Volume 8 Supplement 2

Anemia in Critical Care: Etiology, Treatment and Prevention

Open Access

Preoperative recombinant human erythropoietin in anemic surgical patients

Critical Care20048(Suppl 2):S45

https://doi.org/10.1186/cc2824

Published: 14 June 2004

Abstract

Preoperative anemia in a surgical patient predisposes to poor outcomes and allogeneic blood transfusions. As an alternative to transfusions, pharmacologic management of preoperative anemia with recombinant human erythropoietin (rHuEPO) has been well studied in many different types of surgery. rHuEPO, when used alone or in combination with preoperative autologous blood donation before elective surgery, stimulates erythropoiesis and helps to avoid or reduce the need for allogeneic blood transfusions. The clinical evidence on preoperative use of rHuEPO in orthopedic, cardiac, and cancer surgery, as well as in bloodless surgery, is reviewed.

Keywords

allogeneic blood transfusionsanemiarecombinant human erythropoietinsurgical patients

Anemia, which can be defined as hemoglobin less than 13 g/dl or hematocrit less than 36%, is a relatively common preoperative finding. Approximately one third of patients are anemic before they undergo joint arthroplasty, with baseline hemoglobin levels between 10 and 13 g/dl [1]. In veterans undergoing noncardiac surgery, the incidence of preoperative anemia (hematocrit <36%) was 34% [2], and in surgical patients who refused transfusions because of religious reasons, 28% had preoperative hemoglobin levels less than 12 g/dl [3]. The incidence of anemia also increases with age [4]. In a recent study of 296 elderly patients with hip fractures, the mean hemoglobin on hospital admission was 12.1 ± 1.7 g/dl [5]. Anemia is especially prevalent in patients with cancer, and treatment plans often include surgery. A low initial hemoglobin level measured at disease presentation is a risk factor for further development of anemia throughout the course of treatment. In patients with colorectal cancer the incidence of preoperative anemia was 46% [3]. Following radical mastectomy for breast cancer, 38% of women were anemic (hemoglobin <12 g/dl) before their first chemotherapy cycle, and 59% became anemic after surgery and chemotherapy [6].

Ensuring adequate tissue oxygenation in the surgical setting frequently involves the administration of blood transfusions. Patients with preoperative hemoglobin levels between 10 and 13 g/dl may be three or more times as likely to receive allogeneic blood than those with baseline hemoglobin greater than 14 g/dl [7]. Although it has been documented that patients prefer to receive autologous blood [8], those who are anemic before surgery are not candidates for preoperative autologous donation (PAD). Patients with coronary artery disease have impaired hemodynamic and nonhemodynamic responses to hypoxia, and autologous blood donation is not feasible because the hemodilution that ensues may not be tolerated [9]. Endogenous erythropoietin normally stimulates the bone marrow to increase red blood cell (RBC) mass under hypoxic conditions, but if this nonhemodynamic response to hypoxia is impaired then hemoglobin levels do not rebound sufficiently. If hemoglobin levels fall even further during surgery due to blood losses, as commonly occurs, the likelihood of receiving an allogeneic blood transfusion increases [10]. RBC transfusions are associated with an increased risk for postoperative infections [11] and tumor recurrence [12], as well as with a variety of immunologic complications [13] that may adversely affect surgical patients. Longer hospital stays and higher health care costs have also been linked to blood transfusions [14].

Although allogeneic blood is now reportedly safer than ever [15], safety issues with the blood supply still exist [16]. Furthermore, blood is a scarce resource that is becoming even more so. As the 'baby boomer' population ages, two factors are converging that will limit blood availability and drive up its cost. First, the eligible donor pool is shrinking and, second, surgery in these patients, whether elective or otherwise, is on the increase. Because of these quality-of-care and economic factors, the decision to transfuse should be carefully weighed by all members of the surgical team, and transfusion alternatives considered.

The importance of correcting preoperative anemia cannot be overemphasized because this condition is known to be associated with poor outcomes after surgery. Coronary artery disease patients with anemia exhibit higher mortality rates and experience more cardiac, abdominal, and renal complications after cardiac or noncardiac surgery than do patients with normal hemoglobin levels [9]. Myocardial ischemia is one of the major complications that occur in anemic patients without overt cardiac disease. In elderly men undergoing radical prostatectomy, ST-segment changes and postoperative ischemic episodes were seen more frequently in those with lower hematocrit [17]. In another study of noncardiac surgical patients of various types comprising a large Veterans Administration database, perioperative anemia and blood transfusions were associated with an increased risk for infection, higher mortality rates, and substantial consumption of health care resources [2]. Dunne and coworkers [18] recently documented a relationship between preoperative anemia and stage of colorectal cancer at diagnosis, and a study of 198 patients with rectal cancer [19] showed that low preoperative hemoglobin levels were an independent risk factor for mortality (P < 0.0001). Taken together, these reports indicate that preoperative anemia is prevalent, that anemia and blood transfusions are associated with risks and poor outcomes, and that anemia should be treated, preferably with strategies that exclude allogeneic blood.

The human recombinant form of endogenous erythropoietin (rHuEPO; epoetin alfa) is indicated for the treatment of anemic patients who are scheduled to undergo elective surgery (noncardiac and nonvascular) to reduce the need for allogeneic blood transfusions [20]. Multiple clinical studies involving many different surgical types have shown that preoperative rHuEPO is safe and effective. Patients with initial hematocrits between 33% and 39% and who stand to lose up to 3000 ml blood during surgery are among those who can benefit the most [2123]. Less benefit can be expected in patients with relatively normal preoperative hemoglobin levels [24].

The positive impact of rHuEPO is readily apparent in patients undergoing orthopedic surgery, which is often elective and associated with substantial blood losses [25]. Oral iron supplementation and treatment with rHuEPO should be considered in any anemic patient (hemoglobin >10 and ≤ 13 g/dl) whose risk for transfusion is estimated to exceed 10% [7]. Patients undergoing major orthopedic surgery who received rHuEPO 300 units/kg per day for 10 days preoperatively, on the day of surgery, and 4 days postoperatively had a nearly six-fold reduction in allogeneic transfusion risk as compared with patients who received placebo [1, 26]. In another study that compared rHuEPO administered daily (300 units/kg per day) with rHuEPO administered weekly (600 units/kg per week) for four doses beginning 21 days before surgery [27], transfusion requirements were comparable, indicating that the weekly rHuEPO regimen also reduces transfusion requirements while improving patient convenience. Importantly, weekly dosing can result in cost savings of approximately 43%. rHuEPO has also been demonstrated to reduce transfusion requirements in elderly patients undergoing major hip or knee reconstruction [28], in more heterogeneous populations of patients needing total joint arthroplasty or major hip or knee surgery [29, 30], and even in children requiring craniosynostosis repair [31].

In cardiac surgery, all of seven randomized studies included in a meta-analysis [32] provided evidence that rHuEPO, with or without PAD, produced significant decreases in the proportion of patients transfused with allogeneic blood. In another single-blind, randomized study of patients undergoing coronary artery bypass graft surgery [33], patients treated with low dose (100 units/kg) rHuEPO for 4 days before surgery received less than half the amount of autologous blood (P < 0.01) as compared with the control group.

Surgery in cancer patients represents a particular challenge because these patients may suffer severe anemia caused by their cancer or its treatment. In patients with a hemoglobin under 8.5 g/dl and with colorectal cancer, 300 IU/kg rHuEPO on day 4 before surgery followed by 150 IU/kg for the next 7 days thereafter stimulated erythropoiesis and reduced transfusion requirements compared with placebo [34]. Transfusion requirements were reduced and hemoglobin levels were improved with preoperative rHuEPO treatment in patients with gastrointestinal tract cancer [35] and in those with rectal cancer undergoing surgery [36]. Epoetin beta has shown similar effects in patients with colon cancer [37]. Other patient groups for whom surgery is indicated and in whom preoperative rHuEPO exerts beneficial effects include those with prostate cancer [38], head and neck cancer [39], and women undergoing gynecologic surgery for benign conditions [40].

When surgical blood losses are anticipated to exceed 3000 ml, rHuEPO is effectively used in conjunction with PAD [41]. In patients who were to undergo total hip replacement, rHuEPO facilitated dose-dependent increases in PAD amounting to 4.3 units (300 IU/kg), 3.4 units (150 IU/kg), and 3.0 units (75 IU/kg), as compared with 2.1 units with placebo, and it minimized reductions in hematocrit associated with repeated phlebotomy [42]. Treatment with rHuEPO resulted in rapid increases in RBC production (3.5 days) in nonanemic (hematocrit >39%) patients who were participating in an aggressive program for autologous blood donation [43, 44]. This treatment allowed for higher RBC volumes to be donated compared with placebo-treated patients. Even in anemic gastrointestinal cancer patients, rHuEPO facilitated PAD compared with patients who were supplemented with iron alone [45]. Other examples of the utility of rHuEPO in PAD before gynecologic surgery [46] and orthopedic surgery [32, 47] can be found.

Although a field of medicine unto itself, the practice of bloodless surgery is gaining attention and therefore deserves brief mention [48]. Jehovah's Witnesses refuse transfusions on the basis of religious convictions, but are known to survive trauma and surgery with remarkably low hemoglobin levels. In many cases, these patients do so with the pharmacological support of erythropoietic agents [4951]. In a case study involving 48 Jehovah's Witness patients, rHuEPO was successfully used to avoid transfusions completely during and after elective coronary and heart valve surgery [52]. When used in combination with products that can substitute for blood [53] (e.g. the hemoglobin-based oxygen carriers, also known as HBOCs), there may be complementary effects. Thus, patients wishing to avoid transfusions may have even more options in the future.

In conclusion, preoperative anemia can be effectively managed with minimal exposure to allogeneic transfusions in virtually all surgical specialties. rHuEPO reduces transfusion requirements, facilitates collection of preoperative autologous blood, and is effective alone or with other blood conservation strategies in severe anemia. Surgeons should enthusiastically adopt available therapies that help to avoid transfusions and their accompanying risks, conserve blood, and treat preoperative anemia, with the goal of improving surgical outcomes.

Abbreviations

PAD: 

PAD = preoperative autologous donation

RBC: 

RBC = red blood cell

rHuEPO: 

rHuEPO = recombinant human erythropoietin.

Declarations

Authors’ Affiliations

(1)
Professor, Department of Anesthesiology, Duke University Medical Center

References

  1. Keating EM, Ritter MA: Transfusion options in total joint arthroplasty. J Arthoplasty 2002, 17: 125-128. 10.1054/arth.2002.32459View ArticleGoogle Scholar
  2. Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM: Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 2002, 102: 237-244. 10.1006/jsre.2001.6330View ArticlePubMedGoogle Scholar
  3. Carson JL, Duff RM, Berlin JA, Spence RK, Trout R, Noveck H, Strom BL: Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996, 348: 1055-1060. 10.1016/S0140-6736(96)04330-9View ArticlePubMedGoogle Scholar
  4. Baraldi-Junkins CA, Beck AC, Rothstein G: Hematopoiesis and cytokines. Relevance to cancer and aging. Hematol Oncol Clin North Am 2000, 14: 45-61.View ArticlePubMedGoogle Scholar
  5. Adunsky A, Lichtenstein A, Mizrahi E, Arad M, Heim M: Blood transfusion requirements in elderly hip fracture patients. Arch Gerontol Geriatr 2003, 36: 75-81. 10.1016/S0167-4943(02)00059-6View ArticlePubMedGoogle Scholar
  6. Denison U, Baumann J, Peters-Engl C, Samonigg H, Krippl P, Lang A, Obermair A, Wagner H, Sevelda P: Incidence of anaemia in breast cancer patients receiving adjuvant chemotherapy. Breast Cancer Res Treat 2003, 79: 347-353. 10.1023/A:1024016508925View ArticlePubMedGoogle Scholar
  7. Keating EM, Meding JB: Perioperative blood management practices in elective orthopaedic surgery. J Am Acad Orthop Surg 2002, 10: 393-400.PubMedGoogle Scholar
  8. Lee SJ, Liljas B, Churchill WH, Popovsky MA, Stowell CP, Cannon ME, Johannesson M: Perceptions and preferences of autologous blood donors. Transfusion 1998, 38: 757-763. 10.1046/j.1537-2995.1998.38898375515.xView ArticlePubMedGoogle Scholar
  9. Nappi J: Anemia in patients with coronary artery disease. Am J Health Syst Pharm 2003, Suppl 3: S4-S8.Google Scholar
  10. Benoist S, Panis Y, Pannegeon V, Alves A, Valleur P: Predictive factors for perioperative blood transfusions in rectal resection for cancer: a multivariate analysis of a group of 212 patients. Surgery 2001, 129: 433-439. 10.1067/msy.2001.112068View ArticlePubMedGoogle Scholar
  11. Chang H, Hall GA, Geerts WH, Greenwood C, McLeod RS, Sher GD: Allogeneic red blood cell transfusion is an independent risk factor for the development of postoperative bacterial infection. Vox Sang 2000, 78: 13-18. 10.1159/000031143View ArticlePubMedGoogle Scholar
  12. Amato AC, Pescatori M: Effect of perioperative blood transfusions on recurrence of colorectal cancer: meta-analysis stratified on risk factors. Dis Colon Rectum 1998, 41: 570-585.View ArticlePubMedGoogle Scholar
  13. Brand A: Immunological aspects of blood transfusions. Blood Rev 2000, 14: 130-144. 10.1054/blre.2000.0131View ArticlePubMedGoogle Scholar
  14. Vamvakas EC, Carven JH: Allogeneic blood transfusion, hospital charges, and length of hospitalization: a study of 487 consecutive patients undergoing colorectal cancer resection. Arch Pathol Lab Med 1998, 122: 145-151.PubMedGoogle Scholar
  15. McCullough J: Progress toward a pathogen-free blood supply. Clin Infect Dis 2003, 37: 88-95. 10.1086/375232View ArticlePubMedGoogle Scholar
  16. Hutchinson AB, Fergusson D, Graham ID, Laupacis A, Herrin J, Hillyer CD: Utilization of technologies to reduce allogeneic blood transfusion in the United States. Transfus Med 2001, 11: 79-85. 10.1046/j.1365-3148.2001.00290.xView ArticlePubMedGoogle Scholar
  17. Hogue CW Jr, Goodnough LT, Monk TG: Perioperative myocardial ischemic episodes are related to hematocrit level in patients undergoing radical prostatectomy. Transfusion 1998, 38: 924-931. 10.1046/j.1537-2995.1998.381098440856.xView ArticlePubMedGoogle Scholar
  18. Dunne JR, Gannon CJ, Osborn TM, Taylor MD, Malone DL, Napolitano LM: Preoperative anemia in colon cancer: assessment of risk factors. Am Surg 2002, 68: 582-587.PubMedGoogle Scholar
  19. Arnoux R, Corman J, Peloquin A, Smeesters C, St Louis G: Adverse effect of blood transfusions on patient survival after resection of rectal cancer. Can J Surg 1988, 31: 121-126.PubMedGoogle Scholar
  20. Procrit ® epoetin alfa [prescribing information] Bridgewater, NJ: Ortho Biotech Products, LP 2002.Google Scholar
  21. Goodnough LT, Monk TG, Andriole GL: Erythropoietin therapy. N Engl J Med 1997, 336: 933-938. 10.1056/NEJM199703273361307View ArticlePubMedGoogle Scholar
  22. Monk TG, Goodnough LT, Brecher ME, Colberg JW, Andriole GL, Catalona WJ: A prospective randomized comparison of three blood conservation strategies for radical prostatectomy. Anesthesiology 1999, 91: 24-33. 10.1097/00000542-199907000-00008View ArticlePubMedGoogle Scholar
  23. Brecher ME, Goodnough LT, Monk T: Where does preoperative erythropoietin therapy count? A mathematical perspective. Transfusion 1999, 39: 392-395. 10.1046/j.1537-2995.1999.39499235672.xView ArticlePubMedGoogle Scholar
  24. Avall A, Hyllner M, Bengtson JP, Carlsson L, Bengtsson A: Recombinant human erythropoietin in preoperative autologous blood donation did not influence the haemoglobin recovery after surgery. Acta Anaesthesiol Scand 2003, 47: 687-692.View ArticlePubMedGoogle Scholar
  25. Goldberg MA: Perioperative epoetin alfa increases red blood cell mass and reduces exposure to transfusions: results of randomized clinical trials. Semin Hematol 1997, 34: 41-47.PubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. Goldberg MA, McCutchen JW, Jove M, Di Cesare P, Friedman RJ, Poss R, Guilfoyle M, Frei D, Young D: A safety and efficacy comparison study of two dosing regimens of epoetin alfa in patients undergoing major orthopedic surgery. Am J Orthop 1996, 25: 544-552.PubMedGoogle Scholar
  28. Lofthouse RA, Boitano MA, Davis JR, Jinnah RH: Preoperative administration of epoetin alfa to reduce transfusion requirements in elderly patients having primary total hip or knee reconstruction. J South Orthop Assoc 2000, 9: 175-181.PubMedGoogle Scholar
  29. Rauh MA, Bayers-Thering M, LaButti RS, Krackow KA: Preoperative administration of epoetin alfa to total joint arthroplasty patients. Orthopedics 2002, 25: 317-320.PubMedGoogle Scholar
  30. de Andrade JR, Jove M, Landon G, Frei D, Guilfoyle M, Young DC: Baseline hemoglobin as a predictor of risk of transfusion and response to epoetin alfa in orthopedic surgery patients. Am J Orthop 1996, 25: 533-542.PubMedGoogle Scholar
  31. Fearon JA, Weinthal J: The use of recombinant erythropoietin in the reduction of blood transfusion rates in craniosynostosis repair in infants and children. Plast Reconstr Surg 2002, 109: 2190-2196. 10.1097/00006534-200206000-00002View ArticlePubMedGoogle Scholar
  32. Laupacis A, Fergusson D: Erythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials. The International Study of Perioperative Transfusion (ISPOT) Investigators. Transfus Med 1998, 8: 309-317. 10.1046/j.1365-3148.1998.00171.xView ArticlePubMedGoogle Scholar
  33. Yazicioglu L, Eryilmaz S, Sirlak M, Inan MB, Aral A, Tasoz R, Eren NT, Kaya B, Akalin H: Recombinant human erythropoietin administration in cardiac surgery. J Thoac Cardiovasc Surg 2001, 122: 741-745. 10.1067/mtc.2001.115426View ArticleGoogle Scholar
  34. Qvist N, Boesby S, Wolff B, Hansen CP: Recombinant human erythropoietin and hemoglobin concentration at operation and during the postoperative period: reduced need for blood transfusions in patients undergoing colorectal surgery: prospective double-blind placebo-controlled study. World J Surg 1999, 23: 30-35. 10.1007/s002689900561View ArticlePubMedGoogle Scholar
  35. Kosmadakis N, Messaris E, Maris A, Katsaragakis S, Leandros E, Konstadoulakis MM, Androulakis G: Perioperative erythropoietin administration in patients with gastrointestinal tract cancer: prospective randomized double-blind study. Ann Surg 2003, 237: 417-421. 10.1097/00000658-200303000-00017PubMed CentralPubMedGoogle Scholar
  36. Levine EA, Laborde C, Hambrick E, McKnight CA, Vijayakumar S: Influence of erythropoietin on transfusion requirements in patients receiving preoperative chemoradiotherapy for rectal cancer. Dis Colon Rectum 1999, 42: 1065-1069.View ArticlePubMedGoogle Scholar
  37. Kettelhack C, Hones C, Messinger D, Schlag PM: Randomized multicentre trial of the influence of recombinant human erythropoietin on intraoperative and postoperative transfusion need in anaemic patients undergoing right hemicolectomy for carcinoma. Br J Surg 1998, 85: 63-67. 10.1046/j.1365-2168.1998.00564.xView ArticlePubMedGoogle Scholar
  38. Rosenblum N, Levine MA, Handler T, Lepor H: The role of preoperative epoetin alfa in men undergoing radical retropubic prostatectomy. J Urol 2000, 163: 829-833. 10.1097/00005392-200003000-00029View ArticlePubMedGoogle Scholar
  39. Scott SN, Boeve TJ, McCulloch TM, Fitzpatrick KA, Karnell LH: The effects of epoetin alfa on transfusion requirements in head and neck cancer patients: a prospective, randomized, placebo-controlled study. Laryngoscope 2002, 112: 1221-1229. 10.1097/00005537-200207000-00015View ArticlePubMedGoogle Scholar
  40. Sesti F, Ticconi C, Bonifacio S, Piccione E: Preoperative administration of recombinant human erythropoietin in patients undergoing gynecologic surgery. Gynecol Obstet Invest 2002, 54: 1-5. 10.1159/000064688View ArticlePubMedGoogle Scholar
  41. Mercuriali F, Zanella A, Barosi G, Inghilleri G, Biffi E, Vinci A, Colotti MT: Use of erythropoietin to increase the volume of autologous blood donated by orthopedic patients. Transfusion 1993, 33: 55-60. 10.1046/j.1537-2995.1993.33193142311.xView ArticlePubMedGoogle Scholar
  42. Mercuriali F, Inghilleri G, Biffi E, Colotti MT, Vinci A, Oriani G: Epoetin alfa in low hematocrit patients to facilitate autologous blood donation in total hip replacement: a randomized, double-blind, placebo-controlled, dose-ranging study. Acta Haematol 1998, 100: 69-76. 10.1159/000040868View ArticlePubMedGoogle Scholar
  43. Goodnough LT, Price TH, Rudnick S, Soegiarso RW: Preoperative red cell production in patients undergoing aggressive autologous blood phlebotomy with and without erythropoietin therapy. Transfusion 1992, 32: 441-445. 10.1046/j.1537-2995.1992.32592327718.xView ArticlePubMedGoogle Scholar
  44. Goodnough LT, Price TH, Friedman KD, Johnston M, Ciavarella D, Khan N, Sacher R, Vogler WR, Wissel M, Abels RI: A phase III trial of recombinant human erythropoietin therapy in nonanemic orthopedic patients subjected to aggressive removal of blood for autologous use: dose, response, toxicity, and efficacy. Transfusion 1994, 34: 66-71. 10.1046/j.1537-2995.1994.34194098608.xView ArticlePubMedGoogle Scholar
  45. Braga M, Gianotti L, Vignali A, Gentilini O, Servida P, Bordignon C, Di Carlo V: Evaluation of recombinant human erythropoietin to facilitate autologous blood donation before surgery in anaemic patients with cancer of the gastrointestinal tract. Br J Surg 1995, 82: 1637-1640.View ArticlePubMedGoogle Scholar
  46. Hyllner M, Avall A, Swolin B, Bengtson J-P, Bengtsson A: Autologous blood transfusion in radical hysterectomy with and without erythropoietin therapy. Obstet Gynecol 2002, 99: 757-762. 10.1016/S0029-7844(02)01661-7View ArticlePubMedGoogle Scholar
  47. Lee J-H, Lee SH, Oh JH: Minimal effective dosage of recombinant human erythropoietin in spinal surgery. Clin Orthop 2003, 413: 71-76.View ArticleGoogle Scholar
  48. Cogliano J, Kisner D: Bloodless medicine and surgery in the OR and beyond. AORN J 2002, 76: 830. 832–837, 839, 841View ArticlePubMedGoogle Scholar
  49. Beholz S, Liu J, Thoelke R, Spiess C, Konertz W: Use of desmopressin and erythropoietin in an anaemic Jehovah's Witness patient with severely impaired coagulation capacity undergoing stentless aortic valve replacement. Perfusion 2001, 16: 485-489.View ArticlePubMedGoogle Scholar
  50. Sarac TP, Clifford C, Waters J, Clair DG, Ouriel K: Preoperative erythropoietin and blood conservation management for thoracoabdominal aneurysm repair in a Jehovah's Witness. J Vasc Surg 2003, 37: 453-455. 10.1067/mva.2003.73View ArticlePubMedGoogle Scholar
  51. Murphy DP, O'Donnell T, McDonnell J, McElwain JP: Treatment of anaemia in the polytrauma Jehovah's Witness. Ir Med J 2003, 96: 8-10.PubMedGoogle Scholar
  52. Podesta A, Parodi E, Dottori V, Crivellari R, Passerone GC: Epoetin alpha in elective coronary and valve surgery in Jehovah's Witnesses patients. Experience in 45 patients. Minerva Cardioangiol 2002, 50: 125-131.PubMedGoogle Scholar
  53. Cothren C, Moore EE, Offner PJ, Haenel JB, Johnson JL: Blood substitute and erythropoietin therapy in a severely injured Jehovah's witness. N Engl J Med 2002, 346: 1097-1098. 10.1056/NEJM200204043461420View ArticlePubMedGoogle Scholar

Copyright

© BioMed Central Ltd 2004

Advertisement