Autologous Transfusion and Directed Donations: Current Controversies and Future Directions

Autologous Transfusion and Directed Donations: Current Controversies and Future Directions James P. AuBuchon

HE PRACTICES of autologous transfusion and directed donation have become so commonplace in transfusion medicine that a review of these subjects may be most useful in highlighting unresolved issues. Most of these remain points of contention because of a lack of substantial data to address underlying issues. By reconsidering that which is known and that which is yet to be determined in these rapidly evolving areas of transfusion medicine, a further appreciation of the appropriate roles of these two methodologies may be gained.

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SAFETY IN TRANSFUSION

The primary motivation behind the recent upsurge in interest in autologous transfusion and directed donations is transfusion safety. The definition of safety has different elements for different participants in the transfusion process. For the patient, risk-free medical therapy is the goal-albeit unrealistic-and any steps that could be taken to eliminate, reduce, or control risks are sought, sometimes with intense perseverance. For physicians, limitation of risk is also important, although avoidance of litigation may be an important factor as well. For blood collection agencies, these concerns must be melded with the overall mission of its operation, which, until recently, may have been defined primarily in terms of volunteer homologous blood products. The ancient dictum, primum non nocere, continues to be of practical utility in transfusion medicine. Therapies should be applied in a judicious, circumspect manner so that their expected benefits outweigh their potential risks. The understanding of fa<::tors to be entered into the transfusion equation of risks and benefits has undergone dramatic changes in the last 5 to 10 years. The messages of transfusion medicine consultations-transfuse

From the American Red Cross Blood Services, Washington Region, Washington, DC. Address reprints to James P. AuBuchon, MD, Director, Washington Region, American Red Cross Blood Services, 2025 E Street, NW, Washington, DC 20006. © 1989 W.B. Saunders Company. 0887-7963/89/0304-0006$03.00/0. 290

only when necessary, consider all possible alternatives, beware of infectious and immunologic complications-have not changed with the advent of newly recognized viral transmission hazards of homologous transfusion. 1 What has changed is the intensity of the message, the receptivity of clinicians to the message (because of an increased perception of risks), and the demand for consideration of alternatives on the part of patients more involved in their own health care. The end result of these circumstances has been an intensified focus of attention on unnecessary transfusions, estimated to represent 20% to 70% of the transfusions of certain components in some surgical settings, 2 and a burgeoning of interest in the alternatives of autologous transfusion and directed donations. These two options, autologous transfusion and directed donations, are certainly not the entire retinue of a transfusion medicine specialist who wishes to provide optimal therapy. These alternatives should be integrated into the broad perspective of clinical care applied individually to each patient's case: transfusion for specific indications to alleviate clinically significant conditions, consideration of all alternative modalities, including transfusion of products with reduced potential for disease transmission, and autologous transfusion options. Only by weighing the potential risks and expected benefits on a case-by-case basis can clinical decisions determine the true necessity of the first homologous blood exposure, possibly the consideration in which alternatives to homologous transfusion offer their greatest benefit. 3 Furthermore, avoidance of transfusion entirely should always be considered as a primary option. For example, application of desmopressin acetate (DDAVP) has been shown to decrease blood loss by 40% in complex cardiac surgery procedures. 4 ,5 Pharmacologic intervention, refinements in surgical techniques, and careful consideration of the indications for transfusion may allow more patients to avoid transfusion entirely. Ordering autologous transfusion on reflex without thorough examination of all the practical alternatives in each case deprives the individual patient of the best care available and deprives the health-care system of optimal use of its resources. Transfusion Medicine Reviews, Vol III, No 4 (October), 1989: pp 290-306

AUTOLOGOUS TRANSFUSION AND DIRECTED DONATION

DIRECTED DONATIONS

The concept of recruitment of blood donors for a specific patient has been a part of blood banking throughout its history. In earlier times when community donor recruitment techniques were not yet refined, an adequate supply of blood could be anticipated only by a patient recruiting his own donors. Selection of donors on immunologic grounds, eg, recruitment of an HLA-matched plateletpheresis donor, occurs commonly today and represents a form of designated or recipient-specific donation. However, the current wave of directed donations, in which recipients serve as their own donor recruiters in the belief that they are better able to select donors free from transmissible disease than the blood collection agency, represents a departure from past motivations for the recipient's involvement in the donor recruitment process. Initially meeting fierce opposition from most blood bankers, directed donations came to be accepted as the clamor for them reached a fevered pitch. One survey found that over 90% of responding patients indicated that the availability of directed donations was "important" or "very important" in their selection of a hospital. 6 Given the importance that marketing has achieved in the health-care delivery system and the ever-present fear of litigation, ultimate acceptance of directed donations might, in retrospect, have been predictable. Furthermore, the acceptance of directed donations by some blood collecting facilities served to make defense of the principles underlying a refusal to offer the service (on scientific grounds) even more difficult. Today there are few blood collection facilities in the United States that do not provide the service of collecting donors recruited by the patient and few hospitals that do not transfuse directed donations. A revised concept of directed donation has recently been developed by some blood bankers. In those circumstances in which autologous transfusion is not feasible, a single directed donor or a restricted number of donors might be used intensively to provide the products needed for a particular patient. 7 While the scientific benefits of directed donations may be debated, this "single donor" approach would seem to be effective in at least reducing the number of exposures received by the transfusion recipient. 8 This approach has also

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been used in experimental protocols to provide cryoprecipitate support for a patient with von Willebrand's disease or hemophilia A from just one donor undergoing periodic plasmapheresis/ plasma exchange procedures. 9 While this concept may offer some potential benefits of exposure reduction to the recipient, the donor is faced with increased risks, risks undertaken for someone else's, not his own, benefit. Whether these risks are appropriate to be assumed, particularly when preoperative selection of transfusion alternatives to voluntarily donated homologous blood products may lead to inappropriate ordering,1O and whether these protocols can be reconciled with the Code of Federal Regulations and the standards of accrediting agencies remain to be seen. Almost three quarters of patients seeking directed donations have stated that fear of acquired immune deficiency syndrome (AIDS) is the motivating force, and over one third cite concern about hepatitis,11 but do directed donations truly provide a safer source of blood products? Theoretical bases for decreased safety in directed donations include coercion from a close friend (cited as operative in 3% of directed donations 6), or fear of exposure of a covert activity that should preclude donation. These potentially detrimental forces must be balanced with the presumption that the directed donor has a strong interest in the health of the recipient. The initial study on the prevalence of infectious disease markers demonstrated comparable rates in directed donations and the overall community supply. 12 Since 71 % of the 2,883 directed donors in this study were first-time donors, the similarity between the rate of infectious disease marker positivity in this group and first-time nondesignated volunteer homologous donors was not surprising. In other studies, the point has been made that the marker prevalence rate, at least for hepatitis B surface antigen, may be higher among directed donors than among the previously tested repeat donor population. 13 ,14 Given that test sensitivity is not 100%, this difference in prevalence may represent a greater risk of transfusion-associated infection to the recipient from directed donations. In some situations, the case may be made that directed donations represent a source of homologous blood that does not represent a new exposure for the recipient, a neonate receiving a transfusion from its mother, or a patient receiving a transfusion from a spouse. Because the directed donation situation

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differs from the community-based model in that the donors are known to the recipient, and vice versa, the donor may be even further motivated to provide a truthful health history and defer himself, if appropriate. 15 However, it is interesting to note that directed donors have as their primary motivation participation in the patient's care rather than their own fear of transfusion-transmitted infection. 6 This observation augments the concern that directed donors faced with social pressures may not be as forthcoming in divulging negative aspects of their health history. In any case, since infectious disease risks, particularly those of human immunodeficiency virus (mY) transmission, have declined to such low levels, it may be impossible to demonstrate conclusively that directed donations offer a different level of risk than community-recruited donations. The sum of all the arguments and currently available data is that many blood bankers today do not regard directed donations as less safe than blood recruited through the usual communitybased system-or at least regard directed donations as not posing a substantially increased risk such that patients who seek this recruitment option should not have access to it. Certainly, however, directed donations are not as safe as autologous transfusion options, and patients, particularly those able to take advantage of autologous transfusion strategies, should not forgo these opportunities in the mistaken belief that directed donations are equivalent in safety to receiving their own blood, a belief unfortunately held by one fifth of all patients. 11 AUTOLOGOUS TRANSFUSION

Autologous transfusion has become the focus of transfusion medicine in the last several years, hailed by the public and professionals alike as the safest form of transfusion therapy. 16 While there is no doubt that various forms of autologous transfusion are underutilized or inappropriately overutilized,IO,17 support of the concept of autologous transfusion has become a cardinal tenet of transfusion medicine. Techniques of autologous transfusion have been known since the last century, 18,19 and their advantages have been appreciated for many years by some blood bankers and clinical transfusion therapists, orthopedic surgeons ordering the greatest number of preoperative autologous donations

(PADs).20 However, the value of this approach to transfusion was not generally appreciated until more recently. This review of autologous transfusion will outline the various forms available today and focus on some of the controversies that surround the most commonly practiced form, PAD. Types of Autologous Transfusion Available Preoperative autologous donation. For elective surgery planned well in advance, consideration of PAD should be an integral part of preoperative counseling. Being one's own blood donor not only provides blood incapable of infecting the intended recipient with a viral pathogen, but may also accelerate erythropoiesis, thus affording the patient quicker recovery from postoperative hemorrhagic anemia. The use of PAD will also help conserve the community blood supply for the majority of patients who must depend on it. As patients and physicians became knowledgeable of the benefits and availability of PAD, the procedure became more widely accepted and practiced. 17 The growth has appeared to be exponential, increasing from 18,737 U collected annually by members of the American Association of Blood Banks in a 1982 survey to almost 290,000 U 5 years later. 21 While some anecdotal reports have suggested that the dramatic increase of the past several years is abating, the full potential for PAD has not yet been achieved. Examining the records of 18 university hospitals, Toy et al22 documented that, in a 2-month period in early 1986, 46% of patients for whose surgeries blood had been ordered were medically eligible to make PADs; however, only 5% actually did so. Full participation by all those patients eligible for PAD would have supplied 72% of the red cells needed for their procedures. Another study looked at the use of PAD from a different perspective and projected that of those patients undergoing elective surgery who did not utilize PAD, a third could have avoided homologous blood product exposure entirely had they participated in a PAD program. 23 Despite the potential for increased application of PAD, full implementation of this technique will not eliminate the need for homologous support in 15% to 80% of patients' surgeries, the proportion depending on the type of procedures considered. 1o,24-26 In a study of patients undergoing cardiac surgery, 21 % of those participating in a PAD program required homologous blood support as opposed to 83% of

AUTOLOGOUS TRANSFUSION AND DIRECTED DONATION

those who did not participate for various reasons?7 Furthennore, participation in a PAD program does not lead to increased need for transfusion with other components. 28 For example, aggressive tracking of opportunities, by contacting surgeons about the potential for PADs when a case is posted to the surgical schedule, may lead to increased use of PAD. On the other hand, overprescription of this option is also seen, with patients having almost no likelihood of needing a transfusion being referred for PAD. IO ,17 (The indications for PAD will be discussed later.) Development of educational and infonnational systems to alert physicians and patients of the possibilities of PAD while avoiding indiscriminant overuse remains the difficult job of the transfusion medicine specialist and the health-care system as a whole. PADs are usually collected with the intent of providing the red cell transfusion requirements of the surgical patient from an autologous source in order to reduce the risks of infectious disease transmission. However, other components and other intentions must also be mentioned. Some hematologists have successfully used autologous platelets, collected during remission from a hematologic malignancy, to provide platelet transfusion support during later courses of chemotherapy. 29 For these patients, the motivation for autologous donation (avoiding or circumventing refractoriness due to allomimmunization) is different than for surgical patients. Patients undergoing certain cardiac surgery procedures, such as replacement of a prosthetic valve and other procedures associated with large volumes of blood loss, may have need for products other than red cells. Platelet and plasma replacement therapy may occasionally be indicated in these patients. 30 ,31 With current technology, it is feasible to collect platelets by plateletpheresis several days prior to surgery, or plasma several weeks or more prior to surgery, with storage under appropriate conditions until needed for transfusion. 32 Whole blood collected preoperatively from a patient can also be used to prepare not only red cells but also other products that may be of use in particular circumstances, such as autologous "fibrin glue" (essentially cryoprecipitate) for hemostatic and adhesive applications in otorhinolaryngology and in orthopedic and neurologic surgery. 33 While the need for components beyond red cells is infrequent, their collection does avoid the unfortunate

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situation in which a patient and the blood collection facility may have devoted considerable effort and expense to collecting several units of red cells for perioperative transfusion only to have multiple homologous donor exposures accrue to the patient with administration of platelets and plasma. The concept of PAD includes the inherent stipulation that the patient has the physiologic reserve to donate the units while not suffering an untoward change in hematologic status that would result in reduced ability to withstand the surgical procedure. This concept implies that the patient's initial red cell mass and total blood volume are above some minimums that will allow the donation to be completed without serious reaction, that the hematopoietic reserve is sufficient to maintain the red cell mass above this limit throughout the donation series and that the patient's overall health and nutrition status will allow for this hematopoietic potential to be realized. For these reasons, patients under consideration for referral for PADs should be evaluated for their health status (see below for health criteria), offered supplemental oral iron therapy (such as 320 mg ferrous sulfate three times daily), and other dietary supplements as needed in specific cases, 34 and begin the PAD series as early as possible prior to surgery consonant with the expected storage system's capabilities. Given that most surgical procedures require 4 or fewer units of red cells,35 this volume can be accommodated by most patients' hematopoietic potential through use of liquid storage systems. Provided that donations begin 5 or 6 weeks prior to the scheduled surgery date, most patients can donate the required number of units, maintain their hematocrits above the usually prescribed minimum of 33% to 34%, and begin to reconstitute their red cell mass prior to surgery. 1,36 On the other hand, patients donating blood in the last week or two prior to surgery may be accomplishing little other than perioperative hemodilution-with normovolemia being maintained through hepatic synthesis of plasma proteins rather than infusion of solutions on the operating table. Red cell units intended for autologous transfusion can also be frozen. In cases where the patient is not able to tolerate collection of units according to common schedules, such as 1 U per week, or where the intended surgery is expected to require a greater number of units than can be accommodated within a 5- or 6-week liquid storage interval, frozen storage of these donations may be appropriate

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(although more costly),z5 This approach appears to be more widely used than the so-called "leap frog" technique to collect large numbers of units preoperatively and is certainly less cumbersome. 37 Freezing can also be used when the surgery is unexpectedly delayed beyond the expiration date of the liquid unit. Frozen storage without anticipated need has received some attention in the lay press but is usually regarded as an expensive and ineffective means of providing autologous red cells for future surgery or trauma. 38 The importance of erythropoietin in the stimulation of erythropoiesis is evident in the physiology of PAD. This polypeptide hormone's central role in the regulation of erythropoiesis has been well documented and recently reviewed elsewhere.39 For the patient undergoing PAD, administration of erythropoietin may accelerate erythropoiesis threefold to fourfold after a lag of 7 to 10 days.40 This pharmacologic use may allow more units to be collected preoperatively.36 Although clinical trials regarding this potential use of erythropoietin are still underway, preliminary reports suggest that administration of 600 Ulkg is well tolerated by patients in a PAD program and may increase the mean achievable donation volume by an average of at least I U. In a study in which patients were administered recombinant human erythropoietin or a placebo over a 3-week period in which 6 U were scheduled to be collected, 98% of patients receiving erythropoietin were able to donate at least 4 U while 70% of those receiving a placebo could donate that number. 36 (The need for administration of supplemental iron may be especially crucial here as the availability of iron may be the limiting factor of accelerated erythropoiesis, and iron depletion is not uncommon, even in developed countries. 41 ) Inasmuch as one study indicated that 10 of 17 orthopedic patients enrolled in a PAD program could have avoided homologous transfusion with donations of 4 U preoperatively, the administration of erythropoietin in a PAD program may be substantial.42 As additional education of surgeons on the use of PAD has been shown to more than double the number of requests for collection of 4 or more PAD units,43 the use of erythropoietin may be greater than currently anticipated. Administration of exogenous erythropoietin may also lead to complete or more complete recovery of the patient's red cell mass prior to surgery. This may be explained by the observation that endogenous

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erythropoietin levels do not increase until the hematocrit falls to approximately 30% to 35%.44 Thus erythropoietin administration may allow for the use of other autologous transfusion techniques, such as perioperative hemodilution (see following section), or it may increase the volume of blood that may be lost during surgery before transfusion for the sake of oxygen carriage would be required. Further research with this approach may lead to widespread usage of this hormone to facilitate PAD. Although conventional wisdom might suggest that PAD may in some way "weaken" the patient or make the postoperative recovery period longer, the mild anemia induced by or accepted in PAD is clinically inapparent. Providing that the patient has sufficient red cell mass to maintain adequate oxygenation during surgery (now understood usually to be a hemoglobin concentration of 7 to 8 g/dL,45 a level far below that at which PAD patients are maintained), anemia does not increase perioperative morbidity nor prolong wound healing. 46 Participation in a PAD program is not associated with longer hospitalization or slower healing and recovery.47 In summary, PAD represents an opportunity for many planned surgical procedures to have blood requirements fulfilled through preoperative donations by the patient. When these donations are timed to occur as early as possible, optimal patient benefit is achieved. Perioperative hemodilution and component collection. Preoperative donation need not occur days or weeks prior to surgery but may take place immediately before surgery. Perioperative (normovolemic) hemodilution is a technique that is gaining in popularity. In this approach, the anesthesiologist, anesthetist, or trained operating-room staff person withdraws several units of blood into a standard anticoagulant/preservative solution usually just after the induction of general anesthesia; the volume lost is compensated by the infusion of crystalloid and/or colloid solutions. 48 The whole blood units, properly labeled, are kept available, usually in the same operating room, for administration later in the case. Although the patient does not receive any preoperative stimulation of erythropoiesis as may occur through PADs, intraoperative blood loss will occur at a lower hematocrit, the patient may be able to reduce or avoid the use of homologous blood products, and the "favorite"

AUTOLOGOUS TRANSFUSION AND DIRECTED DONATION

blood product of many surgeons, "fresh, warm whole blood," is immediately available for transfusion. This technique has not received as much use as might have been expected for several reasons. First, several practical considerations must be addressed. Although the actual phlebotomy is a simple procedure, with equipment now available to easily connect the anticoagulant-filled collection bag through an arterial or venous catheter already in place, the procedure is regarded by many anesthesiologists as requiring monitoring of one or more of the patient's hemodynamic parameters, such as central venous pressure, pulmonary artery wedge pressure, and cardiac output. 49 This approach may require more invasive monitoring techniques than might otherwise be called for in certain cases but does facilitate detection of hemodynamic instability and early pharmacologic intervention should problems arise. Use of this technique also implies the attendance of an anesthesiologist. Although the procedure is relatively quick, additional minutes of operating room time may be required, unless the procedure is coordinated with other preoperative preparative activities. This not only increases the cost to the patient for the procedure, but may increase the time of anesthesia and its attendant risks and reduce the throughput of the operating room. Medical concerns also arise since the phlebotomy is being conducted during administration of anesthetics that may be cardiac depressants. Thus appropriate criteria for patient selection are important. Although cardiac output has been shown to increase by up to 30% and oxygen extraction increases with perioperative hemodilution, the decrease in the hematocrit is associated with an increase in oxygen delivery. 49 (The reduction in hematocrit may also contribute to a reduction in the incidence of thromboembolic complications. 5~ While patients with severe coronary artery arteriosclerotic disease or pulmonary disease may not be able to improve peripheral oxygenation and thus may be poor candidates for hemodilution,50,51 age alone is not a contraindication. In a study comparing the effects of hemodilution in an older patient group (mean age: 69 years) versus a younger group (mean age: 46 years), both groups tolerated the procedure without incident.52 In general, only patients with anemia, renal failure, and severe cardiac disease are ex-

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cluded from consideration. Most practitioners of this therapy state that up to 2 to 6 U of blood can be collected with reduction of the patient's hematocrit to 20% to 30%.48,50,53 Practically, the number of units withdrawn, an average of 1.6 U in one study of 237 patients undergoing fIrst-time coronary artery bypass grafting, does not abrogate the need for homologous products in 41 % of this kind of cardiac surgery. 54 However, selection of patients and the aggressiveness of the practitioner will affect the success of this effort in avoiding or limiting homologous exposure. In withdrawing a significant volume of blood at one time, normovolemia must be maintained for hemodynamic stability. Different solutions are used by different practitioners. Some infuse colloid, either albumin alone or in combination with dextran, in order to maintain normal oncotic pressure; with such an approach, a volume of colloid is infused that is approximately equivalent to the volume of blood removed. Others prefer to use a crystalloid solution, infusing 2 to 3 volumes of lactated Ringer's solution, or some other physiologic solution for every volume of blood removed. 48 This approach may allow for greater control of hemodynamics with renal excretion induced, as necessary, by a diuretic. Still others will use a combination of these approaches. All seem to work well, although certain clinical situations may point to the advisability of one form of replacement fluid over another. Perioperative blood collection has recently expanded to include other components. The development of automated instrumentation to facilitate intraoperative blood salvage (see following section) brought equipment into the operating room that was capable of collecting other components as well, a development that has led to the perioperative collection of plasma, platelets, and platelet-rich plasma. 55 .56 For patients undergoing extensive surgery, particularly cardiac reoperations and valvular replacements, an anticipated need for these components can be met in the same manner as the perioperative collection of whole blood, either through usual automated hemapheresis techniques or through ex vivo separation of whole blood. Certainly the indications for use of these components may be questioned in many procedures, and their current use appears to be beyond their true need. 30 ,31 Nevertheless, collection of these components perioperatively has been shown to reduce

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the transfusion of homologous components. In the study of Giordano et aI, perioperative collection of platelet-rich plasma (containing the equivalent of 2 to 3 U of platelets and 2 U of plasma) in cardiac surgical procedures was associated with at least a halving of the use of homologous red cells, platelets, and plasma. 55 The magnitude of the reduction in usage of homologous blood products was actually greater than the content of the autologous products would have projected, suggesting that surgeon behavior may be influenced by the availability of autologous products. (See following section.) Obviously, the need for these products occurs in few procedures, and patients to be included should be carefully selected. The true utility of this approach and the relative merits of preoperative versus perioperative collection of these components deserve further study. Intraoperative Autologous Transfusion. The salvaging of blood shed intraoperatively is not a new concept, but technologic advances in the last decade have offered new means to accomplish this end. The use of intraoperative autologous transfusion (IAT) has been predicted by market surveys to grow twofold to threefold in the next 5 years. Increased use is expected, particularly in cases outside of cardiac surgery, this field having already put this technique to extensive use. The advantages of transfusing filtered versus washed shed blood are still being debated, and each approach has its own proponents and detractors. 57 Technical advances have been made in simplifying the collection and direct readministration of blood; in some cases, the devices serve as both collection and readministration units, and some may not require external suction to accomplish the collection task. These systems use filtration as the sole means of preparing shed blood for reinfusion, but concerns about the quality of the reinfused blood and the potential for introduction of activated clotting factors and other vasoactive substances are still being debated. 56 ,58 For example, in experimental studies with baboons, reinfusion of unwashed red cells resulted in higher levels of fibrin split products than when the red cells were washed prior to reinfusion. 59 Concerns regarding control of the relative amount of anticoagulant entrained with the suctioned blood, the amount of free hemoglobin due to hemolysis during suction, and the actual red cell content of the reinfused material has caused most programs not using red

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cell washing procedures to limit the volume of blood returned to the patient. 57 ,60 While the administration of filtered blood continues to be used as a means of salvaging autologous blood shed during surgery, there appears to be a large amount of growth in the provision of intraoperative blood salvage through mechanical means that provide washed, concentrated red cells for reinfusion. The newest generation of these instruments provides equipment that is small, portable, and fast. These instruments are capable of washing the shed blood, concentrating the red cells to an hematocrit of 50% to 60% and, in some cases, reinfusing at a rate of 1 U (200 to 250 mL) every 3 to 5 minutes. 61 This equipment includes microprocessing capabilities and standard protocols that require little operator interaction, although faster turnaround, better quality products, and enhanced safety may be provided with dedication of an attentive, trained operator to the instrument. 62 The hazards and contraindications for automated red cell salvage are few with equipment currently available. Infection and malignancy are regarded as contraindications out of fear that these processes may be spread through incomplete removal of bacteria or malignant cells in the washing process. 63-66 The latter of these contraindications need not prevent use of the technique so long as the aspiration of the shed blood is confined to fields or times where potentially malignant tissue has not been transected. Concern has also been expressed that when antibiotics intended only for topical use are added to irrigating solutions (which are then aspirated into the recovery circuit), IAT may be inappropriate because of potential systemic toxicities of residual antibiotics in the washed red cells. However, the amount of antibiotics remaining after washing is minimal, and Paravicini et al67 have shown that the amount of antibiotics infused along with the washed autologous red cells is minuscule and clinically irrelevant in comparison with the amount absorbed from the surgical site directly. Application of topical disinfectants that have the potential to damage red cell membranes, such as hydrogen peroxide, should not occur during suction into the IAT apparatus because of the potential for hemolysis of red cells in the field and in the reservoir. The other major concern with automated equipment has been the potential for infusion of an air embolus through instrumentation that offers the

AUTOLOGOUS TRANSFUSION AND DIRECTED DONATION

opportunity to return washed red cells through direct reinfusion. 62,68-70 However, those instruments so equipped also include foam (air) detectors in the return line; the logic system of the instruments causes a cessation of reinfusion whenever air is detected in the return circuit, thus alleviating this concern. The red cell loss through hemolysis was considerable with some older equipment and has been attributed to mechanical or aspiration trauma;71 however, hemolysis is minimal with currently available equipment.56 The red cells returned to the patient have the biochemical parameters of freshly collected red cells and exhibit a normal posttransfusion survival.56,72 Deposition of platelet aggregates in the washing bowl has been reported but is thought to be a rare phenomenon related to availability of ionized calcium and activation of platelets by heparin when using this anticoagulant. 56 The efficacy of the wash cycle in removing lipids aspirated from the surgical site has also been questioned. However, in a review of over 8,000 cases at the Mayo Clinic in which IAT was used, no incidences of air embolism, sepsis or major coagulopathies were noted. 73 By recovering blood shed intraoperatively, the use of homologous blood can be reduced dramatically. As reviewed by Popovsky,74,75 use oflAT in orthopedic cases may reduce blood use by 50%. The reduction in homologous usage in cardiac and vascular surgery depends on the type of surgery, the presence of adhesions, and the amount of blood loss; reductions reported range from 20% to 90%, amounting usually to 2 to 4 U per case. 76-78 While use of IAT in itself does not increase the need for other homologous components,77 plasma and platelets may need to be administered on an individualized basis-taking into account both clinical and .laboratory parameters-in cases where blood loss is large, particularly when it exceeds 1.5 to 2 L,77,79,80 With extensive use of IAT techniques at the Mayo Clinic, over one third of operating room transfusions were provided through red cell recovery techniques. 73 Combined with PAD techniques, many patients can avoid homologous components entirely, including 70% to 80% of children undergoing spinal surgery.81,82 In orthotopic liver transplantation, 30% or more of red cell usage can be supplied through IAT, although multiple instruments may be necessary at times of peak blood loss to maximize the potential for recovery and reinfusion of autologous red cells. 83 ,84 One novel ap-

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proach to intraoperative blood recovery has even involved salvage of blood from enlarged spleens after splenectomy; the recovery of 100 to 625 mL from spleens represented 24% to 74% of the blood transfused intraoperatively to 3 patients. 85 The logistics and cost efficiency of IAT have also been well investigated. Larger hospitals, particularly those with active cardiovascular surgery services, are able to spread the fixed costs of the service over a large number of cases and use this caseload to maintain staff proficiency. Smaller hospitals, and other surgical services in larger hospitals, have had much less access to this form of autologous transfusion. However, in the last 3 years many regional blood centers have begun to provide IAT on a regional, fee-for-service basis in a manner similar to that in which some offer therapeutic apheresis services. 86 These programs use the resources of a region to provide a service to many hospitals that each hospital would not be able to provide for itself. Even for hospitals already providing IAT in their operating rooms, use of such a community facility may expand application of IAT through off-hour coverage and availability of additional equipment and staff for use in peak times. The importance of this increased availability should not be overlooked since, in one large regional program, service outside of routine operating room hours accounts for 51 % of the total caseload. 86 This approach to the sharing of resources, which has been so successful in the provision of other transfusion-related services, appears to have the potential for increasing the accessibility to IAT throughout a community. Postoperative Autologous Transfusion. The same techniques and approaches used in IAT have also been applied in the recovery of blood shed postoperatively.87 Again, cardiac surgery has been the field most involved in these techniques because of the volume of blood shed postoperatively and the accessibility of that blood to recovery and reinfusion. Blood shed into the mediastinal and pleural cavities can be aspirated into a container system that allows the blood either to be readministered through a filter or first washed in the transfusion service laboratory.88 This blood has been defibrinated through passage through a body cavity and has a low platelet count but may contain activated platelets and clotting factors. Postoperative blood recovery was shown to be beneficial by reducing the need for homologous transfusion by

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50% in one study 89 but did not lead to any reduction in blood usage in another. 9o The volume of red cells obtained is usually small, and the hematocrit is often reduced by two-thirds or more. 87,91 Recently, equipment similar to that used for IAT having the capability to wash and concentrate shed blood, has become available for postoperative use. However, the cost effectiveness of using such equipment may become apparent only in cases of substantial postoperative blood loss.

Controversies in Preoperative Autologous Donation The most widely used form of autologous transfusion, PAD, has generated a number of controversies that appear not to be headed for resolution in the near future. Although there is universal agreement that PAD should be readily available and used whenever appropriate, the specifics, logistics and indications of this form of transfusion therapy continue to be problematic. Indications and criteria for collection. The donation of a unit of whole blood is regarded by many as an innocuous event unlikely to result in any significant untoward reaction. This impression is founded on most blood donations having been made by donors who were carefully screened to be free of systemic disease that might make phlebot0my difficult or dangerous. In addition, most clinicians are familiar with phlebotomy only in controlled settings where emergency medical assistance is immediately available. However, in PAD the patients referred for donation may have significant underlying health problems and may undergo phlebotomy in a location where emergency assistance may not be readily available. On the other hand, while a patient may face increased risks from phlebotomy because of health problems, these risks may be overshadowed by the benefits to be gained through the subsequent opportunity for autologous transfusion. Many blood bankers use more liberal and flexible requirements for autologous donors than for volunteer donors. 92 ,93 The more liberal sets of these restrictions preclude donation only from patients with severe aortic stenosis, left anterior descending coronary artery obstruction, idiopathic hypertrophic subaortic stenosis, unstable angina or active cardiac failure, and a severe conduction disturbance or arrhythmia. To date, few cases of significant morbidity have been reported in associa-

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tion with PAD. Mann et al collected PAD from 346 "high risk" patients in a hospital setting with a postdonation reaction rate (4%) no higher than that seen among regular blood donors and without severe reactions. 94 In a study of 336 patients with a mean age of 65 years undergoing a course of PAD without volume replacement, the reaction rate was 2.2% and no postdonation angina was observed. 95 Others have reported similar safety records despite the patient/donors having significant cardiac or malignant disease. 96.98 Nevertheless, some blood bankers have continued to use restrictive acceptability criteria originally intended for volunteer homologous donors. 93 Some have taken the approach that patients with significant underlying disease, particularly cardiac disease, should undergo PAD under different protocols. For example, at the Beth Israel Hospital in Boston patients with significant cardiovascular disease undergo PAD with the simultaneous infusion of normal saline, tolerating the procedure well. 26 ,27 In 101 PAD patients with cardiovascular disease, only one patient had a severe reaction, that of postdonation angina, symptomatology that had been intermittently present prior to donation. Others have suggested that saline be infused to donors when collecting a volume greater than 10% of the patient's estimated blood volume to avoid a hypovolemic reaction,99 although vasovagal reactions and their sequelae are much more frequent than hypovolemic ones; in following the hemodynamic parameters of 63 patients (all over the age of 65 years or having cardiac disease), those receiving intravenous fluid replacement had higher systolic, diastolic and mean arterial pressures, and lower heart rates after donation. 99 Others have moved to phlebotomy of high risk patient/donors to a setting affording a higher degree of monitoring and potential for emergency response, such as the hospital recovery room. 100 Children do not seem to be at increased risk of vasovagal reactions and often can complete a program of PAD to supply most or all of the blood needed in surgery.101 However, most patients seeking to be their own blood donors are in sufficiently good health to allow donations to take place in less-controlled environments. Serious postdonation sequelae occurred in less than 1% of 5,660 preoperative autologous donations in outpatient, nonhospital settings in a study conducted by the American Red Cross. 102 Donors with preexistent arteriosclerotic

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disease that had serious reactions were not distinguishable, on the basis of their history, from those that tolerated the procedure well. While the overall reaction rate in donors not meeting usual donation criteria (4.2%) was higher than in those who did (2.7%, P < .001), donors over 75 years of age, those with a history of cardiac disease, medication or surgery, and those with other deviations from usual health acceptance criteria for volunteer homologous donors, did not have an increased risk of postdonation reaction. Donors who were less than 17 years, who weighed less than 100 pounds, or who had suffered previous reactions, were more likely to have a reaction. Documentation of the safety of PAD in nonhospital settings may be important in promoting the expansion of the availability of PAD: up to one quarter of a large regional PAD program's collections may occur on blood mobiles in order to make this approach to autologous transfusion as widely available as possible. 103,104 The collection of blood during pregnancy remains controversial. That the procedure appears to have infrequent complications has been established by several studies. Donor reaction rates appear to be low, approximately 1% to 2%, and the left lateral position is often used for phlebotomy in order to improve venous return, minimize donor hypotension, and optimize fetal oxygenation. lOS ,106 The Beth Israel Hospital in Boston has reported their experience of over 500 donations from pregnant women without a significant peridonation reaction. 107 With fetal monitoring, fetal heart rates may be seen to increase, but the phlebotomy is usually tolerated without incident, at least as detected through these monitoring methods. 107 ,108 Other groups have also found no evidence of fetal distress due to the change in maternal blood volume. lOS Some prefer not to collect blood during the [mal 4 to 8 weeks of gestation for fear of inducing premature labor subsequent to a donor reaction. lOS While the actual risks of donating may be small, another consequence of donation may be iron depletion; most pregnant women are in an iron deficient or, at least, depleted status, and limitations of iron absorption capacity must be taken into account. For example, of 48 pregnant women desiring to participate in a PAD program and receiving oral iron supplementation, eight (17%) had hematocrits persistently below 34%, and seven (15%) were able to donate only 1 U because of

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their hematocrits falling below 34% after the first donation and not returning above that level; thus anemia is a major impediment to PAD during pregnancy. 106 These apparently small risks of donation during pregnancy must be compared with the low likelihood of a transfusion being required after most deliveries. Even with selecting for participation in a PAD program those women whose pregnancies are most likely to result in their needing transfusion, only a small proportion of the units are used for transfusion. For example, 3 of 48 unselected patients in one study were transfused during or after delivery. 106 In a study of PAD in nine women with placenta praevia, an obstetrical complication with a higher likelihood of requiring transfusion, three required transfusion of their autologous units and one of these required additional homologous units. 108 Insofar as over a quarter of obstetrical transfusions are regarded as not being warranted,109 and because major obstetrical complications may lead to the need to transfuse many more units than the 1 or 2 U usually collected, one may wonder whether alternative, conservative approaches to transfusion might do more to reduce homologous blood usage in the puerperium than antenatal blood donation. 110 While one may conclude that most patients seeking autologous donations may do so safely in most any setting, and those with more serious systemic disease may do so with additional monitoring, this discussion raises the important questions of risks and benefits. In the essentially well patient, donation poses no more risk than to the normal volunteer; some have suggested that this low risk may justify collection even when the probability of needing a transfusion is small-a situation where the benefit, on a global basis, may also appear to be small. On the other hand, in patients in whom donation may carry with it a substantial risk of serious morbidity, the expected benefits to be gained should be correspondingly higher in order to justify these risks. In such cases, other alternative means of providing autologous transfusion, such as IAT, must be considered. Especially in these problematic cases, the transfusion service or blood center physician should offer his or her expertise regarding the likelihood and type of postdonation reaction and the capability of the donation service to cope with a severe emergency. The role of the transfusion medicine specialist can be

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very important in such situations, allowing the patient and the clinician access to knowledge that will allow accurate assessment of the true risks and benefits of PAD. The collection of any component for autologous transfusion should occur only when the expected benefits outweigh the potential risks. Supplementary justifications, such as the ability to use an unneeded component for another patient (see following section), are extraneous to the risk! benefit calculations for the patient/donor. Indications for transfusion. "Transfusion triggers," the combination of hematologic parameters and clinical situations that prompt transfusion of a blood component, have received much attention. The red cell transfusion trigger is lower than was generally accepted even a few years ago,1,45,111 and lower platelet counts are now accepted in the understanding that prophylactic transfusions may not have the desired long-term effects. 112 Nevertheless, absolute criteria, unrelated to the patient's clinical condition, are still in use. It is commonly agreed among transfusion medicine specialists that consideration of the indications for transfusion should include determination of the risks and benefits of transfusion, but exactly what indications are appropriate when the component to be transfused is autologous in origin remains controversial. Given that any potential risks of donation have already passed, what risks are associated with transfusion of autologous red cells? Many would respond, "None," but this response ignores the potential for misidentification of patients and units, the small but real possibility of bacterial contamination of the units and other problems not directly associated with the quality of the unit, such as· volume overload. 43 Some advocate return of all components that would not produce volume overload regardless of the magnitude of the expected immediate clinical benefit because of iron depletion during PAD. 113 On the other end of the spectrum, some would argue that the potential adverse consequences of receiving the wrong unit mandate that autologous transfusions be given only under the same rigorous indications that should be used for homologous component transfusion. In studying physician behavior regarding transfusion of patients who had or had not participated in a PAD program, Wasman and Goodnough43 were able to show that orthopedic surgeons tolerated

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significantly lower hematocrits in patients who had donated preoperatively throughout their entire hospitalization. This study reiterates the question of the propriety of transfusion triggers in common use. Thus, although the risks of administering an autologous unit are small, the benefits to be gained must at least be commensurate with these risks. Unit handling: testing. The extent to which PADs should be tested has also raised much furor. If the units are intended only for autologous use and are designated as such, why should they be tested? Arguments in favor of testing center around the potential benefits to others rather than to the patient/donor. 114 Health-care workers coming in contact with the patient would, presumably, be made aware of the increased risk that the patient's blood and body fluids represented and take appropriate precautions to avoid transmission. With testing, potentially infectious units would be identified and either discarded or prominently labeled, thus reducing or eliminating the possibility of infectious disease transmission through inadvertent transfusion to the wrong patient. Arguments of practicality and efficiency have also been raised, citing the increased costs of handling autologous units differently than the much more numerous units intended for homologous transfusion in the blood collection and testing system. Proponents of eliminating testing for PADs cite promotion of increased access to this form of transfusion therapy as the primary reason for their position. 115 If hospitals or health-care workers were that concerned about the exposure to HIV or hepatitis B through the blood of patients, these respondents would contend that all patients should be tested prospectively, not just the small proportion utilizing PAD. Furthermore, patients already exposed to one virus, such as hepatitis B virus or HIV, are potentially those that have the most to gain by avoiding exposure to another when that secondary infection may have even more severe and immediate consequences. Civil liberty issues may also be raised in such discussions. Currently, two thirds of blood collection facilities test PADs, although the disposition of units testing positive represents another area of diversity of practice. 93 Over half of the institutions testing PAD units retain HIV-positive units for transfusion to the patient/donor, while the remainder, a sizable

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minority, discard these units. 93 The actions of regulatory agencies may well standardize practices. Unit handling: disposition of unused units. A substantial proportion of PADs are not transfused to the patient/donor. As the public becomes more aware of the benefits of autologous transfusion and mechanisms to provide collection services become more user-oriented, this proportion, now at approximately 30% to 50%, may be expected to grow. 10 As about half of autologous donors qualify as volunteer blood donors and, because many programs fully test all PADs, the question arises whether unused PADs meeting all criteria for homologous transfusion should be "crossed-over" into the general blood supply. (These units may represent 15% to 30% of all PADs.) At the first level, discussion of this issue centers on the philosophical issues of whether it is appropriate to take the blood of one patient and transfuse it to another, or whether it is justifiable to discard a useful medicinal resource that is in short supply. Because the disparate viewpoints on these issues are usually not resolvable, the discussion moves to other venues. Several studies have attempted to determine whether autologous units that apparently meet all criteria for homologous use truly represent a supplement to the blood supply that does not detract from its current level of safety. Different studies using different approaches, different statistical concepts, and based on populations in different parts of the country have reached different conclusions. 1l6. 1l8 For example, autologous and volunteer homologous donors in the Boston area appeared to have equivalent prevalences of commonly used infectious disease markers. 1l7 On the other hand, when 413 autologous donors in the Atlanta area were matched for age, gender, and zip code with volunteer homologous donors, the autologous donors were 3.2 times more likely to have a positive test for hepatitis B core antibody. These studies raise numerous questions that remain unresolved, including the most appropriate form of data analysis to be usedY9,120 While these considerations of study structure and data analysis may lead to a fuller appreciation of the importance of key variables, the "ultimate study" may need to be so cumbersome in design and large in size that the answer of whether the practice of crossover adversely affects the safety of the homologous

blood supply may never be known. 121 Beyond infectious disease worries, other problems may arise from the crossover of unused PAD units, eg, the erroneous appearance of a positive pregnancy test that confused the homologous recipient's true clinical diagnosis following transfusion with 2 U of plasma derived from donations of pregnant women. 122 A common practice regarding crossover has yet to evolve. While many regard crossover as a practice with a long record of utility, others decry its use without documentation of its safety. As pointed out by Anderson and Tomasulo,93 if PAD units entered into the community supply are later documented as representing a lower order of safety, a huge number of unsuspecting recipients may need to be notified. Clearly, appropriate use of PAD, prescribing it in cases where transfusion is truly likely, will limit the number of units not returned to the donor and thus be eligible for consideration of crossover. ECONOMIC ISSUES

Reimbursement As health-care resources continue to be limited, funding for autologous transfusion practices cannot be assumed just because they represent the "safest form of transfusion therapy." While patients regard autologous transfusion as an approach well worth the expenditure of considerably more money than for homologous products,123,124 most patients do not pay for these services directly, leaving third-party carriers, governmental programs, hospitals and blood centers to determine how best to fund these options. Blood products are a small part of most patients' hospital bills, and the additional costs of handling and tracking autologous donations would seem almost inconsequential. However, when many patients requiring transfusion have the associated health-care costs routed through governmental plans that fail to recognize the additional costs of providing autologous units, hospitals may find this form of transfusion beneficial to the patient but disadvantageous to their own financial well being. Financial pressures have spurred some hospitals to (re)open donor phlebotomy services for the purpose of providing autologous collections, although a complete cost accounting of these operations would probably not

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show them to be more cost effective than collec, 125 126 Wh'l tion through regional blood supplIers.' 1e some insurance carriers have recognized the overall system benefit to autologous transfusion and have developed specific programs to incorporate the costs of PAD into payment for surgical procedures where PAD is generally appropriate, payment for PAD services remains a problem. Cost/Benefit Analysis

What does autologous transfusion cost and what are its economic benefits? The benefits can be projected on the basis of avoidance of disease transmission or alloimmunization. Such calculations are problematic given the dichotomy of potential lifespan lost (little in some cases, enormous in others) and the uncertain probability of disease transmission. Although non-A, non-B hepatitis (NANB) probably represents the most frequent health risk associated with homologous transfusion, the current estimate of incidence of NANB transmission through transfusion is less than 1%.127 This level of risk may make the economic impact of potential benefits of autologous transfusion seem small. On the other hand, the supplemental costs of providing the additional safety benefits of autologous transfusion are also small. For PAD, they include costs for special scheduling and slower donor throughout (one third the usual rate l28 ), and the costs of tracking mechanisms. The usual additional cost associated with collection and handling of PADs is $20 to $30 per unit, and IAT costs are the equivalent of collecting, processing and administering 2 to 3 U of red cells. 129 When considered on a personal basis, these appear to be good "investments" to the patient in removing even a low risk of infection. Where should limited resources be applied: to the use of autologous transfusion methods in large-volume cases or in those where a smaller amount of blood is lost? Although IAT may conserve the greatest amount of homologous blood in vascular and other procedures where large amounts of blood may be lost, such procedures are likely to require at least some homologous blood product exposure for the patient. As the first unit of homologous blood may represent the greatest incremental risk of exposure to an infectious agent, application of autologous transfusion methods to cases with blood losses that are anticipated to be

JAMES p, AUBUCHON

small may allow them to provide the greatest opportunity for reduction in transfusion risks. 3 AUTOLOGOUS TRANSFUSION AND THE EVOLUTION OF TRANSFUSION MEDICINE

The recognition of the threat of retrovirus transmission through the blood supply and of the dangers of transmission of NANB have changed, probably permanently, the practice of transfusion medicine. The pressures that these concerns have brought to bear on transfusion practice have not always been welcomed or beneficial. The avoidance of PAD by some patients in the mistaken belief-held by one-fifth of patients-that directed donations offer safety that is equivalent to autologous transfusion 11 is an example of decision making moving too far from adequate sources of information. Nevertheless, the drive for thorough consideration of all transfusion options highlights the necessity of the redefinition of the role of trans. , . . I'IstS.· 130 131 Th'IS ev 01 ufUSIOn medIcme specla tion of blood bankers into clinically oriented specialists 132 has promoted the development of more effective and visible autologous transfusion programs that meet the needs of patients and the concerns of physicians. Certainly the position that transfusion medicine specialists find themselves in today is an exciting one----a field with rapidly changing products and procedures and the great need for these to be individually tailored to optimize transfusion practice for each patient. The clinically oriented transfusion medicine specialist has the opportunity and the responsibility to continue to serve as a visible clinical consultant to ensure that the patient receives the best transfusion therapy possible. Further investigation of the remaining questions surrounding autologous transfusion and directed donations may clarify more fully their proper roles in transfusion medicine. ACKNOWLEDGMENT I would like to acknowledge the continued support of the development of autologous transfusion services over many years by Dr. S, Gerald Sandler, American Red Cross Blood Services, who has served as an inspirational guide for me. I would also like to thank Ms. Pamela Leach, also of the American Red Cross, for her assistance in researching articles on some of the topics discussed in this review.

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sues. Arlington, VA, American Association of Blood Banks, 1988, pp xi-xii 22. Toy PrCY, Strauss RG, Stehling LC, et al: Predeposited autologous blood for elective surgery. A national multicenter study. N Engl I Med 316:517-520, 1987 23. Toy PT, Stehling LC, Strauss RG, et al: Underutilization of autologous blood donation among eligible elective surgical patients. Am J Surg 152:483-486, 1986 24. Axelrod FB, Fisher F, Pepkowiz C, et al: Current utilization and potential for growth of pre-deposit liquid stored autologous blood programs. Transfusion 28:59S, 1988 (abstr) 25. Haugen RK, Hill GE: A large-scale autologous blood program in a community hospital. A contribution to the community's blood supply. JAMA 257:1211-1214, 1987 26. Kruskall MS, Glazer EE, Leonard S, et al: Utilization and effectiveness of a hospital autologous preoperative blood donor program. Transfusion 26:335-340, 1986 27. Owings DV, Kruskall MS, Thurer RL, et al: The safety and efficacy of preoperative autologous blood donation for elective cardiac surgery. Transfusion 289:335, 1988 (abstr) 28. Cordell AR, Lavender SW: An appraisal of blood salvage techniques in vascular and cardiac operations. Ann Thorac Surg 31:421-425, 1981 29. Schiffer CA, Aisner I, Wiernik PH: Frozen autologous platelet transfusion for patients with leukemia. N Engl J Med 299:7-12, 1978 30. National Institutes of Health Consensus Development Conference: Fresh frozen plasma: Indications and risks. NIH, 1984 31. National Institutes of Health Consensus Development Conference: Platelet transfusion therapy. NIH, 1986 32. Fehir K, Jones J, Noon G, et al: Preoperative autologous plateletpheresis and plasmapheresis in patients undergoing cardiopulmonary bypass procedures. Transfusion 25:465, 1985 (abstr) 33. Rabe DE, Taswell HF: Uses of autologous fibrin glue. Transfusion 28: lIS, 1988 (abstr) 34. Gilcher RO, Belcher L: Preoperative autologous blood donation programs, in Garner RI, Silvergleid AJ (eds): Autologous and Directed Blood Programs. Arlington, VA, American Association of Blood Banks, 1987, pp 15-29 35. Mintz PO, Nordine RB, Henry JB, et at: Expected hemotherapy in elective surgery. NY State J Med 76:532-537, 1976 36. Goodnough LT, Rudnick S, Price T, et al: Erythropoietin therapy in autologous blood donors. Blood 72:118a, 1988 (suppl) 37. Lubin I, Greenberg II, Yahr WZ, et al:The use of autologous blood in open heart surgery. Transfusion 14:602607, 1974 38. Greenwalt, TJ: Autologous and aged blood donors. lAMA 257:1220-1221, 1987 39. Zanjani ED, Ascensao IL: Erythropoietin. Transfusion 29:46-57, 1989 40. Hillman RS, Finch CA: Erythropoiesis: Normal and abnormal. Semin Hematol 4:327-336, 1967 41. Finch CA, Beutler E, Brown EB, et al: Iron deficiency in the United States. JAMA 203:407-410, 1968 42. Goodnough LT, Rudnick S: Erythropoietin, in Menitove

304 JE, Edwards-Moulds J, Lasky LC (eds): Transfusion Medicine Applications for Growth Factors and Biologic Response Modifiers. Arlington, VA, American Association of Blood Banks, 1988, 43. Wasman J, Goodnough LT: Autologous blood donation for elective surgery: Effect on physician transfusion behavior. JAMA 258:3135-3137, 1987 44. KickIer TS, Pivack JL: Effect of repeated whole blood donations on serum immunoreactive erythropoietin levels in autologous donors. JAMA 260:65-67, 1988 45. National Institutes of Health Consensus Development Conference: Perioperative red cell transfusion. NIH, 1988 46. Carson JL, Spence RK, Poses PM et al: Severity of anemia and operative mortality and morbidity. Lancet 1:727728, 1988 47. Mandel MA: Autotransfusion in elective plastic surgical operations. Plast Reconstr Surg 77:767-771, 1986 48. Stehling LC: Acute normovolemic hemodilution, in Maffei LM, Thurer RL (eds): Autologous Blood Transfusion: Current Issues. Arlington, VA, American Association of Blood Banks, 1988, pp 13-20 49. Shah DM, Prichard MN, Newell JC, et al: Increased cardiac output and oxygen transport after intraoperative isovolemic hemodilution: A study in patients with peripheral vascular disease. Arch Surg 115:597-600, 1980 50. Martin E, Hansen E, Peter K: Acute limited normovolemic hemodilution: A method for avoiding homologous transfusion. World J Surg 11:53-59, 1987 51. Messmer K, Kreimeier D, Intaglietta M: Present state of intential hemodilution. Eur Surg Res 18:254-263, 1986 52. Vara-Thorbeck R, Guerrero-Fernandez MA: Hemodynamic response of elderly patients undergoing major surgery under moderate normovolemic hemodilution. Eur Surg Res 17:372-376, 1985 53. Kafer ER, Isley MR, Hansen T, et al: Automated acute normovolemic hemodilution reduces homologous blood transfusion requirements for spinal fusion. Anesth Analg 65:S76, 1986 54. Goodnough LT, Kruskall M, Stehling L, et al: A multi-center audit of transfusion practice in coronary artery bypass (CABG) surgery. Blood 72:277a, 1988 (abstr) 55. Giordano GF, Rivers SL, Chung GKT, et al: Autologous platelet-rich plasma in cardiac surgery: Effect on intraoperative and postoperative transfusion requirements. Ann Thorac Surg 46:416-419, 1988 56. Yawn DH, Bull BS: Intraoperative salvage: Quality of products, in Maffei LM, Thurer RL (eds): Autologous Blood Transfusion: Current Issues. Arlington, VA, American Association of Blood Banks, 1988, pp 43-56 57. Glover JL, Broadie TA: Intraoperative autotransfusion. World J Surg 11:60-64, 1987 58. Cordell AR, Lavender SW: An appraisal of blood salvage techniques in vascular and cardiac operations. Ann Thorac Surg 31:421-425, 1981 59. Kingsley JR, Valeri CR, Peters H, et al: Citrate anticoagulation and cell washing for intraoperative autotransfusion in the baboon. Am J Surg 131:717-721, 1976 60. Dzik WH: Perioperative blood salvage. NIH Consensus Development Conference: Perioperative red cell transfusion, 1988 61. Hallet JW, Popovsky M, Ilstrup Director: Minimizing

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blood transfusions during abdominal aortic surgery: Recent advances in rapid autotransfusion. J Vasc Surg 5:601-606, 1987 62. Automated intraoperative processing autotransfusion machines. Health Devices 17:219-242, 1988 63. Boudreaux JP, Borside GH, Cohn I: Emergency autotransfusion: Partial cleansing of bacteria-laden blood by cell washing. J Trauma 23:31-35, 1983 64. Yaw PB, Sentany M, Link WJ, et al: Tumor cells carried through autotransfusion: Contraindication to intraoperative blood recovery? JAMA 231:480-491, 1975 65. Klimberg I, Sirios R, Wajaman Z et al: Intraoperative autotransfusion in urologic oncology. Arch Surg 121:13261329, 1986 66. Jacobs LM, Hseih JW: A clinical review of autotransfusion and its role in trauma. JAMA 251:3283-3287, 1984 67. Paravicini D, Thys J, Hein H: Rinsing the operative field with neomycin-bacitracin solution with intraoperative autotransfusion in orthopaedic surgery. Arzheimittelforschung/ Drug Res 33:242-246, 1983 68. Deysine M: Intraoperative autotransfusion and air embolism. Surgery 81:729, 1977 (letter) 69. Mattox KL: Comparison of techniques of autotransfusion. Surgery 84:700-702, 1978 70. Duncan SE, Klebanoff G, Rogers W: A clinical experience with intraoperative autotransfusion. Ann Surg 180:296304, 1974 71. Marth JA, Berkman EM: Intraoperative erythrocyte salvage with a high speed device. Blood 66:285a, 1985 (abstr) 72. Ray JM, Flynn JC, Bierman AH: Erthrocyte survival following intraoperative autotransfusion in spinal surgery: An in vivo comparative study and 5-year update. Spine 11:879882, 1986 73. Williamson KR, Taswell HF: Intraoperative autologous transfusion CIAT): Experience in over 8,000 surgical procedures. Transfusion 28: 11S, 1988 (abstr) 74. Popovsky MA: The role of autologous transfusion in surgery and the emergency room, in Gamer RJ, Silvergleid AI (eds): Autologous and Directed Blood Programs, Arlington, VA, American Association of Blood Banks, 1987, pp 47-63 75. Popovsky MA, Devine PA, Taswell HF: Intraoperative autologous transfusion. Mayo Clin Proc 60:125-134, 1985 76. Hallet JW, Popovsky MA, Ilstrup MS: Minimizing blood transfusions during abdominal aortic surgery: Recent advances in rapid autotransfusion. J Vasc Surg 5:601-606, 1987 77. McCarthy PM, Popovsky MA, Schaff HV, et al: Effect of blood conservation efforts in cardiac operations at the Mayo Clinic. Mayo Clin Proc 63:225-229, 1988 78. Tawes RL, Scribner RG, Duval TB, et al: The CellSaver and autologous transfusion: An underutilized resource in vascular surgery. Am J Surg 152:105-109, 1986 79. Popovsky MA: The role of autologous transfusion in surgery and the emergency room, in Garner RJ, Silvergleid AJ (eds): Autologous and Directed Blood Programs. Arlington, VA, American Association of Blood Banks, 1987, 47-63 80. Collins JA: Recent developments in the area of massive transfusion. World J Surg 11:75,81, 1987 81. Kruger LM, Colbert JM: Intraoperative autologous transfusion in children undergoing spinal surgery. J Pediatr Orthop 5:330-332, 1985 82. Novak R, Apati J, Bethem, et al: A successful program

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of autologous blood transfusion for pediatric scoliosis surgery. Transfusion 27:530, 1987 (abstr) 83. Williamson K, Taswell HF, Rettke SR, et al: Intraoperative autologous transfusion: Its role in orthotopic liver transplantation. Mayo Clin Proc 64:340-345, 1989 84. Dzik WH, Jenkins R: Use of intraoperative blood salvage during orthotopic liver transplantation. Arch Surg 120: 946-948, 1985 85. De Rai P, Biffi R, Rebulla P: Postsplenectomy blood salvage in anemic patients. JAMA 258:1332, 1987 (letter) 86. Giordano G: Intraoperative salvage: Administrative aspects, in Maffei LM, Thurer RL (eds): Autologous Blood Transfusion: Current Issues. Arlington, VA, American Association of Blood Banks, 1988, pp 21-30 87. Johnson RG: Postoperative salvage, in Maffei LM, Thurer RL (eds): Autologous Blood Transfusion: Current Issues. Arlington, VA, American Association of Blood Banks, 1988, pp 57-66 88. Symbas PN: Autotransfusion from hemothorax: Experimental and clinical studies. J Trauma 12:689-692, 1972 89. SchaffHV, Hauer JM, Bell WR, et al: Autotransfusion of shed mediatinal blood after cardiac surgery. J Thorac Cardiovasc Surg 75:632-635, 1978 90. Thurer RL, Lytle BW, Cosgrove DM et al: Autotransfusion following cardiac operations: A randomized, prospective study. Ann Thorac Surg 27:500-505, 1979 91. Hartz RS, Smith JA, Green D: Autotransfusion after cardiac operation: Assessment of hemostatic factors. I Thorac Cardiovasc Surg 96:178-182, 1988 92. Blazina I, Schumacher M, Kennedy MS, et aI: A survey of policies for exclusion of predeposit autologous donors. Transfusion 28:42S, 1988 (abstr) 93. Anderson BV, Tomasulo PA: Current autologous transfusion practices. Implications for the future. Transfusion 28:394-396, 1988 94. Mann M, Sacks HI, Goldfinger D: Safety of autologous blood donation prior to elective surgery for a variety of potentially "high-risk" patients. Transfusion 23:229-232, 1983 95. Nicholls MD, Ianu MR, Davies VI: Autologous blood transfusion for elective surgery. Med I Australia 144:396-399, 1986 96. Cove H, Matloff J, Sacks HJ, et al: Autologous blood transfusion in coronary artery bypass surgery. Transfusion 16:245-248, 1976 97. Baker N, Kickey K, Koplin B: A blood center and a major medical center: A team effort in bleeding high risk autologous donors. Transfusion 28:59S, 1988 (abstr) 98. Ness PM, Baldwin ML, Walsh PC: Pre-deposit autologous transfusion in radical retropubic prostatectomy. Transfusion 27:518, 1987 (abstr) 99. Daneshvar A: Fluid replacement after blood donation: Implications for elderly and autologous blood donors. Maryland Med J 37:787-791, 1988 100. Sassetti R, Spiess B, McLeod B, et al: Hemodynamic changes in high risk autologous donors. Transfusion 28:34S, 1988 (abstr) 101. Silvergleid AI: Safety and effectiveness of predeposit autologous transfusions in preteen and adolescent children. lAMA 257:3403-3404, 1987 102. AuBuchon IP, Popovsky MA: Autologous donor safety in non-hospital programs. Transfusion 28:34S, 1988 (abstr)

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103. Sobol D, Ross D, Heaton A: A mobile autologous blood program provides convenience and flexibility. Transfusion 27:573, 1987 (abstr) 104. Popovsky MA, McGuff J, Connolly, et al: A blood center based predeposit autologous program. Transfusion 27:573, 1987 (abstr) 105. Wentworth L, Pura L, Pepkowitz S, et al: Obstetrical autologous donors, an issue of safety. Transfusion 27:573, 1987 (abstr) 106. Kruskall MS, Leonard S, Klapholz H: Autologous blood donation during pregnancy: Analysis of safety and blood use. Obstet Gynecol 70:938-941, 1987 107. Kruskall MS: Autologous blood donations during pregnancy. AABB Newsbriefs, FebruarylMarch, 1989, p 12 108. Malynn ER, Kruskall MS, Nessen SL, et al: Analysis of autologous donations in pregnant women with placenta previa. Transfusion 28:345, 1988 (abstr) 109. Gibbs CE, Misenhimer HR: The use of blood transfusion in obstetrics. Am J Obstet Gynecol 93:26-31, 1965 110. Simon TL: Postpartum blood requirements: Should autologous donation programs be considered? lAMA 259:2021, 1988 111. Stehling LC, Ellison N, Faust RJ, et al: A survey of transfusion practices among anesthesiologists. Vox Sang 52:60-62, 1987 112. Murphy S, Litwin S, Herring LM,et al: Indications for platelet transfusion in children with acute leukemia. Am I Hematol 12:347-356, 1982 113. Gilcher RO: Indications for the use of autologous blood and blood components, in Maffei LM, Thurer RL (eds): Autologous Blood Transfusion: Current Issues. Arlington, VA, American Association of Blood Banks, 1988, pp 145-150 114. Silvergleid AI: All blood collected should be tested for infectious disease markers, in Maffei LM, Thurer RL (eds): Autologous Blood Transfusion: Current Issues. Arlington, VA, American Association of Blood Banks, 1988, pp 177-182 115. Holland PV: Why test autologous units, in Maffei LM, Thurer RL (eds): Autologous Blood Transfusion: Current Issues. Arlington, VA, American Association of Blood Banks, 1988, pp 167-176 116. Nicely I, Lugo I, Glackin K, et al: Infectious disease markers in autologous donors compared to the random population. Transfusion 27:517, 1987 (abstr) 117. Kurskall MS, Popovsky MA, Pacini 00, et al: Autologous versus homologous donors: Evaluation of markers for infectious disease. Transfusion 28:286-288, 1988 118. Grossman BI, Stewart NC, Grindon AJ: Increased risk of a positive test for antibody to hepatitis B core antigen (anti-HBc) in autologous blood donors. Transfusion ,28:283-285, 1988 119. AuBuchon JP, Dodd RY: Analysis of the relative safety of autologous blood units available for transfusion to homologous recipients. Transfusion 28:403-405, 1988 (editorial) 120. Kurskall MS, Chambers LA, Pacini D, et al: Estimating the safety of autologous blood units available for transfusion to homologous recipients. Transfusion 29:373-374, 1989 (letter) 121. AuBuchon JP, Dodd RY: Estimating the safety of autologous blood units available for transfusion to homologous recipients. Transfusion 29:374-375, 1989 (letter)

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