JBJS | Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Current Options and Approaches for Blood Management in Orthopaedic Surgery*†

The Journal of Bone & Joint Surgery, Volume 80, Issue 5

Instructional Course Lecture | May 01, 1998

Instructional Course Lectures, The American Academy of Orthopaedic Surgeons - Current Options and Approaches for Blood Management in Orthopaedic Surgery*†

E. MICHAEL KEATING, M.D.‡, MOORESVILLE, INDIANA

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*Printed with permission of the American Academy of Orthopaedic Surgeons. This article will appear in Instructional Course Lectures, Volume 48, American Academy of Orthopaedic Surgeons, Rosemont, Illinois, March 1999.

The Journal of Bone & Joint Surgery. 1998; 80:750-62

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Introduction

Although the implementation of blood-screening measures has vastly reduced the risk of transmission of the human immunodeficiency virus through transfusion of donated blood products, several factors preclude the blood supply from achieving a zero-risk status. Patients who receive perioperative allogenic blood transfusions, for instance, have been reported to have higher rates of infection^80,85,116 (although this finding remains controversial^37,120) and perioperative blood loss, longer hospital stays^26,40, more consecutive days of fever and administration of antibiotics, and a postoperative decrease in natural killer cells¹¹⁶. Furthermore, in a retrospective quantitative analysis of transfusion-associated immunomodulation, transfusion was the most important prognostic factor for postoperative infection¹³. Finally, the risk of transmission of infectious diseases, such as those caused by hepatitis-B and C viruses⁹⁹ and to a lesser extent cytomegalovirus²⁹ and Epstein-Barr virus¹²⁹, as well as the risk of transfusion reactions, alloimmunization, and immunomodulation, remains substantive. Optimization of blood management is thus as important today as it was a decade ago, despite the markedly improved safety of allogenic blood.

Cost-management pressures in the 1990s and continued public concern about the safety of the blood supply have precipitated a concerted movement among the operative specialties to refine the existing blood-conservation measures as well as to develop new approaches^67,110. These efforts have included development of transfusion practice standards; improvement in the techniques of operative hemostasis; perioperative blood salvage; promotion of preoperative autologous blood donation; and, more recently, development of blood substitutes or temporary oxygen carriers (currently under investigation)^11,28,101 and clinical utilization of recombinant human erythropoietin (epoetin alfa) to stimulate erythropoiesis (Table I)^{16,26,32,34,40,70,77,125}. These strategies and options, and their potential importance in orthopaedic procedures, are reviewed.

†Although the author has not received and will not receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this article, benefits have been or will be received but are directed solely to a research fund, foundation, educational institution, or other non-profit organization with which the author is associated. No funds were received in support of this study.

‡The Center for Hip and Knee Surgery, 1199 Hadley Road, Mooresville, Indiana 46158-1788.

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TABLE I CURRENT OPTIONS FOR BLOOD MANAGEMENT IN ORTHOPAEDIC PROCEDURES

Option	Comment
Transfusion practice standards	Lower transfusion triggers: hemoglobin concentration of less than seventy to eighty grams per liter.
Operative technique	Emphasis on maintaining careful operative technique. Modified operative technique (for example, modified approach). Hypotensive anesthesia has potential.
Topically or locally active agents	Thrombin, collagen, and fibrin glue. Antifibrinolytics (aprotinin, tranexamic acid, and ?-aminocaproic acid).
Blood salvage	Intraoperative and postoperative collection, processing, and transfusion of blood.
Preoperative autologous blood donation	Considered a standard of care in some orthopaedic procedures. Often used in conjunction with perioperative administration of epoetin alfa.
Perioperative administration of epoetin alfa	Increases reticulocyte count, red blood-cell production, hematocrit, and hemoglobin concentration. Facilitates preoperative autologous blood donation and reduces need for allogenic blood transfusion during elective orthopaedic procedures in patients who have a hemoglobin concentration of more than 100 to 130 grams per liter.

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TABLE I CURRENT OPTIONS FOR BLOOD MANAGEMENT IN ORTHOPAEDIC PROCEDURES

Option	Comment
Transfusion practice standards	Lower transfusion triggers: hemoglobin concentration of less than seventy to eighty grams per liter.
Operative technique	Emphasis on maintaining careful operative technique. Modified operative technique (for example, modified approach). Hypotensive anesthesia has potential.
Topically or locally active agents	Thrombin, collagen, and fibrin glue. Antifibrinolytics (aprotinin, tranexamic acid, and ?-aminocaproic acid).
Blood salvage	Intraoperative and postoperative collection, processing, and transfusion of blood.
Preoperative autologous blood donation	Considered a standard of care in some orthopaedic procedures. Often used in conjunction with perioperative administration of epoetin alfa.
Perioperative administration of epoetin alfa	Increases reticulocyte count, red blood-cell production, hematocrit, and hemoglobin concentration. Facilitates preoperative autologous blood donation and reduces need for allogenic blood transfusion during elective orthopaedic procedures in patients who have a hemoglobin concentration of more than 100 to 130 grams per liter.

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TABLE II INVESTIGATIONAL OPTIONS FOR BLOOD MANAGEMENT

Product	Type	Clinical Status	Indication
Oxygent (Alliance Pharmaceutical, San Diego, California)	Perfluorocarbon	Phase II	Hemodilution, cardiopulmonary bypass, cerebral hypoxia
PHP (pyridoxalated and conjugated hemoglobin) (Apex Bioscience, Research Triangle Park, North Carolina)	Human hemoglobin	Phase I/II	Septic shock
HemAssist (Baxter Healthcare, Deerfield, Illinois)	Human hemoglobin	Phase III	Trauma, operation, dialysis, stroke, shock
Hemopure (Biopure Pharmaceuticals, Cambridge, Massachusetts)	Bovine hemoglobin	Phase I/II	Operation, hemodilution, sickle-cell disease
PEG-Hemoglobin (Enzon, Piscataway, New Jersey)	Bovine hemoglobin	Phase II	Radiation-therapy sensitization
Oxyfluor (Hemagen/PFC, St. Louis, Missouri)	Perfluorocarbon	Phase II	Cardiopulmonary bypass
Hemolink (Hemosol, Etobicoke, Ontario, Canada)	Human hemoglobin	Phase II	Operation, hemodilution
PolyHeme (Northfield, Chicago, Illinois)	Human hemoglobin	Phase II/III	Trauma, operation
Optro (Somatogen, Boulder, Colorado)	Recombinant hemoglobin	Phase II	Hemodilution, erythropoiesis

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TABLE II INVESTIGATIONAL OPTIONS FOR BLOOD MANAGEMENT

Product	Type	Clinical Status	Indication
Oxygent (Alliance Pharmaceutical, San Diego, California)	Perfluorocarbon	Phase II	Hemodilution, cardiopulmonary bypass, cerebral hypoxia
PHP (pyridoxalated and conjugated hemoglobin) (Apex Bioscience, Research Triangle Park, North Carolina)	Human hemoglobin	Phase I/II	Septic shock
HemAssist (Baxter Healthcare, Deerfield, Illinois)	Human hemoglobin	Phase III	Trauma, operation, dialysis, stroke, shock
Hemopure (Biopure Pharmaceuticals, Cambridge, Massachusetts)	Bovine hemoglobin	Phase I/II	Operation, hemodilution, sickle-cell disease
PEG-Hemoglobin (Enzon, Piscataway, New Jersey)	Bovine hemoglobin	Phase II	Radiation-therapy sensitization
Oxyfluor (Hemagen/PFC, St. Louis, Missouri)	Perfluorocarbon	Phase II	Cardiopulmonary bypass
Hemolink (Hemosol, Etobicoke, Ontario, Canada)	Human hemoglobin	Phase II	Operation, hemodilution
PolyHeme (Northfield, Chicago, Illinois)	Human hemoglobin	Phase II/III	Trauma, operation
Optro (Somatogen, Boulder, Colorado)	Recombinant hemoglobin	Phase II	Hemodilution, erythropoiesis

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TABLE III EFFICACY OF EPOETIN ALFA IN MAJOR ORTHOPAEDIC PROCEDURES

Study	No. of Patients	Procedure	Treatment, Dose	Key Findings in Patients Managed with Epoetin Alfa
Cazenave et al.¹⁹ (1997)	80	Orthopaedic or cardiovascular	Epoetin alfa, 600 or 300 IU/kg of body weight intravenously, or placebo, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production
Tryba¹¹⁷ (1997)	125	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks. beginning 18 to 21 days preop.; iron intravenously	Increased reticulocyte count; increased predonation of =4 units of blood; reduced risk of exposure to allogenic blood
de Andrade et al.²⁶ (1996)	290	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count and hematocrit; reduced risk of exposure to allogenic blood
Faris et al.³⁴ (1996)	185	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count, hemoglobin concentration, and hematocrit; reduced risk of exposure to allogenic blood
Goldberg et al.⁴⁰ (1996)	140	Hip and knee arthroplasty	Epoetin alfa, 600 IU/kg of body weight subcutaneously for 4 doses beginning 21 days preop., or 300 IU/kg of body weight intravenously daily for 15 days beginning 10 days preop.; iron orally	Increased hemoglobin concentration from baseline to preop.; weekly subcutaneous regimen equivalent to daily intravenous regimen in terms of transfusion needs
Cazenave et al.¹⁸ (1995)	103	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related red blood-cell volume and production
Lefevre et al.⁷³ (1995)	112	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. beginning 11 to 13 days preop.; iron orally	Increased predonation of =4 units of blood; minimized decrease in hematocrit
Mercuriali et al.⁷⁶ (1995)	38	Total hip arthroplasty	Epoetin alfa, 300, 150, or 75 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production and in units donated
Price et al.⁹⁴ (1995)	102	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; reduced risk of exposure to allogenic blood
Tryba et al.¹¹⁸ (1995)	124	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight, or placebo, subcutaneously, x 2/wk. for 3 wks.; iron intravenously	Dose-related increase in red blood-cell volume and production and in units donated
Goodnough et al.⁴⁸ (1994)	116	Orthopaedic	Epoetin alfa, 600, 300, or 150 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased reticulocyte count and red blood-cell volume
Mercuriali et al.⁷⁸ (1994)	23	Total hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =2 units of blood; reduced risk of exposure to allogenic blood
Beris et al.¹⁰ (1993)	101	Orthopaedic	Epoetin alfa, 150 to 180 IU/kg of body weight, subcutaneously, 6 x in 3 wks., or placebo; iron orally	Increased reticulocyte count; minimized decrease in hemoglobin concentration
Canadian Orthopedic Perioperative Erythropoietin Study Group¹⁶ (1993)	198	Hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight daily for 14 days beginning 10 days preop.; placebo for 5 days, beginning 10 days preop., and then Epoetin alfa, 300 IU/kg of body weight, for next 9 days; or placebo	Dose-related increase in reticulocyte count and hemoglobin concentration; reduced risk of exposure to allogenic blood
Mercuriali et al.⁷⁷ (1993)	50	Total hip arthroplasty	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously	Increased predonation of blood; reduced risk of exposure to allogenic blood
Goodnough et al.⁴⁶ (1992)	44	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; increased red blood-cell production
Hochreiter et al.⁵⁴ (1992)	82	Total hip arthroplasty	Epoetin alfa, 200 or 100 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.	Increased predonation of blood by mildly anemic patients
Tasaki et al.¹¹² (1992)	25	Orthopaedic	Epoetin alfa, 9000, 6000, or 3000, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously daily x 2/wk.	Dose-related increase in red blood-cell volume
Graf et al.⁵⁰ (1990)	10	Total hip arthroplasty	Epoetin alfa, 150 to 200 IU/kg of body weight intravenously, x 3/wk. for 2 to 6 wks. (6 to 18 doses)	Predonation of a mean of 4.4 units of blood; no safety concerns
Goodnough et al.⁴⁹ (1989)	47	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Minimized decrease in hematocrit caused by phlebotomy; increased red blood-cell volume

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TABLE III EFFICACY OF EPOETIN ALFA IN MAJOR ORTHOPAEDIC PROCEDURES

Study	No. of Patients	Procedure	Treatment, Dose	Key Findings in Patients Managed with Epoetin Alfa
Cazenave et al.¹⁹ (1997)	80	Orthopaedic or cardiovascular	Epoetin alfa, 600 or 300 IU/kg of body weight intravenously, or placebo, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production
Tryba¹¹⁷ (1997)	125	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks. beginning 18 to 21 days preop.; iron intravenously	Increased reticulocyte count; increased predonation of =4 units of blood; reduced risk of exposure to allogenic blood
de Andrade et al.²⁶ (1996)	290	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count and hematocrit; reduced risk of exposure to allogenic blood
Faris et al.³⁴ (1996)	185	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count, hemoglobin concentration, and hematocrit; reduced risk of exposure to allogenic blood
Goldberg et al.⁴⁰ (1996)	140	Hip and knee arthroplasty	Epoetin alfa, 600 IU/kg of body weight subcutaneously for 4 doses beginning 21 days preop., or 300 IU/kg of body weight intravenously daily for 15 days beginning 10 days preop.; iron orally	Increased hemoglobin concentration from baseline to preop.; weekly subcutaneous regimen equivalent to daily intravenous regimen in terms of transfusion needs
Cazenave et al.¹⁸ (1995)	103	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related red blood-cell volume and production
Lefevre et al.⁷³ (1995)	112	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. beginning 11 to 13 days preop.; iron orally	Increased predonation of =4 units of blood; minimized decrease in hematocrit
Mercuriali et al.⁷⁶ (1995)	38	Total hip arthroplasty	Epoetin alfa, 300, 150, or 75 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production and in units donated
Price et al.⁹⁴ (1995)	102	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; reduced risk of exposure to allogenic blood
Tryba et al.¹¹⁸ (1995)	124	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight, or placebo, subcutaneously, x 2/wk. for 3 wks.; iron intravenously	Dose-related increase in red blood-cell volume and production and in units donated
Goodnough et al.⁴⁸ (1994)	116	Orthopaedic	Epoetin alfa, 600, 300, or 150 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased reticulocyte count and red blood-cell volume
Mercuriali et al.⁷⁸ (1994)	23	Total hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =2 units of blood; reduced risk of exposure to allogenic blood
Beris et al.¹⁰ (1993)	101	Orthopaedic	Epoetin alfa, 150 to 180 IU/kg of body weight, subcutaneously, 6 x in 3 wks., or placebo; iron orally	Increased reticulocyte count; minimized decrease in hemoglobin concentration
Canadian Orthopedic Perioperative Erythropoietin Study Group¹⁶ (1993)	198	Hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight daily for 14 days beginning 10 days preop.; placebo for 5 days, beginning 10 days preop., and then Epoetin alfa, 300 IU/kg of body weight, for next 9 days; or placebo	Dose-related increase in reticulocyte count and hemoglobin concentration; reduced risk of exposure to allogenic blood
Mercuriali et al.⁷⁷ (1993)	50	Total hip arthroplasty	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously	Increased predonation of blood; reduced risk of exposure to allogenic blood
Goodnough et al.⁴⁶ (1992)	44	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; increased red blood-cell production
Hochreiter et al.⁵⁴ (1992)	82	Total hip arthroplasty	Epoetin alfa, 200 or 100 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.	Increased predonation of blood by mildly anemic patients
Tasaki et al.¹¹² (1992)	25	Orthopaedic	Epoetin alfa, 9000, 6000, or 3000, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously daily x 2/wk.	Dose-related increase in red blood-cell volume
Graf et al.⁵⁰ (1990)	10	Total hip arthroplasty	Epoetin alfa, 150 to 200 IU/kg of body weight intravenously, x 3/wk. for 2 to 6 wks. (6 to 18 doses)	Predonation of a mean of 4.4 units of blood; no safety concerns
Goodnough et al.⁴⁹ (1989)	47	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Minimized decrease in hematocrit caused by phlebotomy; increased red blood-cell volume

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Fig. 1 Graph demonstrating the total oxygen-carrying capacity of 90 per cent (weight per volume) perflubron emulsion compared with that of whole blood, 20 per cent (weight per volume) perfluorodecalin, and plasma. The solubility of perfluorocarbons obeys Henry's law; therefore, perfluorocarbons are particularly effective oxygen carriers at higher ambient partial pressures of oxygen. (Reprinted, with permission, from: Keipert, P. E.; Faithfull, N. S.; Bradley, J. D.; Hazard, D. Y.; Hogan, J.; Levisetti, M. S.; and Peters, R.: Oxygen delivery augmentation by lowdose perfluorochemical emulsion during profound normovolemic hemodilution. In Oxygen Transport to Tissue XV, p. 203. Edited by P. Vaupel, R. Zander, and D. F. Bruley. New York, Plenum Press, 1994.)

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Fig. 2 Schematic overview showing the physiological effects of pharmacological doses of epoetin alfa. In the perioperative setting, epoetin alfa is administered two to three weeks preoperatively, to accelerate erythropoiesis, and once on the day of the operation, to increase both tissue oxygenation during the operation and the rate at which hemostasis is reestablished and the patient recovers after the procedure. PO = by mouth and IV = intravenous.

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Fig. 3 Graph demonstrating the prevalence of allogenic blood transfusion in orthopaedic patients who had a baseline hemoglobin concentration of more than 100 to 130 grams per liter. The patients received a placebo or epoetin alfa at a dose of 300 international units per kilogram of body weight daily for ten days before the procedure^16,26,34 or at a dose of 600 international units per kilogram of body weight once a week for three weeks (a total of four doses)⁴⁰. The p values denote the level of significance of the difference between the patients who were managed with epoetin alfa and those who received the placebo.

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Fig. 4 Chart summarizing the options for blood management in the orthopaedic setting. Measures that have been taken to eliminate patient exposure to the risks associated with allogenic blood transfusion include the development and promotion of transfusion standards, improvements in operative technique, autotransfusion of blood that has been salvaged perioperatively, use of antifibrinolytics to reduce blood loss, and perioperative administration of Epoetin alfa to accelerate erythropoiesis and the preoperative buildup of red blood-cell volume. Oxygen carriers, including those that are hemoglobin-based (HBOCs) and perfluorocarbons, are currently under investigation to determine their potential role in orthopaedic procedures. SC = subcutaneous.

Transfusion Practice Standards

Guidelines for blood management in orthopaedic procedures have been developed and promoted as a way to improve, in a cost-effective manner, the outcomes associated with perioperative loss of red blood cells (that is, to reduce patient exposure to allogenic blood transfusion)⁴². In general, the guidelines encourage and support good operative anesthetic and hemostatic technique, preoperative autologous blood donation, intraoperative and postoperative blood salvage, acute normovolemic hemodilution, unit-by-unit transfusion when blood is necessary, and pharmacological intervention with epoetin alfa when indicated. Allogenic blood transfusion should be limited on the basis of individual need. Despite the development of general blood-management guidelines related to the hemoglobin level and the hematocrit to trigger transfusion, the transfusion-triggering levels should be established for each patient on the basis of that patient's overall health^5,17.

One of the challenges in the implementation of transfusion practice standards is to change the way that surgeons approach transfusion or to change their behavior, or both. Changes in transfusion practice—for instance, the lowering of transfusion-triggering thresholds for well characterized physiological indicators such as the hemoglobin level or the hematocrit—have been suggested as a way to reduce the need for transfusion. Clinical data indicate that adequate tissue oxygenation is supported at hemoglobin concentrations of less than 100 grams per liter, the level previously considered an indicator for transfusion^{87,88,107,108,122}; these data provide a rationale for the tolerance of more perioperative blood loss without intervention with use of allogenic blood. Thus, although a hemoglobin level of 100 grams per liter is a transfusion trigger in patients with impaired cardiac function and in those with cardiopulmonary disease, the trigger is seventy to eighty grams per liter in otherwise healthy patients having orthopaedic procedures¹⁰⁷. However, surgeons generally recognize that the hemoglobin level alone is not a basis for transfusion and that multiple clinical factors should be assessed for each patient⁸⁶.

Blood Management in the Orthopaedic Setting

Operative Technique and Pharmacological Intervention

Surgeons should minimize blood loss by carefully maintaining operative hemostasis¹⁰⁷. Several operative techniques, including electrocautery, argon-beam coagulation, and use of topical agents, reduce blood loss safely and effectively^36,81,127. Furthermore, many orthopaedic procedures have been modified to reduce blood loss and to minimize the need for transfusion of allogenic blood^103,113. The application of hypotensive anesthesia is also gaining credibility as an option for blood management in the orthopaedic setting¹⁰⁴.

In addition to improvements in operative technique, several pharmacological options for blood management are available to orthopaedic surgeons or are under active investigation. Many topically or locally active agents, such as thrombin, collagen, and fibrin glue, may hold promise for the maintenance of perioperative hemostasis^69,107. Another class of pharmacological agents, the antifibrinolytics, includes promising agents such as aprotinin, tranexamic acid, ?-aminocaproic acid, and, to a lesser extent, desmopressin. The antifibrinolytics are administered intraoperatively or postoperatively, are generally safe, and are variably effective in reducing perioperative blood loss and the need for allogenic blood transfusion. The ?-aminocaproic acid is administered as an intravenous injection of ten grams, followed by infusion of two grams per hour for five hours; tranexamic acid, as an intravenous injection of ten milligrams per kilogram of body weight, followed by infusion of one milligram per kilogram of body weight per hour for ten hours; aprotinin, as an intravenous infusion of two million kallikrein inactivation units (a unit of measure referring to inhibition of kallikrein) over a twenty-minute period preoperatively, followed by infusion of 500,000 kallikrein inactivation units per hour intraoperatively; and desmopressin, as an intravenous infusion of 0.3 microgram per kilogram of body weight over a twenty-minute period.

Although its mechanism of action is still unknown, aprotinin is an antifibrinolytic agent that has been approved by the Food and Drug Administration to reduce blood loss in cardiopulmonary bypass procedures and it has recently been investigated for use in patients having major orthopaedic procedures^{52,62,74,84,91,119,128}. In the orthopaedic setting, aprotinin has been shown to be safe^52,62,84 and effective in reducing intraoperative blood loss^62,74, postoperative blood loss^62,119, and the need for allogenic blood transfusion^62,84. However, Hayes et al. found no effect of aprotinin on blood loss or transfusion requirements in patients having total hip replacement⁵².

Tranexamic acid is another promising antifibrinolytic agent. This agent, which is administered intravenously near the end of the operation, has been found to markedly reduce postoperative blood loss^7-9,53,56 and patient exposure to allogenic blood^9,53,56. No difference was found, in several studies, with regard to the prevalence of thrombolytic events in patients who had received tranexamic acid and those who had been given a placebo^9,53,56.

A third antifibrinolytic agent, ?-aminocaproic acid, is effective in reducing blood loss when it is administered before cardiac procedures^20,71,93. However, its use in the orthopaedic setting has not yet been investigated.

Several clinical studies have suggested that desmopressin is ineffective in reducing blood loss and the need for allogenic blood transfusion in the orthopaedic setting^63,98,114.

As a class of agents, the antifibrinolytics (aprotinin, tranexamic acid, and ?-aminocaproic acid) have an important role in the management of perioperative blood loss and exert no apparent adverse effect on the prevalence of thrombolytic events.

Blood Salvage

Despite numerous advances in operative technique and intraoperative pharmacological interventions, blood loss in orthopaedic procedures may be extensive^47,115. Intraoperative and postoperative blood salvage is a technique that is used to return washed or unwashed autologous blood to the patient, potentially reducing the need for allogenic blood transfusion. Blood-salvage devices that are currently in use or are under active investigation include the Cell Saver (Haemonetics, Braintree, Massachusetts), the ConstaVac Blood Conservation System (Stryker, Kalamazoo, Michigan), and Solcotrans Plus (Smith and Nephew Richards, Memphis, Tennessee). The lost blood is collected by aspiration or drainage and then is filtered, washed or unwashed (the Solcotrans Plus system does not wash the blood), and centrifuged before being transfused. The necessity of washing collected blood before autotransfusion has been questioned; however, filtering alone does not markedly reduce cytokine concentrations in the processed blood³. Intraoperative blood salvage can allow as much as 60 per cent of the red blood cells that are lost during the operative procedure to be recovered for subsequent autotransfusion¹⁰².

There also may be a large amount of blood drainage from the wound postoperatively—for example, after primary or revision joint arthroplasty. Postoperative blood salvage resulted in autotransfusion of approximately 437 milliliters after primary total hip procedures and 883 milliliters after primary total knee procedures; volumes of salvaged blood were as high as 946 milliliters^51,105. However, the cost-effectiveness of returning washed autologous blood to patients has been questioned because the technique requires an expensive device and technical expertise to operate it¹⁰⁶. In contrast, reinfusion of unwashed filtered autologous blood has been shown to be cost-effective in decreasing the need for allogenic blood transfusion³⁹. Ideally, unwashed autologous blood should be filtered and transfused within four hours after collection to avoid potential febrile reactions³⁵.

Both the safety and the efficacy of intraoperative and postoperative blood salvage have been documented in the orthopaedic setting^{6,39,45,51,59,105}. Blood salvage has reduced the need for allogenic blood transfusion in several orthopaedic procedures, including total hip and knee arthroplasty and bilateral total knee arthroplasty^6,51,59. Although blood salvage is safe and can provide a considerable volume of autologous blood, it does not decrease the need for allogenic blood transfusion in many orthopaedic procedures^59,75. Furthermore, the use of salvaged blood that is washed before autotransfusion may be too costly to be recommended as a standard practice. Blood salvage may be most effective in reducing the need for allogenic blood transfusion when it is used in conjunction with other blood-management options, particularly preoperative autologous blood donation^6,59,72.

Preoperative Autologous Blood Donation

Preoperative autologous blood donation is based on the premise that the patient's own blood is the safest blood. It decreases the need for allogenic blood transfusion in elective operative procedures in which a large amount of blood loss is expected^{22,27,86,111,123}, and it has become a standard of care as a blood-conservation strategy in some orthopaedic procedures^43,126. However, its usefulness may be limited in many patients because of preexisting medical conditions, such as anemia, advanced age, an unacceptable preoperative hematocrit and hemoglobin concentration, and a poor erythropoietic response to phlebotomy.

A poor erythropoietic response to phlebotomy has been observed by numerous investigators in patients who have donated autologous blood preoperatively^21,41,66. Kickler and Spivak noted that the degree of anemia caused by repeated phlebotomy was inadequate to increase erythropoietin production, resulting in the onset of mild anemia in most donors⁶⁶. A mathematical analysis used to examine the benefits and detriments of preoperative autologous blood donation showed that patients who donate blood preoperatively are more likely to need transfusion earlier and more frequently than are non-donating patients²¹. A prospective study of seventy-two consecutive patients who were scheduled to have an elective orthopaedic procedure demonstrated an inadequate erythropoietic response in thirty-three (58 per cent) of fifty-seven patients who had donated blood preoperatively⁴¹. This study and others^2,66 also demonstrated that a major portion of the donated units had red blood-cell volumes that were less than the minimum standards for blood donation. Preoperative autologous blood donation alone thus may not stimulate erythropoiesis sufficiently to meet the need for blood in orthopaedic procedures.

Another limitation to the successful implementation of a preoperative autologous blood-donation program is the high cost. Not only are there logistical obstacles, such as the collection, storage, and transfusion of the blood, but a high percentage of predonated autologous blood units are never used^4,30,97. Two studies revealed that approximately 50 per cent of predonated autologous blood units (no numbers were reported) are routinely wasted^30,83, and a rate of waste as high as 70 per cent (164 of 234 units) has been reported⁹⁷. Such waste reduces the cost-effectiveness of any preoperative autologous blood-donation program.

Acute Normovolemic Hemodilution

A proposed alternative to the high cost of preoperative autologous blood donation is acute normovolemic hemodilution, a blood-management technique in which whole blood is withdrawn preoperatively or intraoperatively and is isovolumetrically replaced with colloid or crystalloid solutions⁷⁹. Patients thus lose fewer red blood cells during procedures involving ongoing blood loss, and the collected units are held in reserve until the hemoglobin concentration or the hematocrit reaches a predetermined level or the patient demonstrates a physiological need for transfusion. Acute normovolemic hemodilution is contraindicated in patients who have coronary artery, renal, or pulmonary disease and in those who have severe hepatic disease²⁴.

Acute normovolemic hemodilution has been investigated in the orthopaedic setting, although only superficially. Of seventeen patients who had a total hip arthroplasty and were managed with hemodilution, seven required autologous blood compared with twelve of sixteen patients in the control group⁹⁰. The clinical safety and efficacy of acute normovolemic hemodilution for reducing the need for allogenic blood transfusion is under investigation; however, because of the short duration of many orthopaedic procedures and the precision with which the technique must be implemented, it may be impractical in many orthopaedic settings¹⁰². Nevertheless, there undoubtedly will be additional investigation of acute normovolemic hemodilution as a strategy for blood management in orthopaedic procedures.

Pharmacological Strategies for Blood Management

The rationale behind the use of pharmacological strategies for blood management includes a forecasted shortage of four million units of red blood cells by the year 2030¹²¹; the high cost of acquisition, screening, storage, transport, and administration of blood; the goal of elimination of transmission of disease^23,29,31, transfusion reactions, and suppression of normal immune function¹⁰⁰; preexisting medical conditions such as anemia; and inadequate erythropoietic response to phlebotomy^21,41,66. Thus, several temporary oxygen carriers and blood substitutes are now under investigation in phase-III clinical trials. Furthermore, epoetin alfa, administered perioperatively, has been shown to be safe and effective for treating anemia and decreasing patient exposure to allogenic blood transfusion^26,40.

Oxygen Carriers

The potential for oxygen carriers to temporarily increase oxygen delivery and tissue oxygenation during procedures associated with high blood loss, as well as for the treatment of conditions such as cerebral hypoxia, is compelling. However, numerous obstacles, including a short shelf-life, difficulty of use, side effects and the low concentrations that must be used to avoid them, and a short intravascular half-life, have slowed the emergence of oxygen carriers in the operative setting. Nevertheless, two classes of oxygen carriers—those that are hemoglobin-based and perfluorocarbons—have shown clinical potential (Table II). Both classes include agents that are currently under phase-II or phase-III clinical development.

Hemoglobin-Based Oxygen Carriers (Red Blood-Cell Substitutes)

Research involving hemoglobin-based oxygen carriers, as a class, has necessarily evolved from the initial investigation of free hemoglobin, which is nephrotoxic^1,14, to the study of structurally modified hemoglobin. Hemoglobin has been structurally modified in various ways, by cross-linking, polymerization, conjugation, lipid encapsulation, and genetic engineering³⁸, in an attempt to prevent nephrotoxicity and to circumvent other, unexpected deleterious biological interactions. However, many of these modified hemoglobins continue to elicit unexpected adverse effects, including fever, headache, chest and abdominal pain, and hypertension, in the clinical setting³⁸. Further modification of the hemoglobin molecule may reduce many of these side effects.

Numerous hemoglobin-based oxygen carriers have been developed and have been investigated in phase-I and phase-II clinical trials. Much of the preliminary data indicates that many of the limitations, with regard to biological safety, of previous hemoglobin-based oxygen-carrier formulations have been overcome⁹⁶. However, data demonstrating that these hemoglobin-based oxygen carriers support tissue oxygenation in humans as well as transfusion does are not yet available. In the next two to three years, data on safety and efficacy should emerge from phase-III trials of several hemoglobin-based oxygen carriers.

Temporary Oxygen Carriers (Perfluorocarbons)

As a class, perfluorocarbons are inert organic compounds that have an exceptionally high solubility for gases, including oxygen and carbon dioxide. The oxygen-carrying capacity of perfluorocarbons is directly proportional to the ambient partial pressure of oxygen³³. Unlike hemoglobin, which is saturated at oxygen partial pressures of 100 torr (13.3 kilopascals) (room air), perfluorocarbons can continue to load oxygen in a linear manner as oxygen partial pressure is increased. Thus, perfluorocarbons can carry more oxygen at a point where hemoglobin is already fully saturated with oxygen and can provide no additional benefit (Fig. 1)⁶⁵.

Of the perfluorocarbons that are under investigation, only perfluorodecalin, a first-generation perfluorocarbon, has been approved by the Food and Drug Administration for use in humans having percutaneous transluminal coronary angioplasty. However, broad-based acceptance of perfluorodecalin as a temporary oxygen carrier has not occurred because of several limitations, including difficulty of use, limited oxygen-carrying capacity (only seven volumes per cent of oxygen at an ambient partial pressure of oxygen of 760 millimeters of mercury [101.31 kilopascals]), long retention in the reticuloendothelial system, complement activation, and temperature instability^12,55,57,95. As a result of these disadvantages, perfluorodecalin has been removed from the market.

In 1986, a change in the manufacturing process allowed the production of more stable, highly concentrated perfluorocarbons that exhibited a higher oxygen-carrying capacity. These new perfluorocarbons were termed second generation to distinguish them from the first-generation products, which also were associated with numerous side effects.

Perflubron emulsion (Oxygent; Alliance Pharmaceutical, San Diego, California), a second-generation perfluorocarbon, lacks many of the limitations observed with the first-generation agents. It is stable at room temperature, is highly concentrated, and appears to be well tolerated by humans⁶⁴. This agent is currently under investigation in phase-II trials. The enhancement of oxygen delivery by synthetic perfluorocarbon emulsions gives these agents a wide range of potential clinical applications as temporary oxygen carriers in orthopaedic surgery; these uses include support of tissue oxygenation during ongoing blood loss and avoidance of the need for allogenic blood transfusion.

Epoetin Alfa

Recombinant human erythropoietin (epoetin alfa), a secretory glycoprotein of 165 amino acids that is identical in sequence to endogenous human urinary erythropoietin¹⁰⁹, is indicated for facilitating preoperative autologous blood donation by anemic patients (those with a hemoglobin level between more than 100 and 130 grams per liter) who are scheduled to have a major elective operation. The physiological implications of epoetin alfa-accelerated erythropoiesis include improved tissue oxygenation and reduced need for allogenic blood transfusion, secondary to increased concentrations of hemoglobin. Each gram per deciliter increase of blood hemoglobin concentration results in an increase in oxygen-carrying capacity of approximately 1.39 milliliters of oxygen per deciliter¹²⁴ and a decrease in the need for allogenic blood transfusion of approximately 15 per cent (no numbers were reported)^16,34. Epoetin alfa is ideal for procedures in which a large amount of blood loss and associated tissue hypoxia are expected.

Patients having orthopaedic procedures may require as many as four to six units of blood perioperatively^44,47,115. The effectiveness of perioperative use of epoetin alfa in stimulating erythropoiesis in these patients has been established in clinical studies (Table III)^{10,16,18,19,26,34,40,46,48-50,54,73,76-78,94,112,117,118}. The preoperative administration of epoetin alfa was found to increase the preoperative hemoglobin concentration^16,26,34,40, hematocrit^{26,34,48,49,117}, and reticulocyte count^{16,26,34,48,49,77,117} (Fig. 2). It also was found to facilitate preoperative autologous blood donation by patients who were scheduled to have an elective orthopaedic procedure^{18,19,46,48-50,54,73,76-78,94}.

In several large clinical studies, perioperative use of epoetin alfa (without preoperative autologous blood donation) markedly decreased the requirements for allogenic blood transfusion compared with those for the placebo group, and it was particularly effective in patients who had hemoglobin concentrations of more than 100 to 130 grams per liter (Fig. 3)^16,26,34,40. As many as 78 per cent (twenty-one) of twenty-seven anemic patients who had received a placebo required a transfusion³⁴ compared with only 14 per cent (three of twenty-one) to 32 per cent (eight of twenty-five) of the patients who were managed with epoetin alfa at daily doses of 300 international units per kilogram of body weight^16,26,34,40. The need for allogenic blood transfusion was similarly reduced in patients who were managed with a weekly regimen of 600 international units of epoetin alfa per kilogram of body weight, for a total of four doses, beginning three weeks preoperatively compared with those who were managed with a daily regimen of 300 international units per kilogram of body weight for fifteen days, beginning ten days before the operation⁴⁰.

Epoetin alfa is well tolerated by orthopaedic patients and has an adverse-event profile similar to that of a placebo. Because Epoetin alfa-accelerated erythropoiesis increases red blood-cell mass and blood viscosity, clinicians have been particularly concerned about the potential for deep venous thrombosis. However, in several major clinical studies, the prevalence of deep venous thrombosis in patients who had been managed with epoetin alfa was similar to that in patients who had received a placebo^16,26,34; it also was similar to the range of prevalences of deep venous thrombosis (3 per cent [six] of 203 patients⁶⁸ to 37 per cent [231] of 617 patients⁵⁸) reported in the literature^{15,25,60,61,82,89,92}.

Overview

In summary, the ultimate goal of blood management by orthopaedic surgeons is to eliminate the need for allogenic blood transfusion. Despite numerous important advances in operative procedures, including changes in transfusion practices, improvements in operative technique, and the use of intraoperative and postoperative blood salvage, patients still receive transfusions of allogenic blood. The risks associated with such transfusions are well known. Because approximately two-thirds of blood transfusions in the United States are related to operative procedures, all clinicians working in the orthopaedic setting should be aware of the blood-conservation strategies that are currently available and should be cognizant of the potentially clinically relevant agents that are under development. These pharmaceutical agents include hemoglobin-based oxygen carriers and second-generation perfluorocarbons. To date, however, epoetin alfa is the only agent available for the treatment of perioperative anemia. Besides being a powerful tool for the clinical management of this condition, it also reduces the need for allogenic blood transfusion.

Blood management has advanced to the point where the need for allogenic blood transfusion can be eliminated or markedly reduced (Fig. 4). In the operative setting, it is likely that combinations of blood-management options will be employed to make the possibility of allogenic blood transfusion remote. The relative cost-effectiveness of these options, used either alone or in conjunction with other techniques, is a subject of ongoing investigation and debate.

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TABLE I CURRENT OPTIONS FOR BLOOD MANAGEMENT IN ORTHOPAEDIC PROCEDURES

Option	Comment
Transfusion practice standards	Lower transfusion triggers: hemoglobin concentration of less than seventy to eighty grams per liter.
Operative technique	Emphasis on maintaining careful operative technique. Modified operative technique (for example, modified approach). Hypotensive anesthesia has potential.
Topically or locally active agents	Thrombin, collagen, and fibrin glue. Antifibrinolytics (aprotinin, tranexamic acid, and ?-aminocaproic acid).
Blood salvage	Intraoperative and postoperative collection, processing, and transfusion of blood.
Preoperative autologous blood donation	Considered a standard of care in some orthopaedic procedures. Often used in conjunction with perioperative administration of epoetin alfa.
Perioperative administration of epoetin alfa	Increases reticulocyte count, red blood-cell production, hematocrit, and hemoglobin concentration. Facilitates preoperative autologous blood donation and reduces need for allogenic blood transfusion during elective orthopaedic procedures in patients who have a hemoglobin concentration of more than 100 to 130 grams per liter.

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TABLE I CURRENT OPTIONS FOR BLOOD MANAGEMENT IN ORTHOPAEDIC PROCEDURES

Option	Comment
Transfusion practice standards	Lower transfusion triggers: hemoglobin concentration of less than seventy to eighty grams per liter.
Operative technique	Emphasis on maintaining careful operative technique. Modified operative technique (for example, modified approach). Hypotensive anesthesia has potential.
Topically or locally active agents	Thrombin, collagen, and fibrin glue. Antifibrinolytics (aprotinin, tranexamic acid, and ?-aminocaproic acid).
Blood salvage	Intraoperative and postoperative collection, processing, and transfusion of blood.
Preoperative autologous blood donation	Considered a standard of care in some orthopaedic procedures. Often used in conjunction with perioperative administration of epoetin alfa.
Perioperative administration of epoetin alfa	Increases reticulocyte count, red blood-cell production, hematocrit, and hemoglobin concentration. Facilitates preoperative autologous blood donation and reduces need for allogenic blood transfusion during elective orthopaedic procedures in patients who have a hemoglobin concentration of more than 100 to 130 grams per liter.

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TABLE II INVESTIGATIONAL OPTIONS FOR BLOOD MANAGEMENT

Product	Type	Clinical Status	Indication
Oxygent (Alliance Pharmaceutical, San Diego, California)	Perfluorocarbon	Phase II	Hemodilution, cardiopulmonary bypass, cerebral hypoxia
PHP (pyridoxalated and conjugated hemoglobin) (Apex Bioscience, Research Triangle Park, North Carolina)	Human hemoglobin	Phase I/II	Septic shock
HemAssist (Baxter Healthcare, Deerfield, Illinois)	Human hemoglobin	Phase III	Trauma, operation, dialysis, stroke, shock
Hemopure (Biopure Pharmaceuticals, Cambridge, Massachusetts)	Bovine hemoglobin	Phase I/II	Operation, hemodilution, sickle-cell disease
PEG-Hemoglobin (Enzon, Piscataway, New Jersey)	Bovine hemoglobin	Phase II	Radiation-therapy sensitization
Oxyfluor (Hemagen/PFC, St. Louis, Missouri)	Perfluorocarbon	Phase II	Cardiopulmonary bypass
Hemolink (Hemosol, Etobicoke, Ontario, Canada)	Human hemoglobin	Phase II	Operation, hemodilution
PolyHeme (Northfield, Chicago, Illinois)	Human hemoglobin	Phase II/III	Trauma, operation
Optro (Somatogen, Boulder, Colorado)	Recombinant hemoglobin	Phase II	Hemodilution, erythropoiesis

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TABLE II INVESTIGATIONAL OPTIONS FOR BLOOD MANAGEMENT

Product	Type	Clinical Status	Indication
Oxygent (Alliance Pharmaceutical, San Diego, California)	Perfluorocarbon	Phase II	Hemodilution, cardiopulmonary bypass, cerebral hypoxia
PHP (pyridoxalated and conjugated hemoglobin) (Apex Bioscience, Research Triangle Park, North Carolina)	Human hemoglobin	Phase I/II	Septic shock
HemAssist (Baxter Healthcare, Deerfield, Illinois)	Human hemoglobin	Phase III	Trauma, operation, dialysis, stroke, shock
Hemopure (Biopure Pharmaceuticals, Cambridge, Massachusetts)	Bovine hemoglobin	Phase I/II	Operation, hemodilution, sickle-cell disease
PEG-Hemoglobin (Enzon, Piscataway, New Jersey)	Bovine hemoglobin	Phase II	Radiation-therapy sensitization
Oxyfluor (Hemagen/PFC, St. Louis, Missouri)	Perfluorocarbon	Phase II	Cardiopulmonary bypass
Hemolink (Hemosol, Etobicoke, Ontario, Canada)	Human hemoglobin	Phase II	Operation, hemodilution
PolyHeme (Northfield, Chicago, Illinois)	Human hemoglobin	Phase II/III	Trauma, operation
Optro (Somatogen, Boulder, Colorado)	Recombinant hemoglobin	Phase II	Hemodilution, erythropoiesis

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TABLE III EFFICACY OF EPOETIN ALFA IN MAJOR ORTHOPAEDIC PROCEDURES

Study	No. of Patients	Procedure	Treatment, Dose	Key Findings in Patients Managed with Epoetin Alfa
Cazenave et al.¹⁹ (1997)	80	Orthopaedic or cardiovascular	Epoetin alfa, 600 or 300 IU/kg of body weight intravenously, or placebo, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production
Tryba¹¹⁷ (1997)	125	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks. beginning 18 to 21 days preop.; iron intravenously	Increased reticulocyte count; increased predonation of =4 units of blood; reduced risk of exposure to allogenic blood
de Andrade et al.²⁶ (1996)	290	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count and hematocrit; reduced risk of exposure to allogenic blood
Faris et al.³⁴ (1996)	185	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count, hemoglobin concentration, and hematocrit; reduced risk of exposure to allogenic blood
Goldberg et al.⁴⁰ (1996)	140	Hip and knee arthroplasty	Epoetin alfa, 600 IU/kg of body weight subcutaneously for 4 doses beginning 21 days preop., or 300 IU/kg of body weight intravenously daily for 15 days beginning 10 days preop.; iron orally	Increased hemoglobin concentration from baseline to preop.; weekly subcutaneous regimen equivalent to daily intravenous regimen in terms of transfusion needs
Cazenave et al.¹⁸ (1995)	103	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related red blood-cell volume and production
Lefevre et al.⁷³ (1995)	112	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. beginning 11 to 13 days preop.; iron orally	Increased predonation of =4 units of blood; minimized decrease in hematocrit
Mercuriali et al.⁷⁶ (1995)	38	Total hip arthroplasty	Epoetin alfa, 300, 150, or 75 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production and in units donated
Price et al.⁹⁴ (1995)	102	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; reduced risk of exposure to allogenic blood
Tryba et al.¹¹⁸ (1995)	124	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight, or placebo, subcutaneously, x 2/wk. for 3 wks.; iron intravenously	Dose-related increase in red blood-cell volume and production and in units donated
Goodnough et al.⁴⁸ (1994)	116	Orthopaedic	Epoetin alfa, 600, 300, or 150 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased reticulocyte count and red blood-cell volume
Mercuriali et al.⁷⁸ (1994)	23	Total hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =2 units of blood; reduced risk of exposure to allogenic blood
Beris et al.¹⁰ (1993)	101	Orthopaedic	Epoetin alfa, 150 to 180 IU/kg of body weight, subcutaneously, 6 x in 3 wks., or placebo; iron orally	Increased reticulocyte count; minimized decrease in hemoglobin concentration
Canadian Orthopedic Perioperative Erythropoietin Study Group¹⁶ (1993)	198	Hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight daily for 14 days beginning 10 days preop.; placebo for 5 days, beginning 10 days preop., and then Epoetin alfa, 300 IU/kg of body weight, for next 9 days; or placebo	Dose-related increase in reticulocyte count and hemoglobin concentration; reduced risk of exposure to allogenic blood
Mercuriali et al.⁷⁷ (1993)	50	Total hip arthroplasty	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously	Increased predonation of blood; reduced risk of exposure to allogenic blood
Goodnough et al.⁴⁶ (1992)	44	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; increased red blood-cell production
Hochreiter et al.⁵⁴ (1992)	82	Total hip arthroplasty	Epoetin alfa, 200 or 100 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.	Increased predonation of blood by mildly anemic patients
Tasaki et al.¹¹² (1992)	25	Orthopaedic	Epoetin alfa, 9000, 6000, or 3000, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously daily x 2/wk.	Dose-related increase in red blood-cell volume
Graf et al.⁵⁰ (1990)	10	Total hip arthroplasty	Epoetin alfa, 150 to 200 IU/kg of body weight intravenously, x 3/wk. for 2 to 6 wks. (6 to 18 doses)	Predonation of a mean of 4.4 units of blood; no safety concerns
Goodnough et al.⁴⁹ (1989)	47	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Minimized decrease in hematocrit caused by phlebotomy; increased red blood-cell volume

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TABLE III EFFICACY OF EPOETIN ALFA IN MAJOR ORTHOPAEDIC PROCEDURES

Study	No. of Patients	Procedure	Treatment, Dose	Key Findings in Patients Managed with Epoetin Alfa
Cazenave et al.¹⁹ (1997)	80	Orthopaedic or cardiovascular	Epoetin alfa, 600 or 300 IU/kg of body weight intravenously, or placebo, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production
Tryba¹¹⁷ (1997)	125	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks. beginning 18 to 21 days preop.; iron intravenously	Increased reticulocyte count; increased predonation of =4 units of blood; reduced risk of exposure to allogenic blood
de Andrade et al.²⁶ (1996)	290	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count and hematocrit; reduced risk of exposure to allogenic blood
Faris et al.³⁴ (1996)	185	Hip and knee arthroplasty	Epoetin alfa, 300 or 100 IU/kg of body weight subcutaneously, or placebo, daily for 15 days beginning 10 days preop.; iron orally	Dose-related increase in reticulocyte count, hemoglobin concentration, and hematocrit; reduced risk of exposure to allogenic blood
Goldberg et al.⁴⁰ (1996)	140	Hip and knee arthroplasty	Epoetin alfa, 600 IU/kg of body weight subcutaneously for 4 doses beginning 21 days preop., or 300 IU/kg of body weight intravenously daily for 15 days beginning 10 days preop.; iron orally	Increased hemoglobin concentration from baseline to preop.; weekly subcutaneous regimen equivalent to daily intravenous regimen in terms of transfusion needs
Cazenave et al.¹⁸ (1995)	103	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. for 1 wk. beginning 18 to 21 days preop.; iron orally	Increased predonation of =4 units of blood; dose-related red blood-cell volume and production
Lefevre et al.⁷³ (1995)	112	Orthopaedic or vascular	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 3/wk. beginning 11 to 13 days preop.; iron orally	Increased predonation of =4 units of blood; minimized decrease in hematocrit
Mercuriali et al.⁷⁶ (1995)	38	Total hip arthroplasty	Epoetin alfa, 300, 150, or 75 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =4 units of blood; dose-related increase in red blood-cell volume and production and in units donated
Price et al.⁹⁴ (1995)	102	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight intravenously, or placebo, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; reduced risk of exposure to allogenic blood
Tryba et al.¹¹⁸ (1995)	124	Orthopaedic	Epoetin alfa, 150, 100, or 50 IU/kg of body weight, or placebo, subcutaneously, x 2/wk. for 3 wks.; iron intravenously	Dose-related increase in red blood-cell volume and production and in units donated
Goodnough et al.⁴⁸ (1994)	116	Orthopaedic	Epoetin alfa, 600, 300, or 150 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased reticulocyte count and red blood-cell volume
Mercuriali et al.⁷⁸ (1994)	23	Total hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron intravenously	Increased predonation of =2 units of blood; reduced risk of exposure to allogenic blood
Beris et al.¹⁰ (1993)	101	Orthopaedic	Epoetin alfa, 150 to 180 IU/kg of body weight, subcutaneously, 6 x in 3 wks., or placebo; iron orally	Increased reticulocyte count; minimized decrease in hemoglobin concentration
Canadian Orthopedic Perioperative Erythropoietin Study Group¹⁶ (1993)	198	Hip arthroplasty	Epoetin alfa, 300 IU/kg of body weight daily for 14 days beginning 10 days preop.; placebo for 5 days, beginning 10 days preop., and then Epoetin alfa, 300 IU/kg of body weight, for next 9 days; or placebo	Dose-related increase in reticulocyte count and hemoglobin concentration; reduced risk of exposure to allogenic blood
Mercuriali et al.⁷⁷ (1993)	50	Total hip arthroplasty	Epoetin alfa, 600 or 300 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously	Increased predonation of blood; reduced risk of exposure to allogenic blood
Goodnough et al.⁴⁶ (1992)	44	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Increased predonation of blood; increased red blood-cell production
Hochreiter et al.⁵⁴ (1992)	82	Total hip arthroplasty	Epoetin alfa, 200 or 100 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.	Increased predonation of blood by mildly anemic patients
Tasaki et al.¹¹² (1992)	25	Orthopaedic	Epoetin alfa, 9000, 6000, or 3000, intravenously, x 2/wk. for 3 wks.; iron orally and intravenously daily x 2/wk.	Dose-related increase in red blood-cell volume
Graf et al.⁵⁰ (1990)	10	Total hip arthroplasty	Epoetin alfa, 150 to 200 IU/kg of body weight intravenously, x 3/wk. for 2 to 6 wks. (6 to 18 doses)	Predonation of a mean of 4.4 units of blood; no safety concerns
Goodnough et al.⁴⁹ (1989)	47	Orthopaedic	Epoetin alfa, 600 IU/kg of body weight, or placebo, intravenously, x 2/wk. for 3 wks.; iron orally	Minimized decrease in hematocrit caused by phlebotomy; increased red blood-cell volume