algorithm with point-of-care testing
Use of IMA (either 1 or 2)
Reduced heparin dose
Low body temperature in intensive care unit
From Ferraris, Ann Thorac Surg., 2007.

Many of the risk factors are listed as a single factor; however, the risk may be present in the range of low to high. For example, the risk associated with patients older than 75 years is significantly higher than the risk in patients aged 55 years or younger. It is quite possible that the risk of transfusion associated with age is not a continuous function. Similarly, the risk associated with some anti-thrombotic drugs such as aspirin is lower than other agents (eg, clopidogrel). No attempt was made to measure the risk spectrum of variables listed since the evidence base for these variables as risk factors is limited and few quantitative descriptors of risk are available (Ferraris, 2007).

Physician practices influence bleeding and need for blood transfusion. Surgical practices differ widely and can dramatically influence perioperative bleeding and physician responses with transfusion. In addition, physicians do not consistently apply the same triggers or indications for ordering blood transfusions, regardless of the patient's condition at operation or immediately postoperatively. As discussed previously, transfusion rates vary widely among centers (Goodnough 1991, 1993, 1995; Belisle, 1996; Stover, 1998, 2000). The variability in transfusion triggers and in "practice patterns relative to recognition, correction, and/or exploration for excessive postoperative hemorrhage also contribute to wide variability in transfusion practices" (Ferraris, 2006).

There are several procedure-related factors that increase the risk of bleeding. Repeat procedures have higher transfusion rates and, in addition, the type and urgency of the operation are independent predictors for transfusion (Bracey, 1995; Moskowitz 2004). Hypothermia inhibits platelet function and coagulation, and persists into the postoperative period (Michelson, 1999; Despotis, 1996). Patients undergoing CABG who have bilateral internal mammary artery grafts have greater postoperative blood loss than patients with saphenous vein or single mammary artery grafts (Davies, 1998). Replacement of the aortic valve with a pulmonary autograft (Ross procedure) is a technically challenging operation and is associated with up to a 20% incidence of postoperative bleeding necessitating re-exploration and an above-average mortality rate (Santini, 1997; Stelzer, 1989). Patients who have ventricular assist devices or artificial hearts often have hemostatic dysfunction and concomitant coagulation abnormalities. These procedure-related variables influence perioperative bleeding and should alert the surgeon/anesthesiologist to additional risk.

Preoperative antiplatelet and anticoagulant medications for prophylaxis for coronary occlusive disease may lead to excessive intraoperative and postoperative bleeding and transfusion. Therefore, preoperative medication must be managed to obtain maximum cardioprotective benefit while minimizing the risk of hemorrhagic complications (Ferraris, 2007).

It is common in current cardiology practice for patients to receive both aspirin and the potent antiplatelet agent clopidogrel. In patients with atherosclerotic disease and receiving chronic aspirin therapy, a front-loaded regimen of clopidogrel added to aspirin has shown significant antithrombotic effect at 2 hours (Helft, 2000). This combination results in higher postoperative bleeding, more transfused blood products, and higher rate of re-exploration for mediastinal hemorrhage during emergency CABG surgery (Yende, 2001; Hongo, 2002; Gansera, 2003; Ray, 2003; Ferraris, 2007). In certain high-risk patients, aspirin may not have been discontinued prior to CABG and management of blood conservation will be necessary. For these patients, it is recommended that a combination of interventions (hemostatic drugs, permissive perioperative anemia, peripheral blood-sparing devices) should be considered. For limiting postoperative bleeding, lysine analogs can be used, but this may not be the best option (class IIb recommendation, level B and C evidence) (Ferraris, 1995). In the high-risk, aspirin-treated patient, perioperative blood-sparing techniques (eg, blood pooling at the start of at the onset of cardiopulmonary bypass and salvage of blood from the heart-lung machine) can potentially limit blood loss (class IIa recommendation, level B evidence). Some blood conservation methods, such as predonation of autologous blood and erythropoietin treatment, are not indicated for high-risk, aspirin-sensitive patients (class III recommendation, level B and C evidence) (Ferraris, 1995).

The current AHA/ACC and STS guidelines recommend discontinuing adenosine diphosphate (ADP) inhibitors 5 to 7 days before cardiac surgery, if possible, recognizing that surgery performed within 5 days in patients on ADP inhibitors is associated with an increased risk of perioperative bleeding and transfusions and possibly worse long-term outcomes (Braunwald, 2002). Therefore, it would be optimal to admit RC to the cardiac care unit, continue aspirin treatment, and wait 5 to 7 days for the clopidogrel effect to wear off.

In patients with drug-eluting stents who are at high risk for acute thrombosis upon withdrawal of antiplatelet agents, it may be reasonable to switch to a short-acting GpIIb/IIIa inhibitor prior to CABG surgery. Dipyridamole is not indicated to decrease bleeding, does not prevent graft occlusion after CABG, and may increase bleeding.

The following STS/SCA guidelines are applicable in this situation:

Class IIa Recommendation

  1. It is reasonable to discontinue thienopyridines 5 to 7 days before cardiac procedures to limit blood loss and transfusion. Failure to discontinue these drugs before surgery increases the risk of bleeding and possibly worse outcomes. Caution must be used with sudden withdrawal of antiplatelet therapy in the presence of drug-eluting stents. This can lead to stent thrombosis and the surgical team should consider various alternatives to maintain stent patency (which could include hospitalization to convert thienopyridine therapy to short acting GpIIb/IIIa inhibitors for a few days prior to operation) (Level of Evidence: B).

  2. It is reasonable to discontinue low-intensity antiplatelet drugs (eg, aspirin) only in elective patients without acute coronary syndromes before surgery with the expectation that blood transfusion will be reduced (Level of Evidence: A).

Class IIb Recommendation

Most high-intensity antithrombotic and antiplatelet drugs (including ADP receptor inhibitors, direct thrombin inhibitors, low molecular weight heparins, platelet glycoprotein inhibitors, tissue plasminogen activator [tPA], streptokinase) are associated with increased bleeding after cardiac surgery. It is not unreasonable to stop these medications before surgery in order to decrease minor and major bleeding events. The timing of discontinuation depends on the pharmacodynamic half-life for each agent, as well as the potential lack of reversibility. Unfractionated heparin is the notable exception to this recommendation and is the only agent that requires discontinuation shortly before surgery or not at all (Level of Evidence: C).

Class III Recommendation

Dipyridamole is not indicated to reduce postoperative bleeding, is unnecessary to prevent graft occlusion after coronary artery bypass grafting, and may increase bleeding risk unnecessarily (Level of Evidence: B).

The STS guidelines recommend that when hemoglobin level falls below 6 g/dL, transfusion of RBCs is reasonable since this can be lifesaving, especially when anemia is acute.

Transfused blood does not have the oxygen-carrying capacity of fresh whole blood and therefore may not achieve the outcomes consistent with the goal of treatment (Spiess, 2002, 2004a). Therefore, the overall risk/benefit of transfusion must be carefully weighed, including the possibility of improved tissue oxygenation at the risk of infections or adverse reactions.

The STS/SCA guidelines make the following recommendations:

Class IIa Recommendation

  1. When hemoglobin level falls below 6 g/dL, transfusion of RBCs is reasonable since this can be lifesaving, especially when anemia is acute.

  2. Transfusion is reasonable in most postoperative patients or in patients with chronic anemia whose hemoglobin level is less than 7 g/dL; however, no high-level evidence supports this recommendation (Level of Evidence: C).

  3. It is reasonable to transfuse non-RBC hemostatic blood products based on clinical evidence of bleeding and preferably guided by point-of-care tests that assess hemostatic function in a timely and accurate manner (Level of Evidence: C).

Class IIb Recommendation

It is not unreasonable to transfuse RBCs in certain patients with critical noncardiac end-organ ischemia (eg, central nervous system and gut) whose hemoglobin levels are as high as 10 gm/dL, but more evidence to support this recommendation is required (Level of Evidence: C).

The results of 2 recent observational studies and 1 meta-analysis have raised concerns that aprotinin may be associated with increased thrombotic risk and renal dysfunction (Mangano, 2006; Karkouti, 2006; Ferraris, 2007). Based on these data, the US Food and Drug Administration (FDA) issued a safety alert suggesting that aprotinin be used with caution and only for patients in whom the benefits of the drug outweigh the risks, mostly of renal dysfunction and of hypersensitivity (http://www.fda.gov/cder/drug/advisory/aprotinin.htm).

Previous studies have noted a higher rate of renal dysfunction in patients treated with aprotinin who had cardiac procedures and had diabetes, or who were receiving angiotensin-converting enzyme inhibitors (ACEIs) (D'Ambra, 1996; Kincaid, 2005; Ferraris, 2007). The results of these studies suggest that aprotinin be used cautiously in these patients. Diabetes, pre-existing renal dysfunction, and use of certain medications such as ACEIs, among other factors, are associated with a higher risk of postoperative renal dysfunction independent of aprotinin use (Abu-Omar, 2006; Swaminathan, 2003). In addition, the lack of a standardized definition for renal dysfunction complicates studies, particularly retrospective analyses, evaluating its incidence. The meta-analyses of aprotinin reported do not support the conclusions of the recent retrospective analyses of both Mangano and Karkouti (Mangano, 2006; Karkouti, 2006; Fremes, 1994; Munoz, 1999; Henry, 2001; Sedrakyan, 2004). One meta-analysis suggests association between high-dose aprotinin and an increased risk of renal dysfunction, but not renal failure (Brown, 2007).

Because aprotinin is a bovine protein, hypersensitivity reactions are possible. Recent boxed warning for aprotinin (aprotinin prescribing information) states that ''administration may cause fatal anaphylactic or anaphylactoid reactions." Fatal reactions have been observed with an initial test dose, with components of the dose regimen, and when the initial dose was tolerated. The risk for anaphylactic or anaphylactoid reactions is higher in patients with previous aprotinin exposure, and risk for a fatal reaction may be greater after re-exposure within 12 months. Aprotinin should be administered only in operative settings where cardiopulmonary bypass can be initiated rapidly. The benefit of aprotinin for patients undergoing CABG surgery should be weighed against the risk of anaphylaxis. Aprotinin is contraindicated in patients with a known or suspected exposure to aprotinin during the last 12 months (aprotinin prescribing information). Aprotinin may also be a component of some fibrin sealant products (aprotinin prescribing information). The rate of hypersensitivity reactions increases to 5% if patients have a re-exposure to aprotinin within 6 months of initial dosing, but decreases to 0.9% after 6 months (Royston, 2006; Beierlein, 2005).

Until further information becomes available, the enhanced blood-sparing benefits of aprotinin should be applied with caution in certain patients (Ferraris, 2007).

Supported by an independent educational grant from Bayer Healthcare Pharmaceuticals.


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Authors and Disclosures

Author

Victor A. Ferraris, MD

  Tyler Gill Professor of SurgeryChief, Division of Cardiothoracic Surgery Co-Director, Linda & Jack Gill Heart Institute; University of Kentucky Chandler Medical CenterLexington, Kentucky

Disclosure: Dr. Ferraris has received honoraria from Bayer Healthcare, Aventis, Guildford, and BioMarin.