Commentary & Perspective

Commentary & Perspective on
"Preoperative Use of Recombinant Human Erythropoietin Before Total Joint Arthroplasty"
by Hari P. Bezwada, MD, et al.

Commentary & Perspective by
Clifford W. Colwell Jr, MD*,
Center for Orthopaedic Research and Education, Scripps Clinic, La Jolla, California

With the advancing age of the American population and the technology now available for orthopaedic procedures, blood-management techniques that make use of hard end points for both efficacy and safety are necessary. Currently, more than fourteen million units of blood are collected annually and administered to more than 3.5 million patients in the United States¹. The decision-making process is influenced by the criteria for blood transfusions and the dangers inherent with their use. Approximately 60% of the allogeneic blood and virtually all of the autologous blood transfusions are administered in the perioperative period. A great number of those transfusions are given following orthopaedic procedures. The three major risks of blood transfusions are acute hemolytic transfusion reaction, transmission of disease, and immunosuppression. These risks remain a moving target, as tests are now available for identification of patients with HIV or hepatitis C. A tenfold increase in autologous blood donations has occurred since 1980². In many instances, the use of autologous donation technology is overexploited and lacks cost effectiveness.

The present paper is another of many recent articles that deal with the first genetically engineered drug used in orthopaedic surgery, recombinant human erythropoietin in total joint arthroplasty^3-7. The theory of regulation of erythropoietin production dates back to the late nineteenth century, when it was observed that the stimulant for increased red cell mass was hypoxia. In 1943, Krumdieck demonstrated the erythropoietin factor in serum⁸. Early work established that the protein was made predominantly in the liver before birth and in the kidney thereafter, although it is possible that erythropoietin may be produced in other organs. The methodology for producing recombinant human erythropoietin was approved in Japan, Europe, and Canada in the early 1990s and in the United States in 1996. Early trials provided additional information with relevance to efficacy, safety, and dose scheduling. More recent literature has evaluated smaller doses given over a shorter period of time as a way of minimizing cost while maximizing efficacy.

The present manuscript evaluates the use of recombinant human erythropoietin in total hip and total knee arthroplasty, dividing the groups into unilateral, bilateral, and revision arthroplasties. One group was treated with erythropoietin and preoperative autologous donation, a second group was treated with erythropoietin alone, and a third group was treated with preoperative autologous donation alone. The strengths of the article are in the large number of patients recruited over a short period of time in a single center with an excellent reputation for surgical outcomes. Erythropoietin was administered twenty-one days, fourteen days, seven days, and one day prior to surgery. Patients receiving erythropoietin also received a single dose of 100 mg of intravenous iron dextran at the time of the initial erythropoietin dose followed by oral supplementation with iron sulfate (325 mg, twice daily). In the autologous donation group, patients were asked to donate one unit for primary arthroplasty and two units for either bilateral or revision arthroplasty and received oral supplementation with iron sulfate (325 mg, three times daily). Patients with an initial hemoglobin level that was greater than 140 g/L were excluded from the study. Baseline hemoglobin levels were different in the three groups; the group that received erythropoietin alone had statistically lower hemoglobin levels than either the group that received autologous donation alone or the group that received autologous donation with erythropoietin. Overall, the group that received a combination of erythropoietin with perioperative autologous blood donation appeared to be the most effective in reducing allogeneic blood exposure, with a transfusion rate of 11% as opposed to a rate of 28% in the group that received erythropoietin alone and 33% in the group that received autologous donation alone.

The authors recognize that their study is limited because it is a consecutive series rather than a prospective randomized series and also because only the surgeon was blinded to treatment. Six different types of operations were tracked with three different perioperative blood strategies, and thus the numbers within each subset of patients are small. Despite these limitations, a statistical significance still existed with autologous donation plus erythropoietin, and significantly better results were seen when allogeneic transfusions were used as the common end point.

A number of questions remain unanswered with respect to this technology: Is it necessary to give four preoperative doses? Does the drug, in fact, work more effectively in patients whose hemoglobin levels are close to 14 g/dL as opposed to those whose levels are at 10 to 11 g/dL? Other areas that need additional study include cost-effectiveness and the ease with which patients can obtain the necessary injections. Although other techniques are presently available to decrease the need for transfusions, particularly in primary procedures, the use of erythropoietin is one more tool the surgeon can use in perioperative blood management.

*The authors did not receive grants or outside funding in support of their research or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

References

1. American Association of Blood Banks. Blood banking community comes close to meeting collection goals for January 2003; nation's citizens urged to continue giving "Gift of Life." February 25, 2003. www.aabb.org/pressroom/press_releases/pr022503.htm.
2. American Association of Blood Banks. Preoperative autologous donation: Overexploited? Cost-effective? Peer to Peer 1994;6:2-4.
3. Effectiveness of perioperative recombinant human erythropoietin in elective hip replacement. Canadian Orthopedic Perioperative Erythropoietin Study Group. Lancet. 1993;341:1227-32.
4. Faris PM, Ritter MA, Abels RI. The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation. The American Erythropoietin Study Group. J Bone Joint Surg Am. 1996;78:62-72.
5. Goodnough LT. Clinical application of recombinant erythropoietin in the perioperative period. Hematol Oncol Clin North Am. 1994;8:1011-20.
6. Goodnough LT, Monk TG. Erythropoietin therapy in the perioperative setting. Clin Orthop. 1998;357:82-8.
7. Lee JH, Lee SH, Oh JH. Minimal effective dosage of recombinant human erythropoietin in spinal surgery. Clin Orthop. 2003;412:71-6.
8. Porter DL, Goldberg MA. Regulation of erythropoietin production. Exper Hematol. 1993;21:399-404.