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Ann Thorac Surg 2001;72:S1832-S1837
© 2001 The Society of Thoracic Surgeons

Supplement: Mechanisms and attenuation of abnormalities in hemostasis/inflammation and neurologic injury: implications for patient outcomes

Blood transfusion: the silent epidemic

Bruce D. Spiess, MD*a

a Department of Anesthesiology, Virginia Commonwealth University/Medical College of Virginia, Richmond, Virginia, USA

* Address reprint requests to Dr Spiess, Department of Anesthesiology, Medical College of Virginia, 1200 E Broad St, Richmond, VA 23298-0695, USA
e-mail: bdspiess{at}hsc.vcu.edu

Presented at Mechanisms and Attenuation of Abnormalities in Hemostasis/Inflammation and Neurologic Injury: Implications for Patient Outcomes, Vancouver, BC, Canada, May 6, 2001.


   Abstract
Top
 Abstract
Introduction
 Risks
 Immunosuppression
 Cardiac surgery
 Conclusion
 References
 
Blood transfusion has been widely studied and the risk/benefit ratio remains unclear. Focus historically has been upon viral transmission, particularly hepatitis and HIV. Today, with advanced screening for these viruses, the risk for such transmission has become vanishingly small.

Immunosuppression, with consequent postoperative bacterial infection and ABO incompatibility are now risks that physicians should consider as associated with allogeneic blood transfusion. Other inflammatory events, such as transfusion associated acute lung injury, also occur. The benefits of transfusion have never been well studied and there is scant literature on that area. Therefore, in an evidence-based medical practice the physician should regard transfusion with a skewed risk/benefit ratio. The following article examines that risk/benefit ratio in the post-AIDS era.


   Introduction
Top
 Abstract
 Introduction
Risks
 Immunosuppression
 Cardiac surgery
 Conclusion
 References
 
Blood transfusion has become a mainstay of medical practice, with the individual decision making to transfuse influenced by the way blood transfusion is viewed in society. Focus upon the safety or risks of transfusion have waxed and waned over the last 50 years depending on societal needs and current events. The history of blood transfusion before World War I was largely of an experimental, trial-and-error nature. Just after the start of the 20th century, ABO blood typing became possible and, in conjunction with the invention of calcium chelating solutions and refrigeration/cooling, it started the modern era of blood banking. The first blood bank was established at the Cook County Hospital in Chicago, Illinois.

World War II saw a massive growth in blood banking, as plasma became the popular resuscitation fluid for battle injuries. The ability to separate plasma from red cells and to store and ship these vital products to the war theaters were part of a patriotic fervor to win the war. Giving blood became a patriotic duty, and forever labeled blood donation as not only a good and necessary thing but also one that would help to preserve the future of freedom and other patriotic values. The American Red Cross came into being at this time, and so did the America Association of Blood Bankers. Both of these organizations worked hard to put the best "spin" on blood donation, transfusion, and use of blood products. Therefore, it is through the major world war conflicts that the publicity campaigns have shaped our thinking regarding transfusion. Today it is very common to see newspaper, magazine, television, and billboard advertising with a "poster child" asking for blood donation. We all firmly believe (and have been culturally conditioned to trust) that blood transfusion is a "life-giving" force, and that its use is a good and appropriate medical practice.


   Risks
Top
 Abstract
 Introduction
 Risks
Immunosuppression
 Cardiac surgery
 Conclusion
 References
 
Transfusion, however, carries considerable risk. Those risks have been known for many years and have often been tempered by the attitude that blood transfusion saves lives. From the time of World War II until the mid 1970s, paid blood donors were common in the United States. During the war it was impossible to get enough blood and plasma without paying donors and, therefore, this practice was instituted. In the mid-1970s, the risks of transfusion-transmitted hepatitis virus was well know and publicized [1–3]. It was quite well known in the medical community that the risk of transmission of either hepatitis B or C was approximately 1/100 U transfused and that, because the mean number of units transfused per patient was approximately 4, the risk of seroconversion to hepatitis positive in the recipient was about 10% [4, 5]. The statistics of 10% hepatitis transmission are often quoted and have been present in the transfused population until the late 1980s, when the acquired immunodeficiency syndrome (AIDS) crisis brought blood transfusion into international focus. The medical community practiced according to a transfusion trigger based on teachings from the late 1940s; these stated that levels less than 10 g/dL of hemoglobin would require a transfusion and, that if patients lost more than 15% of their blood volume at operation, they should undergo transfusion. The transfusion trigger so espoused was not based on extensive laboratory testing or human experimentation. The critical hemoglobin for tissue oxygen delivery was not known, especially not for tissues with arteriosclerosis. Therefore, the number 10 was one that could be easily remembered and quickly embraced by all the surgical subspecialties. The trigger of 10 was repeated in surgery and anesthesia texts from 1947 until 1987.

Hepatitis transmission and seroconversion led to approximately a 50% incidence of acute hepatitis, of which 20% will go on to chronic active hepatitis [6]. Those patients with chronic active hepatitis will have a slow downward course and eventually debilitating disease. The cost of that disease in terms of lost productivity, medical needs, and loss of livelihood and enjoyment of life is very hard to measure. Those patients with chronic active hepatitis will experience progression of their disease, and about 25% of them will develop and potentially die of cirrhosis of the liver with all of its complications [7]. A small but significant number of patients with hepatitis C will develop primary hepatomas. The cost in yearly medical dollars (1995) has been estimated for the care (medications and doctors visits) of patients with hepatitis [8–10]. That number, $12,000.00 per year, is based on the cost of doctor’s office visits and medications. It does not take into account the costs of lost productivity and acute hospitalization for gastrointestinal bleeds, infections, etc. The cost of performing a transplant as well as yearly care after a transplant have also been calculated, and these numbers have been used for reports produced in the mid-1990s examining the quality adjusted life-year cost for autologous blood transfusion [8–10]. The numbers presented showed that to save one life the added cost to society, by using autologous blood, was approximately $250,000 to $1,500,000, depending on the type of surgery undertaken. In these studies from the 1990s, the transfusion literature was proud to be discussing the reduction in hepatitis transmission from 10% to 13% of all patients receiving transfusions down to 3% to 3.8% due to voluntary disqualification of donors. Today, voluntary disqualification of donors is standard and a well-accepted practice. Even though hepatitis transmission through blood transfusion now seems to be of historical interest, we are left with the lingering epidemic. If one considers that 2 to 4 million patients per year received transfusions between 1970 to 1987, and that 10% of these patients would have seroconverted to hepatitis positive, the epidemic is staggering. Several studies have examined 300,000 patients with posttransfusion hepatitis B and 160,000 patients with posttransfusion hepatitis C [11, 12]. Of those almost half-million patients, the yearly hospitalizations were 14,000 and the deaths per year [11, 12]. In two studies examining patients with chronic hepatitis B, the risk of development of a hepatoma was approximately 2% [13, 14].

The medical community today is still caring for a very large number of cirrhotic patients who have acquired their disease through transfusion. No one to date has looked in retrospect and examined the medical indications for these transfusions. At the time that hepatitis B and C were rampant, the medical community knew of the risks of transfusion; yet, no one questioned the trigger for transfusion or the basic tenets for transfusion.

With the AIDS crisis, the lay press has made transfusion safety a national priority. Although AIDS has proved to be a tremendous worldwide epidemic, it has had a positive effect on the safety of transfused blood and has changed the way that we approach transfusion. Since 1987 a number of events have taken place (and are still taking place) such that viral transmission is now becoming a far less common event. The latest statistics show that the risks of hepatitis transmission are roughly 1:30,000 to 1:250,000 U and the risks of HIV infection ranges between 1:600,000 to 1:2,000,000 U transfused [15]. It has been said by many that today we have the safest blood supply ever. With that knowledge, some have advocated that the transfusion trigger be liberalized. New viruses are coming into the population all the time. The perfect example is AIDS, inasmuch as before 1987 it was not widely known. Ebola is another example and the literature shows that we can find viruses constantly in our blood supply; it is only a matter of how hard we look for them. Transfusion transmitted virus (TTV), a newly described viral agent, is present in more than 50% of all blood harvested in the United States, and cytomegalovisrus (CMV) is also almost always present [16]. These viruses may not have major effects on patients with intact immune systems or those who have already been exposed; but the very young, very elderly, and immunosuppressed or debilitated populations may be at risk from these otherwise innocuous viruses. In fact, TTV does cause some cases of acute hepatitis and at the present time is not tested for, although nucleic acid testing may detect it in the future. If so, and if the prevalence of 52% is real, one wonders how severe a blood shortage would result if we truly had a virus-free blood supply.

Today the risks of HIV and hepatitis transmission are becoming small; therefore, our focus needs to go beyond viral transmission. Prions (Creutzfeld-Jacob disease), ovine spongiform disease, scrapie, and bovine spongiform encephalopathy (transmitted to humans as variant Creutsfeld-Jacob Disease-vCJD), and others make political headlines in Europe. Those political problems have actually shaped the way in which blood transfusion is carried out in Europe. To date we cannot trace a single case of prion transmission to blood transfusion. Although there are some patients who have received blood transfusions from donors who later went on to die of vCJD, none has actively shown signs of the degenerative neurologic disease [17]. Therefore, we do not know the infectivity of prions. These agents lie dormant or latent for a number of years, and they must be transmitted with cells that have DNA. The infusion of donor white cells therefore might be the potential for transmission of vCJD.


   Immunosuppression
Top
 Abstract
 Introduction
 Risks
 Immunosuppression
Cardiac surgery
 Conclusion
 References
 
Allogeneic transfusion carries with it an infusion of donor white cells. The Food and Drug Administration has suggested that universal white cell reduction makes sense. That decision has vast financial implications (costing some $600,000,000) and the potential to further increase blood scarcity [18]. It is uncertain whether leukoreduction will either decrease the risk of prion transmission or have other effects, both positive and negative. White cells are responsible to a great degree for the immunosuppression that is the cause of the epidemic from blood transfusion today.

No matter how old the infused blood, some of the donor white cells are live and can exist within the recipient for a period of time [19, 20]. Donor DNA can be isolated from the recipient for up to several weeks after an allogeneic blood transfusion. The donor leukocytes actually live in the recipient bone marrow and create a chimerism. That chimerism seems to set up a competition between the donor and recipient leukocytes. The chimerism is not the only reason for immunosuppression, as the infusion of plasma alone, without the donor white cells will also produce a transient immunosuppression, as will the infusion of autologous blood [21, 22].

The effects of allogeneic transfusion upon recipient immunity are multiple. Both the number of circulating lymphocytes as well as the distribution of cell types decline after transfusion. In particular there seems to be a suppression of the CD4 lymphocyte counts and a decline in the CD4/CD8 ratio, leading to decreased helper T cell function [23]. The recipient T cells demonstrate a depressed ability to respond to stimuli and to replicate. Their ability to recognize and opsonize foreign particles such as bacteria are quite depressed [24]. The ability of leukocytes to up-regulate and secrete cytokines as messengers is depressed as well.

The mechanisms of immunosuppression have been widely studied, and it is clear that there are many [24]. Not only do the donor T cells set up a chimerism, but these chimeric cells may themselves have lost their ability to function immunologically. The storage of blood at 4° celsius makes the white cells inside stop functioning immunologically. The length of time in storage also degrades immune competency of the contained cells; however, they do secrete cytokines. The cytokine levels of blood rise over time. Levels of interleukin 2, 6, 8, and tumor necrosis factor can be extremely high in allogeneic or autologous red cell concentrates [25]. Levels 10- to 50-fold those in normal individuals are found in stored blood. In platelet concentrates (which have high concentrations of white cells) that are not stored at cold temperatures, the levels of cytokines can be as high as 100- to 1,000-fold those found in noninfected persons [26]. Other factors may also have immunomodulating effects. In highly purified antihemophiliac factor VIII preparations, which do not contain white cells, immunosuppression still occurs. This has been thought to be due to contamination with transforming growth factor–ß.

White cell transfusion is blamed not only for immunosuppression but also for human leukocyte antigen (HLA) alloimmunization, graft-versus-host disease, and the potential for transference of prions. The presence of HLA alloantigens appears also to play a part in immunomodulation. HLA probably contributes to down-regulation of the recipient’s own T cells by delivering two or more conflicting messages.

In the late 1970s it was a well-accepted fact that if a renal transplant patient underwent transfusion at the time of surgery, the allograft would be far less likely to be rejected [27]. Therefore it became common practice for patients to undergo transfusion during transplantation. In one study of more than 50,000 renal transplant recipients of organs from cadavers, even with cyclosporine the effects of allogeneic transfusion still produced further immunosuppression [28]. Those patients who receive more units (>4 U) of blood have better 1- and 2-year allograft survival rates than do those receiving only 1 or 2 U. In addition, those patients who receive either whole blood or red blood cells have better graft survival than those who receive either frozen deglycerized red cells, leukoreduced blood, or washed red blood cells.

The effects of transfusion upon solid organ tumor growth has been widely studied. A meta-analysis of the risk of colorectal carcinoma recurrence and death has shown that transfusion does affect outcome [29]. The risk of colorectal carcinoma recurrence is increased to 1.8 with allogeneic transfusion, whereas the risk of cancer-related death is increased to 1.76 and death from any cause to 1.63 with transfusion. One study from the Netherlands disputed that allogeneic transfusion increased recurrence rates, but it did show a statistically significant increase in death rates at 3 years (69% vs 81%, p < 0.001) [30]. A study from Germany showed that allogeneic transfusion is an independent predictor of tumor recurrence or metastasis [31]. Although some controversy still exists in the literature, and some investigators dispute whether allogeneic transfusion rate is simply a marker for severity of disease, it seems that the weight of the literature tends toward the conclusion that transfusion does influence rates of metastasis and recurrence.

Data regarding infectious risks after surgery and allogeneic transfusion are far more convincing than tumor data. Allogeneic transfusion is a risk factor for perioperative infection [32]. In multiple orthopedic research studies, the risk of postoperative infection was increased between 35% to 300% [32–34]. In studies in which patients were randomized to receive either autologous or allogeneic blood, those who received autologous blood had far lower infection rates than did those receiving allogeneic blood. Data from colorectal surgery again shows that those patients who received transfusions had postoperative infection rates of 27%, whereas those who did not undergo transfusion had infection rates of 12% [35]. The odds ratio of infection in the transfusion group was 2.84 (p = 0.47, 95% CI 1.02 to 7.98) [35]. The number of units transfused as well as the age of the units of blood transfused both influence the risk of perioperative infection [35]. In patients with penetrating colon injury, the risk of infection was related to the number of units transfused: those patients with 1 to 5 U had an infection rate of 25%; of 6 to 9 U, 37%; and of more than 10 U, 57%. Those who went without transfusion had an infection rate of 7.5%.


   Cardiac surgery
Top
 Abstract
 Introduction
 Risks
 Immunosuppression
 Cardiac surgery
Conclusion
 References
 
In cardiac surgery there have been no randomized prospective trials of autologous blood versus allogeneic blood and associated infection rates. However, postoperative pneumonia risk has been assessed with transfusion and both number of units transfused as well as the age of the unit of blood both effect the risk of postoperative pneumonia in a coronary artery bypass grafting (CABG) patient population [36]. It has been estimated that the risk of pneumonia is increased by 5% with each unit of red blood cells transfused. No data have yet been published regarding the financial implications of these postoperative pneumonias on the CABG surgery population. The same author has looked at length of hospital stay and has shown that the use of allogeneic transfusion is associated with prolonged length of stay in both the hospital and the intensive care unit [37]. This is an independent association that was directly attributed to septic complications. When the authors did a very involved multivariate analysis they incorporated 26 other risk factors for length of stay into their models. The number of units transfused accounts for 38.7% of the variability in postoperative length of stay. Of the remaining variability, 60% could be accounted for by 20 other factors. Thus, it seems that transfusion is the most important factor influencing length of stay.

A large multicenter study of outcome in critical care medicine patients randomized to receive a "liberal" transfusion trigger (>= 9.0 g/dL) versus a "conservative" (<= 8.0 g/dL) trigger has been reported [38]. In this study, 838 patients with a number of bleeding diatheses were randomized into two groups. Officially, the article reports that the 30-day mortality was similar between the restrictive and liberal transfusion groups (18.7% vs 23.3%, p = 0.11). However, the trend is quite interesting, and one wonders whether in a larger cohort statistical significance might well have been met. In subgroups of the study, the restrictive transfusion group did have a lower mortality rate. Those patients who were bleeding and who were younger that 55 years of age had mortality rates of 5.7% for restrictive and 13.0% for liberal transfusion (p = 0.02). If the Acute Physiology and Chronic Health Evaluation score was 20 or less, the same held true: namely, that the restrictive transfusion strategy was associated with a lower mortality (restrictive 8.7% vs 16.1% liberal, p = 0.03). In what might be considered a higher-risk group, those patients with known coronary artery disease did not show a better outcome with a more liberal transfusion strategy. The mortality rate was 20.5% for restrictive versus 22.9% for liberal transfusion (p = 0.69). For the group overall, there was a difference in in-hospital mortality; again, the restrictive transfusion group did better (restrictive 22.5% vs liberal 28.1%, p = 0.05). The types of complications were compared in the intensive care unit and those that showed significance all had lower rates of occurrence in the group with the restrictive transfusion strategy. The most common difference was in cardiac complications. Patients who received fewer units had a lower incidence of myocardial infarctions, angina, and pulmonary edema, as well as a lower rate of acute respiratory distress syndrome. Interestingly, in this study there was no difference demonstrated in sepsis rates between the restrictive and liberal transfusion groups.

Data from the aprotinin database reported at the 2000 Society of Cardiovascular Anesthesiologists Meeting support the findings of the above-mentioned large prospective study [39]. Our work in the aprotinin database has examined the relationships between transfusion and adverse outcomes in the five United States Food and Drug Administration phase III clinical trials of aprotinin. These trials were set to rigorous standards, with independent blinded cardiologists making the diagnosis of myocardial infarction. Transfusion use was one of the most critical end points of these trials and transfusion criteria were predetermined. Adverse event recording was checked and confirmed against source documents and, therefore, the incidence of the recorded adverse outcomes is thought to be as accurate as possible. The overall database contains data on more than 3,000 patients; however, the placebo-treated patients represent a unique group in that they can be studied for the effects of transfusion alone, without the antiinflammatory effects of aprotinin. The aprotinin database abstract and subsequent analysis have involved a retrospective examination, but the findings tend to agree with those of the prospective, critical-care, randomized trial just reviewed. In all of the analyses conducted to date, nowhere does the effect of transfusion stand out statistically in favor of transfusion and better outcomes. In many situations, the patient groups with higher transfusion rates also had an increased incidence of adverse outcomes. The finding of increased perioperative infection associated with increased use of blood transfusion continued in the aprotinin database. One focus was upon the use of platelet transfusions alone. In the placebo-treated patients who received a platelet transfusion (either single-donor or randomly pooled), the rate of postoperative infection was 17.8%, whereas the rate in patients who did not receive a platelet transfusion was 11.0%, p = 0.04. Relationships between platelet transfusion and respiratory complications were found, as were myocardial infarction rates. Most striking was the relationship between platelet infusion and stroke occurrence. The incidence of stroke in patients receiving one or more platelet transfusions was 4.9%, versus 1.6% in patients not receiving such therapy (p = 0.01). Much work needs to be done to examine this relationship; from this preliminary project it cannot be concluded that platelet infusions are in fact causing strokes. However, platelet concentrates have a very high level of cytokines (levels up to 1,000-fold those encountered in normal patients), and the platelets are activated and prothrombotic. These findings do fit the conclusions that blood transfusions are inflammatory in nature and that they carry the risk of immunomodulation.

To date there is no agreed-upon transfusion trigger for coronary artery bypass grafting or other cardiovascular procedures. A number of investigators have looked at databases to find the effects of low hematocrit on outcome [40–43]. Several have found increased adverse outcomes with low hematocrits either during the bypass run or with the lowest hematocrit after surgery. One study noted that there was no increased incidence of adverse outcome until the hematocrit on bypass was less than 14 g/dL [40]. Another study noted that those patients whose hemoglobin was less than 6 g/dL in the postoperative period had a increased incidence of adverse events [41]. A recent study from seven major New England medical centers has shown that patients with hematocrit levels of less than 21% during bypass have an increased number of adverse events [42]. Interestingly, in that study, transfusion per se was not examined. In each of these studies in which low hematocrit was found to be a risk factor for adverse outcomes, it is probable that low hematocrit merely functioned as a surrogate for transfusion.

A study from the Multicentered Study of Perioperative Ischemia (McSPI) database of more than 2,200 patients examined hematocrit on entry to the intensive care unit (ICU) [43]. That number, ICU entry hematocrit, represents the sum total of blood loss, fluid infusion, and transfusion in the operating room. It does not examine postoperative transfusion; however, in the analysis it was found that patients who entered the ICU with a hematocrit of 24% or less did have a slightly higher transfusion rate than those with hematocrit levels on entry to the ICU. In contrast to the other database studies, the McSPI study found that patients with the lowest hematocrit on entry to the ICU after coronary artery bypass grafting had the lowest rates of myocardial infarction and severe congestive heart failure. That database did not have any data available for infection, and there was no association found between ICU entry hematocrit and stroke. In the next McSPI epidemiology database, a number of the questions regarding transfusion and adverse outcomes (including an analysis of platelet infusion and other transfusions) will be addressed.


   Conclusion
Top
 Abstract
 Introduction
 Risks
 Immunosuppression
 Cardiac surgery
 Conclusion
References
 
In summary, medical practitioners have been well informed about the risks of blood transfusion for almost 40 years. The literature weighs heavily with studies enumerating such risks. From the World War II until the late 1980s, the highest risk was for the transmission of hepatitis virus. With a 10% risk of seroconversion, the medical community simply accepted that risk and followed the recommendation of a 10 g/dL trigger for transfusion. There is no doubt that a significant epidemic of viral hepatitis; cirrhosis, and hepatoma have resulted from earlier transfusion practice. There is no way in retrospect to decide how many patients benefited from transfusion versus those that were harmed by viral hepatitis. In the 1990s, viral hepatitis and AIDS virus transmission risks from blood transfusion were small. Today the major risks caused by blood transfusion are largely those of immunosuppression and related adverse events. Other risks associated with blood transfusion include graft-versus-host disease, transfusion-induced acute lung injury, hypotension, allergic reaction, ABO-Rh incompatibility, and many others. Today, after consensus conferences on transfusion at the National Institutes of Health and the publication of many practice guidelines—all recommending lowered transfusion triggers—by surgery and anesthesia societies, blood transfusion practices remain largely unchanged. The use of blood products continues to grow because of acuity of illness, difficulty of surgery, trauma, transplantation, and other factors. Transfusion of allogeneic blood represents a major risk for immunosuppression and adverse outcome in the perioperative period. Indeed, it stands out as an independent predictor of adverse outcome. Interestingly, however, in a recent report to the United States Congress regarding the impending future shortage of blood supply in the United States, there was no mention of lowering the transfusion trigger or acceptance of anemia as a reasonable option [44]. Physicians today are still driven by the widely held belief that transfusion is life saving. The literature does not provide support that transfusion is life saving in all cases, and evidence-based medicine would dictate a very conservative use of blood products.


   References
Top
 Abstract
 Introduction
 Risks
 Immunosuppression
 Cardiac surgery
 Conclusion
 References
 

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