Few, if any, of our perioperative therapeutic approaches has changed as much over the past 10 years as our red blood cell (RBC) transfusion practices. These continue to evolve and various experts and august organizations such as the American Society of Anesthesiologists (ASA), American College of Physicians (ACP), and Canadian Medical Association (CMA) have published evidence based and expert opinioned guidelines on appropriate blood utilization [1-4].

Long-term debate continues to focus on what threshold to use for RBC transfusion and how to minimize RBC transfusion risk (transfusion reaction, infection, immunomodulation, and effects from cold, acidotic, older, stored blood). How low can we safely allow the hemoglobin (Hgb) to decrease prior to transfusion [5]? Does this threshold vary by patient type (age, associated pathology such as cardiopulmonary disease) or duration of anemia (acute intraoperative blood loss vs. chronic compensated anemia)? What parameters should be used to identify transfusion needs (tachycardia, hypotension, absolute Hgb, oxygen delivery deficit and others)? What should we transfuse--packed RBCs? whole blood? leukoreduced RBCs? Blood substitutes [1,6]? What are the best technique(s) to minimize blood loss and to enhance native RBC function and production [6]? Does transfusion therapy improve outcome in critically ill patients? (Dr. P.C. Hebert and colleagues raised interesting questions about this in a Canadian study from last year.)

The two articles reviewed here present interesting clinical studies using different approaches to limiting RBC transfusion. The first study is a multicenter investigation which administered daily doses of subcutaneous or intravenous recombinant erythropoietin (rEPO) at 300units/kg from ICU day 3 - 8 in an attempt to limit RBC transfusion in critically ill medical and surgical patients. The lead authors, Corwin and Gettinger from Dartmouth, have previously presented impressive information on how much blood we remove from and transfuse into the critically ill [7]. They have also shown that with education and changes in practice, we can alter and decrease this amount.

EPO, a glycoprotein hormone, is normally produced in the peritubular interstitial cells of the kidney in response to tissue hypoxia. EPO levels therefore dramatically increase in states of decreased red cell mass and hypoxemia. However, EPO production appears to be limited or inadequate in many critically ill patients. The response to EPO may also be blunted in the critically ill and Fe stores may be inadequate or unavailable. In addition, EPO production or responsiveness is inadequate in patients with renal failure, cancer, and retroviral infection. Currently, rEPO (administered subcutaneously) use is indicated in patients with these pathologies and associated significant anemia. Most recently rEPO has been approved for use in the perioperative period in conjunction with or as a replacement for transfusion therapy in selected patients. (It may be administered preoperatively to increase the Hgb or to facilitate predonation. It is also used selectively in anemic postoperative patients).

rEPO acts by stimulating bone marrow production of RBCs, maturation of RBCs, and finally release of mature RBCs from the marrow. REPO limits red cell apotosis (cell death), and this enhances the survival and development of proerythroblasts to reticulocytes and is crucial to EPOÕs effectiveness. Side effects from rEPO are limited and felt to be commonly related to associated underlying pathology such as cancer or renal failure. EPO-induced cells have normal cell lives (120 days) and function in contrast to allogeneic transfusions.

The search for blood substitutes has been a long standing Holy Grail in transfusion medicine. Current approaches include the use of hemoglobin based oxygen carrying (HBOC) solutions such as restructured human hemoglobin (obtained from outdated human RBCs that are cell and stroma-free processed products), recombinant hemoglobin, xenohemoglobins (Bovine), and synthetic oxygen carriers (2nd generation perfluorocarbons). The Grail quest has been driven by concerns over transfusion-mediated problems, limited availability of RBCs (particularly in time of war, disasters, or in patients with rare blood types), ease of use, costs, and potential profits. Although we are close, we still do not have an ideal product, one that would be readily available, have a reasonable shelf life, relatively long life after infusion, limited to no side effects or toxicity, and be affordable. Current concerns with available blood substitutes can be divided into several areas:

The multicenter European study by Lamy and colleagues investigated the efficacy, safety, hemodynamic effect, and plasma duration of 10% diaspirin-crosslinked hemoglobin (DCLHB) in a randomized, active-control investigation performed in post cardiac bypass patients. DCLHB is a cell and stromal-free tetrameric solution of stabilized human Hgb obtained from outdated blood. It is subjected to heat treatment and ultrafiltration to avoid viral infection and suspended in a hypertonic, iso-osmotic salt solution. It has a slight rightward shift of its 0₂-dissociation curve (P₅₀ of 32 vs. 26 for human blood) which allegedly improves off-loading of 0₂. The study by Lamy and colleagues compared the incidence and number of transfusions required in the week aftter bypass surgery for patients who received diaspirin-crosslinked hemoglobin (DCLHB) vs. those who did not. Patients could receive up to a total of 3 units (750 ml and 75 g of Hgb) of DCLHB. There was no difference in the incidence of death between the two groups, but DCLHB patients had more and more significant (2 fold greater than control) adverse effects including hypertension, change in liver function test, pancreatic enzymes, and hematuria/hemoglobinuria. Nineteen percent of DCLHB patients did not require post operative transfusion while all of the active-controls did. However, there was no difference in the overall amount of transfused RBCs to the two groups of patients at the end of a week.

Several topics were not discussed in this study. There was no mention of intraoperative factors such as what anti-fibrinolytics were used as adjunctive therapy to limit transfusion, what the duration of bypass was, or the degree of cooling while on bypass. It would also be interesting to know if the speed of DCLHB infusion correlated with the development of a pressor response. The accompanying editorials to the study Lamy and colleagues work nicely review the progress in blood substitute or HBOC solutions, but can best be summarized by Dr. LevyÕs title, close but still so far [8,9]. In addition, Baxter Healthcare Corporation is no longer developing DCLHB for clinical use.

RBC transfusion therapy continues to evolve. The American Red Cross is projecting complete leukoreduction of all RBCs by the end of 2000. This potentially limits some of the deleterious effects of white blood cells on immune function and associated transfusion-related acute lung injury. The Red Cross has recently initiated nucleic acid testing of pooled red cells in an attempt to limit viral-transmitted disease. How rEPO and HBOC fit into the equation remains open to investigation. However, on-going studies in the critically ill and perioperative patient population will hopefully shed light on the appropriate use of this glycoprotein. More work needs to be done with HBOC and synthetic oxygen carrying solutions and the possibility of combining them with rEPO in select patients.

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