Oxygen Carriers and Transfusion Medicine

Abstract

The US blood supply is once again expanding (14 million units a year) and annual estimated whole blood and red blood cell (RBC) transfusion now exceeds 12 million units. The observed increase in total transfusions and units transfused per surgical procedure may result from more aggressive therapies, an aging population, and improved access to health care. While autologous blood collection has grown 20-fold in the past decade, autologous blood still accounts for < 8% of transfusions and is unlikely to replace much more of the allogeneic transfusion needs. Although safer than ever, allogeneic blood still transmits infectious disease (HIV: 1 in 225, 000 units, hepatitis: 1 in 3300 units, HTLV I/II:1 in 50, 000 units) and poses additional immunologic and non-immunologic risks. Allogeneic RBCs are probably underutilized because of safety concerns. While the cost of a unit of RBCs has been estimated at $150, costs are substantially higher in some areas and blood processing (filtration, gamma irradiation, washing) add additional expense. The narrowing margin between supply and demand, and repeated regional blood shortages argue for the value of safe, effective oxygen carriers.

The last two decades have witnessed remarkable changes in the growth, use, and public perception of blood transfusion in the United States. National surveys indicate that blood collections and transfusions doubled between 1971 and 19 80 [1]. National Blood Policy, formulated in the early 1970's, outlined principles for an adequate, safe, available, and affordable blood supply; the national commitment to all volunteer blood donation, coupled with the use of sensitive screening tests for hepatitis B virus (HBV), promised to make these goals achievable. By 1980, blood collectors, medical practitioners, most policy makers, and the general public were largely satisfied with the apparent progress in securing a safe and available blood supply.

By 1984 the situation had changed dramatically. Epidemiologic evidence had linked blood transfusion with a new and frightening fatal illness, the acquired immune deficiency syndrome (AIDS) [2]. Non-specific screening techniques that were introduced to improve blood safety by eliminating donors with high risk behavior had deferred large numbers of long-time donors. By 19 85, as many as 34 percent of blood donors in one survey believed that the blood donation process itself likely involved a risk of contracting AIDS [3]. While mass media concerns about blood safety increasingly centered on AIDS, the medical community became concerned simultaneously about the risk of hepatitis. The recognition of transfusion-transmitted hepatitis caused by virus (es) other than HBV led to the widespread and appropriate introduction of non-specific screening tests that eliminated 3 to 5% of American blood donors, most of these safe and healthy volunteers [4,5]. Transfusions of whole blood and red blood cells, which had peaked at 12.2 million units in 1986, declined to 11.6 million units in 1987 and collections of allogeneic blood reached a plateau at 13.3 million units [6]. By the end of the decade, public confidence in the volunteer blood supply had fallen to the extent that many otherwise reasonable and medically informed patients were accepting blood only from friends or relatives or refusing allogeneic transfusion altogether.

Although it is treacherous to divine transfusion trends, several themes are now emerging. Blood transfusion is in fact increasing once more. The total US blood supply in 1989 was 14, 229, 000 units, an expansion of 1.2 percent over collections in 1987 [7]. A portion of this increase resulted from autologous donations. While estimates from a 1986 survey suggested that no more than 5 percent of eligible donors were predepositing autologous blood for elective surgery, predeposited autologous collections increased by 65 percent between 1987 and 1989 alone and represented 4.6 percent of the blood supply in 1989 [7,8]. Various less well controlled estimates place current autologous collections as high as 8 percent of donated units; however, autologous units are unlikely to far exceed 10 percent of total blood collections.

Another source of growth in the American blood supply has been directed donations, blood solicited by patients from friends and relatives. Directed donations accounted for 2.5 percent of the blood supply in 1989. Directed donors must meet all the criteria required of volunteer community donors, however, like autologous blood collected from patient-donors, directed donor units have been found to test positive more frequently for markers of such infectious diseases as hepatitis [9]. The safety for general use of blood from patients and directed donors has been the subject of heated controversy [10]. Although both autologous and directed units, when appropriately collected and tested, may be “crossed over” into the general blood supply (46.7 percent of the autologous units and 55.4 percent of the directed units are not transfused), only 2 percent of autologous and 16.9 percent of directed units end up supplementing the national blood supply [7].

One source of blood for transfusion that is admittedly underestimated is intraoperative autologous blood (IAT), blood salvaged from the operative field and returned to the patient during the surgical procedure. No single reliable source collects and reports the amount of blood salvaged by IAT procedures. IAT is performed by regional blood centers, hospital transfusion services, anesthesia technicians, surgical support groups, and private for-profit companies. IAT is usually restricted to procedures such as cardiac, vascular, orthopedic and transplant surgery where large intraoperative blood loss is anticipated, and to emergency trauma surgery. However in these relatively limited situations, autologous salvage may replace large volumes of blood, 100 units or more in some procedures [11]. Massive IAT requires expensive equipment, trained technical support and costly plastic disposable software.

Why is red blood cell transfusion increasing, will this trend continue, and will the volunteer blood supply be able to meet projected needs? None of these questions has well-documented answers. The most likely explanations include the following: (a) The American population is aging, and elderly patients require more hospitalizations, more surgical procedures, and more transfusions. (b) More sophisticated medical and surgical procedures, including aggressive cancer chemotherapy, organ and marrow transplantation, and anti-viral AIDS therapy depend on transfusion support. (c) As the national network of trauma centers develops, major trauma consumes an increasing number of red blood cell units, particularly group O red blood cells. (d) More Americans are demanding access to medical care and federal health planners appear committed to providing the means for such access. Despite the increase in autologous and directed units, the growth in IAT, the increase in imports of European red blood cells, and the suspected elimination of much of the frivolous use of red blood cell transfusion, segmentation of the national blood resource suggests that by 1989 the margin between blood supply and demand had become perilously thin [7].

Ironically, allogeneic blood is safer today than it has ever been. The major public concern, the risk of transfusion-transmitted viral infection, has been reduced extraordinarily [12,13]. The risk of HIV from transfusion is now estimated at one case per 225, 000 units transfused. Fewer than 25 cases have been reported since specific anti-HIV testing was introduced in March of 1985. The risk of hepatitis B is negligible, an estimated one case in 200, 000 units transfused. Hepatitis from transfusion is estimated at about one case per 3300 units transfused. A variety of other infectious agents, viral parasitic, and bacterial, are thankfully rare in the United States. Nevertheless until cellular blood components can be sterilized, patients will have little choice but to accept the relatively low risk of known infectious agents, and the unsettling concern that some as yet unrecognized infectious agent might threaten either the safety or availability of blood. As an example of the latter concern, the recognition of a small number of infections with the obscure parasite, Leishmania tropicalis, among American forces serving in the middle east during Operation Desert Storm, led to a temporary deferral for one year of 500, 000 potential blood donors.

There are other recognized risks of allogeneic blood transfusion. Minor reactions, fever, chills, and dermatologic reactions, complicate about 1 percent of transfusions. These reactions are of little clinical consequence. However, even minor reactions cause distress to patients and generally trigger laboratory and clinical investigations to eliminate more serious causes of these findings. Hemolytic transfusion reactions complicate about one in 6000 units transfused and fatal reactions may be as frequent as one in 100, 000 transfusions. These complications result from the need to provide red blood cells that are serologically compatible with the recipient's blood. Mounting evidence implicates allogeneic blood transfusion as a modulator of immune changes in the transfusion recipient. A variety of laboratory abnormalities, suggesting alterations of the immune response, have been reported after allogeneic blood transfusion [14]. Clinical correlations have been less apparent. Nevertheless, transfusions have long been used to suppress the recipient's immune response to transplanted kidneys, and numerous reports suggest that patients who receive allogeneic blood during surgery suffer an increased number of postoperative infections compared to patients who receive no transfusion or who receive autologous blood only [15]. Furthermore, patients who undergo surgery for a variety of different tumors, including colon carcinoma, soft tissue sarcoma, lung, breast, and prostate cancer, reportedly have decreased survival and shorter tumor-free survival if they receive allogeneic blood in the perioperative period. Although none of these studies is conclusive and although conflicting evidence has been published [16], no study shows a beneficial effect of transfusion in regard to infections, tumor-free survival, or overall survival from cancer.

Perhaps most distressing are recent reports that allogeneic blood transfusions may reactivate latent viral infections in the recipient [17]. Laboratory investigators have long recognized that allogeneic stimulation of cells in vitro can result in activation and spread of both cytomegalovirus (CMV) and HIV in cell culture systems [18]. Studies have implicated allogeneic transfusion as stimulating reactivation of CMV in bone marrow transplant recipients and in adversely affecting the survival of patients with AIDS [19]. If, as some reports suggest, the mechanism of activation depends upon leukocytes that contaminate red blood cell transfusions, the removal of such cells will at the very least increase the cost of blood transfusion. If the mechanism involves some intrinsic property of the red blood cell, an important and difficult hazard of allogeneic transfusion will need to be addressed.

Estimates of the projected applications of an oxygen carrier as a synthetic blood substitute generally start with the current number of red blood cell units transfused, especially in emergency situations and in the perisurgical setting. Such estimates are clearly conservative. A desire on behalf of both patient and physician to limit the risk of blood transfusion has led to increasingly lowered recommendations for the “transfusion trigger,” the hemoglobin value at which transfusion is indicated [2 0]. In some clinical settings, insistence on the lowest possible hemoglobin concentration as a threshold for transfusion may impair tissue oxygenation and threaten patient safety [21]. Were the risks and perceived risks of transfusion not a factor, there would be little need to titer the hemoglobin concentration so carefully. A safe, effective oxygen carrier might provide a wider margin of safety for patients with impaired cardiovascular and pulmonary compensatory mechanisms.

If superior safety and availability provide a powerful rationale for developing synthetic oxygen carriers, economic considerations have also stimulated recent research and development efforts. A study of 19 hospitals in four geographic regions estimated the cost of delivering a unit of whole blood or red blood cells in 1989 at $155 [22]. This cost estimate was based on an average cost of blood procurement from regional blood centers ($52 or 37 percent of total hospital blood costs) and the additional costs of handling, testing, and administering blood. Investigators at a single university medical center used different methodology, including estimated posttransfusion costs, such as the cost of contracting an infectious disease from transfusion or the cost of developing a transfusion reaction, to estimate that a unit of red blood cells provided for a surgical patient costs $149.25 (DA Lubarsky, Duke University Medical Center, personal communication). Both probably underestimate the average cost of a unit of blood in 1993. Even at current levels of transfusion for urgent surgery and trauma, red cell transfusion represents a multi-billion dollar expense for American health care.

Historic trends suggest that the cost of providing red blood cells is unlikely to plateau or decrease in the foreseeable future. Hospitals with more than 55 beds paid $32 to acquire a unit of blood and charged $84 in 1979, compared to the estimates of $155 and $219 calculated in 1989 [22]. Increased donor selectivity continues to drive up the costs of recruitment; additional laboratory screening tests can be anticipated; increased regulatory oversight may add expense for both the regional blood collector and for the hospital. If fewer components, such as platelets, plasma and cryoprecipitate, are separated from units of whole blood, the cost of the red blood cells will inevitably rise. The growth of single donor platelets and the availability of virus-free clotting factors suggest that fewer “by-product” components may be needed. In addition, more red blood cell units require specialty processing such as leukocyte reduction and gamma irradiation. Twenty-one percent of the units reported by Forbes required such preparation, which added 33 percent to their cost; autologous and directed “specialty donations” added 50 percent [22]. Finally, costs of litigation may add substantial cost. A single award in 1990 had the effect on the health care system of adding one dollar to the cost of every unit transfused in the United States during that year [23].

The desirability of a synthetic red blood cell substitute seems obvious. Although optimists may argue that the narrowing margin between collections and transfusions represents more efficient management of the national blood resource, more likely this slender safety margin presages a return to the era of regional blood shortages. The need for oxygen carriers is still increasing and is likely to do so for the next decade. Autologous collections have cushioned some of the loss of allogeneic units, but the percentage of eligible patients donating autologous blood is approaching predicted levels. Strategies such as marrow stimulation with recombinant human erythropoietin have been demonstrated to increase predeposit collections by up to 41 percent, however such strategies will benefit a limited subset of patients, those who require between 4 and 6 units of blood for an elective procedure that permits several weeks for blood collection [24]. While erythropoietin has already been a major boon to patients with chronic renal disease and some patients with cancer and AIDS, it will probably have little further impact on the nation's blood supply. Intraoperative salvage technology has matured during the past decade, and while IAT remains a valuable adjunct to surgical support, it has technical and economic drawbacks. An effective, safe, and sterile oxygen carrier that is stable at room temperature or at refrigerated storage would provide a major advance in transfusion therapy.