Allogeneic Blood Transfusions
Why Do We Even Care?
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Published: August 2009Print Record of Viewing
Dr. Stubbs reviews the Mayo Clinic experience and the development of evidence-based algorithms for determining when to transfuse.
Presenter: James R. Stubbs, MD
- Chair of the Division of Transfusion Medicine at Mayo Clinic
Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.
Our speaker for this program is Dr. James Stubbs, Chair of the Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology at Mayo Clinic. Dr. Stubbs discusses the costs, risks, and benefits of allogenic blood transfusions. Dr. Stubbs reviews the Mayo Clinic experience and the development of evidence-based algorithms for determining when to transfuse.
Build A Case
Historically, the transfusion of allogeneic blood components has been considered by many to be a routine bedside procedure. The purpose of this presentation is to attempt to convince you that allogeneic blood transfusions are most definitely not routine and that there is no such thing as a “simple blood transfusion.” Today, I am going to try and build a case for your consideration that includes the following points.
- With regards to allogeneic blood transfusion when you look at risks versus benefits, blood transfusion favor risk in most settings. To put it in simpler terms, putting blood from one person into another person is a very bad thing, most of the time. It is not the same as infusing a crystalloid product and it should be considered a temporary allogeneic transplant.
- With regard to usage, historically, this has been driven more by personal inclinations than evidence-based medicine, and practices are extremely variable both within countries and across countries.
- Blood transfusion in and of itself is an extremely non-cost – effective procedure.
- If we are to advance in this discipline, the decisions regarding transfusions will require evidence and interventions to maximize the benefit of such transfusions and to minimize their risk. A review and analysis of the medical literature by a panel of experts at the International Consensus Conference on Transfusions and Outcomes held in Scottsdale, Arizona April of 2009 concluded that there is little evidence to support a beneficial effect from the greatest number of transfusions currently being given to patients.
Well Established Risks
Allogeneic blood transfusions have a number of well-established risks. Today, the leading cause of allogeneic blood transfusion-related mortality in the United States in order of reported deaths are:Transfusion-related acute lung injury (TRALI) ABO and non-ABO hemolytic transfusion reactions (HTRs) Transfusion-associated sepsis (TAS)
The non-TAS infectious causes of death have been declining as a proportion of all deaths caused by allogeneic blood transfusion over the past 3 decades. This represents the outcome of the extreme diligence taken on the part of blood providers in conjunction with the efforts and guidance of regulatory and accreditation oversight agencies to provide maximally safe blood components from the perspective of transfusion-transmitted infections such as hepatitis and HIV.
The number of transfusion-related deaths annually reported to the US Food and Drug Administration has increased steadily from 16 in 1976 to 105 in 2005. Of the 105 deaths reported in 2005, 62 were considered recipient deaths in which transfusion was the likely or major cause of death. Of 63 deaths reported in 2007, 52 were determined to be due to allogeneic blood transfusion.
Approximately 22.3 million units of red blood cells, platelets, and plasma were transfused in the United States in 2006. Using this as the denominator, the risk of a transfusion-related death can be estimated at approximately 2.3 deaths per million transfused components.
Infectious causes accounted for 10.8%, 14.2%, and 22.0% of allogeneic blood transfusion-related deaths according to data from the Serious Hazards of Transfusion (SHOT) database from the United Kingdom, the FDA in the United States, and the French Hemovigilance System in 1996 to 2007, 2005 to 2007, and 1994 to 1999, respectively.
According to FDA databases, there were 8 deaths from transfusion-transmitted babesiosis from 2005 to 2007.
The Serious Hazards of Transfusion data included 1 death from malaria and 1 death from variant Creutzfeldt-Jakob disease.
Transfusion-associated sepsis, therefore, accounted for 44 of the overall 54 deaths accounted for in these databases.
Although still a significant cause of transfusion-associated mortality, the implementation of bacterial detection of apheresis platelets in March 2004 may be having a favorable impact. The 2005 to 2007 FDA data show that deaths from infectious causes are less than 15% of all reported allogeneic blood transfusion-related deaths.
Leukocyte Alloimmunization and TRALI
In October 2003, the United Kingdom started using fresh frozen plasma primarily or exclusively from male donors. They discarded plasma from female donors because this product may contain white blood cell antibodies that resulted from alloimmunization during previous pregnancies.
None of the 12 probable TRALI cases reported to the Serious Hazards of Transfusion database in 2007 was associated with the transfusion of fresh frozen plasma.
The Serious Hazards of Transfusion group concluded that the reduction in TRALI observed in 2006 and 2007, when the lowest TRALI mortality rate was recorded since the Serious Hazards of Transfusion data collection began, was “likely” due to the United Kingdom decision to change to the preferential use of male plasma in 2003/2004.
In November 2006, the United States followed the United Kingdom’s lead with the following recommendations from the AABB.
Recommendation #1: “Blood collection facilities should implement interventions to minimize the preparation of high plasma-volume components from donors known to be leukocyte-alloimmunized or at increased risk of leukocyte alloimmunization.”
As U.S. blood establishments moved toward “male only” plasma between November 2006 and November 2007, the number of TRALI fatalities reported to the FDA that were associated with plasma decreased from 22 in 2006 to 12 in 2007.
Recommendation #2 from the AABB: “blood transfusion facilities should work towards implementing appropriate evidence-based hemotherapy practices in order to minimize unnecessary transfusion.” And, their third recommendation: “blood collection and transfusion facilities should monitor the incidence of reported TRALI and TRALI-related mortality.”
The deadline for complete full implementation of the measures relating of plasma and whole blood components was November of 2007. The deadline for complete full implementation of the measures relating to platelet components was no later than November 2008.
Allogeneic Blood Transfusion
Although measures such as have been described may serve to reduce the risk of TRALI secondary to the “yellow products,” this does not address TRALI occurring in the setting of RBC transfusions.
In 2007, 5 of the 12 probable TRALI cases in the United Kingdom and 12 of the 34 United States’ TRALI cases were associated with the transfusion of red blood cells. Therefore, if TRALI is to be reduced in the setting of red blood cell transfusions, different measures will need to be taken.
It is important to note that the most common cause of transfusion-associated respiratory compromise is not TRALI, but transfusion-associated circulatory overload. So, although it is not the number 1 killer like TRALI, this is an important cause of transfusion-related morbidity. The exact incidence of circulatory overload related to transfusion is unknown. Estimates range from 1 in every 200 transfusions to 1 in every 10,000 transfusions. We do know that certain patient populations are vulnerable to this complication, such as older patients with a history of congestive heart failure.
As you can appreciate by the wide range of incidence estimates, we are just scratching the surface with regard to understanding the scope of this problem, but awareness of transfusion-associated circulatory overload as an important cause of transfusion-related morbidity and mortality is increasing.
Adverse Outcomes Following ABT
Evidence is accruing with regard to the relationship between allogeneic blood transfusions and additional adverse outcomes.
As we know, red blood cell transfusions are common in intensive care unit, trauma, and surgical patients. However, the hematocrit that should be maintained in any particular patient based on the risks versus the benefits of allogeneic blood transfusion remains unclear. Marik, Corwin, and colleagues decided to conduct a systematic review of the literature to determine the association between red cell transfusions and the following outcome measures in high-risk hospitalized patients.
The outcome measures that were reviewed were: mortality, infections, multiorgan dysfunction syndrome, and acute respiratory distress syndrome. Forty-five observational studies with a median of 687 patients per study were analyzed. In 42 of the 45 studies the risks of red cell transfusion outweighed the benefits; the risk was neutral in 2 studies; and the benefits outweighed the risks in a subgroup of a single study and that subgroup consisted of elderly patients with an acute myocardial infarction and a hematocrit <30%.
Seventeen of 18 studies demonstrated that red blood cell transfusions were an independent predictor of death, with a pooled odds ratio derived from 12 studies of 1.7. Twenty-two studies examined the association between red blood cell transfusions and nosocomial infection; in all these studies blood transfusion was an independent risk factor for such infections.
The pooled odds ratio derived from 9 studies for developing an infectious complication was 1.8.
Red blood cell transfusions similarly increased the risk of developing multiorgan dysfunction syndrome (3 studies) and acute respiratory distress syndrome (6 studies).The pooled odds ratio for developing acute respiratory distress syndrome was 2.5.
The authors concluded that their analysis suggests that in adult, intensive care unit, trauma, and surgical patients, red blood cell transfusions are associated with increased morbidity and mortality and, therefore, current transfusion practices may require reevaluation.
The risks and benefits of red cell transfusion should be assessed in every patient before transfusion.
Transfusion Practice Variability: Do We Know What Were Doing?
Next, let’s look and see the consistency or variability of transfusion practices. A publication by Snyder-Ramos and colleagues will serve as an illustration of transfusion practices in cardiac surgical patients. The objective of their evaluation was to compare the perioperative transfusion of blood components in cardiac surgery in multiple centers in different countries.
The authors compared the perioperative transfusion of blood components in cardiac surgery in 70 centers in 16 countries; a total of 5,065 randomly selected cardiac surgical patients were evaluated. Utilization of red blood cells, fresh frozen plasma, and platelets before, during, and after surgery, were assessed daily, until hospital discharge. Intraoperative red cell transfusions varied from 9% to 100% of patients among the 16 countries, and 25% to 87% of patients were transfused with red cells postoperatively.
Similarly, the frequency of transfusion of fresh frozen plasma varied from 0% of patients to 98% of patients intraoperatively, and 3% of patients to 95% of patients postoperatively. The variability in platelet transfusion was 0% to 51% of patients transfused intraoperatively, and 0% to 39% postoperatively.
Moreover, there were not only marked differences in transfusion rates between centers in different countries but also in inter-institutional comparison of multiple centers within the same country.
Transfusion Practice Variability
The authors concluded that, overall, the results of their study indicate that marked variations in perioperative practice patterns exist, both regionally and internationally. Thus, it appears that transfusion guidelines are not uniformly applied. Informal institutional-specific standards, local conditions such as availability of blood products, and individual physicians continue to drive transfusion practice.
The excessive use of blood components not only results in unnecessarily increased costs, but also exposes patients to increased perioperative risks due to transmission of infectious diseases, volume overload, transfusion-related acute reactions, immunomodulation, and TRALI, among other things.
Owing to their cost, their limited availability, and the potential harmful effects of the perioperative administration of blood products, their appropriate utilization, based on established transfusion guidelines, is essential.
Total Perioperative Transfusion Practice By Transfusion Product
This table shows how our transfusion practices in cardiac surgery at Mayo Clinic Rochester compare with the numbers published in the Snyder-Ramos study.
Intraoperatively, the percentage of patients receiving blood components is higher at Mayo Clinic than the published means. The platelet percentages are particularly troubling, as it looks like we transfuse 2 to 3 times as many patients as the published means.
Postoperatively, it appears that we transfuse a higher percentage of patients with fresh frozen plasma and platelets.
The column on the far right represents our calculation of the cost of transfusing a single unit.
Blood utilization and blood costs are accelerating in the United States at a time when blood products, hospital labor, and health care dollars are in short supply, and the outlook for the near future looks even worse. Difficulties in recruiting and retaining blood donors, increases in the cost of testing and processing blood, and higher skilled labor costs have caused the price of blood components to rise markedly in recent times.
Within hospitals, the procurement, storage, processing, and transfusion of blood products involve an array of expensive and increasingly scarce resources that include laboratory supplies, pharmaceuticals, and medical devices, as well as significant amounts of technical and nursing time.
The utilization of these resources in the administration of blood products to patients results in a 3- to 4-fold increase in the total cost of blood beyond the base cost of its acquisition.
True Cost of Transfusion3-5
This slide summarizes our estimate of the costs of transfusing blood components at Mayo Clinic Rochester. Note that the cost of acquisition of these blood components represents only 21.5% of the total cost of transfusing the products. The last bullet on the slide shows benchmark red blood cell cost numbers that were taken into account when we generated our “in-house” numbers.
Blood Product Usage and Expense 2008 Mayo Clinic Rochester
Based on the cost estimates for the individual blood components and the number of units transfused, we were able to estimate the costs of transfusing blood at Mayo Clinic Rochester in 2008 and the numbers are on this slide. Also notable on this slide is that the numbers of transfused units for all components except cryoprecipitate are up when compared to 2006. We are transfusing more and more units of costly blood to our patients.
We Pay to Transfuse: Insured/Private Pay
Now, if we look at the “bottom line” financially as it pertains to blood transfusions, our estimates are summarized on this slide. Based on “best case scenario” reimbursement from the insured/private pay patient population, one can see that there is a significant loss of money associated with every transfusion administered. The average loss per unit transfused for this patient population is $570.
What Did We Get Paid?
So, how did the numbers add up in 2008 if we apply this “best case scenario”? Our calculations are on this slide and you can read them and weep for yourself. In the best of circumstances, we lost almost $52 million transfusing people at Mayo Clinic Rochester in 2008.
Is There Anything We Can Do?
Blood management is one approach that can lead to more cost effective use of blood components. Blood management programs are designed to promote the optimal use of blood products (which should enhance the risk versus benefit relationship in transfused patients). Such programs require the cooperation of multiple disciplines, including a prominent role of the end users, and the practices utilized are based on the best evidence of appropriate transfusion practices available at any given point in time.
The goal of blood management is outlined on this slide. Give the right component, in the right dose, for the right reason, at the right time, to the right patient.
Evidence-Based Red Cell Transfusion
A study by Rana and colleagues is presented here. The authors of this study stated that almost 85% of patients admitted to an intensive care unit for more than a week receive multiple red cell transfusions, and this is despite evidence that the efficacy of allogeneic blood transfusions in restoring oxygen carrying capacity in critically ill patients is limited.
The TRICC trial showed superiority of a restrictive red blood cell transfusion strategy in a heterogeneous population of critically ill patients, with significant cost savings and a trend toward improved outcome with decreased mortality in all patient subgroups except those with severe acute ischemic heart disease.
Despite such evidence, the implementation of a restrictive red cell transfusion strategy had been inefficient at our institution with an observation that 37% of patients in our medical intensive care unit received transfusions outside evidence-based indications. Computerized provider order entry, coupled with a decision-support algorithm, was utilized in this study.
Parameters evaluated included the utilization of red cell transfusion, the proportion of patients receiving red cell transfusions outside of recommended guidelines, and the rate of transfusion complications.
The numbers for these parameters were lower after the implementation of computerized provider order entry.
In conclusion, this study confirmed that implementation of a computerized provider order entry decision-support model based on simple, locally developed evidence-based protocols can result in substantial improvements in clinical practice. This represents an example of an effective blood management intervention.
This slide shows a comparison in the costs of transfusions in cardiac surgical cases at Mayo Clinic Rochester for the years 2006 and 2008. Although the overall number of cases was 5% higher in 2008, the overall cost of transfusions increased by 47%. These numbers would appear to be “out of synch” with one another, with transfusion costs increasing at an alarmingly higher rate than the case load.
So, are there any blood management options available to help with this problem?
Nuttall and colleagues, a group of investigators from Mayo Clinic Rochester, published a study in 2001 looking at a blood management intervention in cardiac surgical patients. The authors stated that abnormal bleeding after cardiopulmonary bypass is a common complication of cardiac surgery and this has important health and economic consequences They further stated that coagulation test-based algorithms may reduce the transfusion of non-red cell allogeneic blood components in patients with abnormal bleeding.
They performed a randomized prospective trial in which they compared allogeneic transfusion practices in 92 adults with abnormal bleeding after cardiopulmonary bypass.
Patients with abnormal bleeding were randomized to 1 of 2 groups: a control group which followed the individual anesthesiologist’s transfusion practices, and a protocol group which used a transfusion algorithm guided by laboratory testing.
The transfusion algorithm group received less allogeneic fresh frozen plasma in the operating room after cardiopulmonary bypass. The median was 0 units, with a range 0 to 7 units. This was statically lower than the control group, which received a median of 3 units of fresh frozen plasma, with a range of 0 to 10 units. The median number of platelet units transfused in the operating room after cardiopulmonary bypass was 4, with a range of 0 to 12 units, in the algorithm group compared to 6, with a range 0 to 18 units, in the control group. And this difference also achieves statistical significance.
An unanticipated but important additional finding of their study was that the lower number of coagulation product transfusions in the operating room in the algorithm group may have resulted in less bleeding in the intensive care unit than the control group. They postulated that the more directed transfusion therapy may have corrected the hemostatic problem more effectively, which resulted in reduced bleeding in the ICU. In addition, the algorithm group had a significantly lower incidence of mediastinal re-exploration for hemorrhage than the control group. Mediastinal re-exploration for hemorrhage increases patient morbidity and mortality, and increases hospital costs.
In conclusion, the use of the transfusion algorithm resulted in greater use of specific types of blood components solely or not at all. This resulted in a reduction in the use of unnecessary or inappropriate blood component transfusions.
Mayo-Implemented Operating Room Transfusion Algorithm
Based on the work of Nuttall and colleagues from the 2001 publication, the following transfusion algorithm was recently implemented at Mayo Clinic Rochester. The overall goal is to reduce transfusions in cardiac surgery patients by 10% in the year 2010. This is the intraoperative algorithm that was used in the 2001 Nuttall study.
Mayo-Implemented ICU Transfusion Algorithm
In addition, unlike the 2001 Nuttall study, algorithm-based transfusion decision making will now include the postoperative period in the intensive care unit as well, and here is the algorithm that has been developed for that setting. As one can see the transfusion decision points are rather liberal, but the expectation is that this algorithm will result in a decrease in the number of transfusions and more focused transfusion therapy in the intensive care unit.
Who Are We
We have formalized our blood management initiatives at Mayo Clinic Rochester and here is the home page for our intranet site. We expect to see positive results in our initiatives in cardiac surgery, and then we will proceed to expand into other disciplines.
To conclude, we are increasingly aware of the variety of risks of allogeneic blood transfusions.
In most settings, particularly the non-bleeding patient, the best choice is to not transfuse allogeneic blood.
Transfusion practices are incredibly inconsistent. It is likely that a patient could go to 2 different facilities with the same problem and receive no transfusions at one facility and multiple transfusions at another, at this particular point in time.
Transfusions are incredibly costly. We do not recover those costs in the current financial environment, so transfusions, therefore, lose your facility money.
We need to evolve to transfusion practices that are evidence based. If we evolve in that direction, we will do a better job of identifying the patients who will truly benefit from transfusions and, therefore, should receive them, and avoid transfusing patients who will not benefit from transfusions and are only exposed to the risks of allogeneic blood. Blood management programs, such as the one we have described in its early stages here at Mayo Clinic Rochester, will help us evolve in that direction.
Copyright © 1995– 2015 Mayo Foundation for Medical Education and Research. All Rights Reserved.
Copyright © 1995– 2015 Mayo Foundation for Medical Education and Research. All Rights Reserved.