The Open Orthopaedics Journal




ISSN: 1874-3250 ― Volume 13, 2019

Should We Use Preoperative Epoetin-α in the Mildly Anemic Patient Undergoing Simultaneous Total Knee Arthroplasty?



Lawrence A Delasotta*, 1, Fabio Orozco 2, 3, 4, S. Mehdi Jafari 5, Jamie L Blair 2, Alvin Ong 2, 3, 4
1 Department of Orthopedics, Kingsbrook Jewish Medical Center, Brooklyn, NY 11203, USA
2 Rothman Institute, Egg Harbor Township, NJ 08234, USA
3 Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA
4 Orthopaedics Division at AtlantiCare Regional Medical Center, USA
5 Nirschl Orthopaedics at Virginia Hospital Center, Arlington, VA 22205, USA

Abstract

Simultaneous knee arthroplasty is associated with significant blood loss. To prevent transfusion, three preoperative doses of epoetin-α were offered to mildly anemic simultaneous knee arthroplasty patients. A retrospective review, using ICD-9 codes, identified twenty patients from 2007-2009. Epoetin-α increased hemoglobin levels preoperatively (12.6 to 13.9, p<0.01). Twenty patients who did not receive epoetin-α were matched to study patients. Study patients were transfused less (55% vs 95%, p=0.012) and had similar inpatient length of stay. The average blood loss without transfusion was 4.6g/dL. The mildly anemic patient is at high-risk for packed red cell transfusion during simultaneous knee arthroplasty. Three preoperative doses of epoetin-α in the mildly anemic patient decreased total transfusions; however, it did not affect inpatient length of stay.

Keywords: Single stage bilateral total knee arthroplasty, simultaneous total knee arthroplasty, epoetin-α, tranexamic acid, degenerative joint disease, pain, anemia.


Article Information


Identifiers and Pagination:

Year: 2013
Volume: 7
First Page: 47
Last Page: 50
Publisher Id: TOORTHJ-7-47
DOI: 10.2174/1874325001307010047

Article History:

Received Date: 22/11/2012
Revision Received Date: 17/1/2013
Acceptance Date: 23/1/2013
Electronic publication date: 22/2/2013
Collection year: 2013

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© Delasotta et al.; Licensee Bentham Open.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/) which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.


* Address correspondence to this author at the Department of Orthopedics, Kingsbrook Jewish Medical Center, 585 Schenectady Avenue, Brooklyn, NY 11203, USA; Tel: 718-604-5483; Fax: 215-707-1915; E-mail: LawrenceDelasotta@Gmail.com




INTRODUCTION

Substantial blood loss occurs during elective knee arthroplasty [1Feagan BG, Wong CJ, Lau CY, Wheeler SL, Sue-A-Quan G, Kirkley A. Transfusion practice in elective orthopaedic surgery Transfus Med 2001; 11(2): 87-95., 2Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty J Bone Joint Surg Am 1999; 81(1): 2-10.]. Simultaneous bilateral total knee replacement has an even higher blood loss and, consequently, these patients are more likely to receive packed red cells [3Peak EL, Hozack WJ, Sharkey PF, Parvizi J, Rothman RH. One-stage bilateral total joint arthroplasty: a prospective, comparative study of total hip and total knee replacement Orthopedics 2008; 31(2): 131.]. However, blood transfusion is associated with morbidity. Furthermore, patients may refuse transfusion due to religious beliefs [4Nelson CL, Bowen W, Rock L. Total hip arthroplasty in Jehovah's Witnesses without blood transfusion J Bone Joint Surg Am 1986; 68(3): 350-53.]. Therefore preoperative interventions are important to prevent transfusion [5Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine. First of two parts--blood transfusion N Engl J Med 1999; 340(6): 438-7.-8Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneic blood transfusion increases the risk of postoperative bacterial infection: a meta-analysis J Trauma 2003; 54(5): 908-14.].

Approximately twelve percent of patients (≥65yoa) are mildly anemic [9Tettamanti M, Lucca U, Gandini F, et al. Prevalence, incidence and types of mild anemia in the elderly: the “Health and Anemia” population-based study Haematologica 2010; 95(11): 1849-56.]. The mildly anemic patient has a four-fold and fifteen-fold transfusion rate increase over patients with preoperative counts of 13.0-15.0g/dl and >15g/dl, respectively [10Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty J Bone Joint Surg 1999; 81(1): 2-10., 11Salido JA, Marín LA, Gómez LA, Zorrilla P, Martínez C. Preoperative hemoglobin levels and the need for transfusion after prosthetic hip and knee surgery: analysis of predictive factors J Bone Joint Surg 2002; 84(2): 216.]. Epoetin-α delivered as three preoperative doses is believed to increase preoperative hemoglobin counts, and has been shown to reduce transfusion and decrease inpatient length of stay in the mildly anemic patient undergoing a revision hip and/or knee arthroplasty [12Delasotta LA, Rangavajjula AV, Frank ML, Blair JL, Orozco FR, Ong AC. The Use of Epoetin-α in Revision Knee Arthroplasty Adv Orthop 2012; 2012: 595027., 13Delasotta LA, Rangavajjula A, Frank ML, Blair J, Orozco F, Ong A. The use of preoperative epoetin-α in revision hip arthroplasty Open Orthop J 2012; 6: 179-83.]. Furthermore, it is unknown whether preoperative epoetin-α is a useful intervention in the mildly anemic simultaneous total knee arthroplasty patient.

Tranexamic acid is another viable option to prevent allogeneic transfusion [14Ortega-Andreu M, Pérez-Chrzanowska H, Figueredo R, Gómez-Barrena E. Blood loss control with two doses of tranexamic Acid in a multimodal protocol for total knee arthroplasty Open Orthop J 2011; 5: 44-8.]. It is a synthetic serine protease analog that reversibly inhibits fibrinolysis – a major cause of postoperative bleeding. It blocks lysine residues that bind plasmin and plasminogen activator molecules. The drug has similar applications in cardiac, urologic, and gynecologic surgeries as well as liver transplantation. Aprotinin and Aminocaproic acid have also been suggested. Aprotinin (derived from bovine lung) inhibits the serine protease during the final stage of fibrinolysis; however, allergies, thrombosis, nephrotoxicity, and spongiform encephalopathy have led to its decreased international use [15Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt–Jakob disease and blood transfusion: results of the UK transfusion medicine epidemiological review study Vox Sang 2006; 91(3): 221-30.]. Furthermore, Aminocaproic acid is less effective, more expensive, and less efficacious than tranexamic acid [16Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients undergoing total knee arthroplasty: results of a meta analysis of randomized controlled trials Transfusion 2005; 45(8): 1302-7.].

This is the first study, to the knowledge of these authors, to assess pre-operative epoetin-α injections on the mildly anemic patient (10-13g/dL) undergoing simultaneous total knee arthroplasty. The purpose is to evaluate the preoperative change in hemoglobin, quantify overall blood loss, and to compare the percent of patients transfused with blood. The hypotheses are that three preoperative doses of epoetin-α will decrease transfusions and reduce inpatient length of stay.

METHODS

Following Institutional Review Board (IRB) approval, we performed this retrospective study. Between April 2007 and August 2009, a retrospective review using ICD-9 coding, identified 95 patients who underwent a simultaneous bilateral total knee arthroplasty. Fifty patients were mildly anemic (10-13g/dL), preoperatively. Twenty of these mildly anemic patients received three preoperative doses of epoetin-α (21, 14, and 7 days prior to surgery). Patient-matching occurred by procedure, gender, BMI, ASA score, and age. Patient’s with pre-operative Hgb values less than 10 g/dL or greater than 13g/dL, dual stage bilateral knee arthroplasty, a history of prior deep venous thrombosis or a pulmonary embolus, patients who received a postoperative drain, and patients with hematological diseases, cancer, or coagulation disorders were excluded. Mild anemia was defined by a Hgb level at or below 13g/dL and at or above 10g/dL [10Bierbaum BE, Callaghan JJ, Galante JO, et al. An analysis of blood management in patients having a total hip or knee arthroplasty J Bone Joint Surg 1999; 81(1): 2-10., 11Salido JA, Marín LA, Gómez LA, Zorrilla P, Martínez C. Preoperative hemoglobin levels and the need for transfusion after prosthetic hip and knee surgery: analysis of predictive factors J Bone Joint Surg 2002; 84(2): 216.].

Prior to epoetin-α administration, all mildly anemic patients were appropriately counseled by an expert about the risks and benefits of preoperative anemia treatment. Anemic patients were considered for three weekly subcutaneous doses of 40,000 U of epoetin-α. All injections were combined with supplemental oral iron. All patients were offered oral multi-vitamins, vitamin B12, folic acid, and iron.

The preoperative work-up, surgical technique, anesthesia, and postoperative management of patients in both groups were similar. All surgeries were completed under combined spinal-epidural anesthesia, with tourniquet control. A straight medial para-patellar approach was used. All knee arthroplasties were cemented. Neither cell saver nor drains were used. Through 4-weeks postoperative, proper anticoagulation (either oral warfarin or subcutaneous enoxaparin) was administered. The target INR was 2.0-2.5. The clinical triggers for blood transfusion during or after the procedure were determined based on peri- and postoperative hemoglobin levels, the ASA score (American Society of Anesthesiologists) of the patient, and/or clinical symptoms consistent with an anemia.

Twenty patients (50%) received epoetin-α. There were no differences between groups based on mean age (66 vs 64 years), BMI (30.7 vs 30.8 kg/m2), preoperative INR (0.97 vs 1.01), or platelet count (268,737 vs 265,750 per mm3) (p>0.05). The distribution of patients according to ASA score was similar (p=0.65) (Table 1).

Table 1

Patient Demographics




An a priori sample size was calculated for a student’s t-test evaluation. The anticipated effect size was 0.85, desired statistical power level was 0.8, and probability level was 0.05. Therefore, the minimum sample size per group to test the hypothesis was 18. A chi-square test for the proportions of cases receiving blood, and Student’s t-test and Chi-square were used for comparing the continuous and categorical variables, respectively. For the statistical analysis, version 18 of PASW® Statistics (SPSS Inc., an IBM Company Headquarters, Chicago, Illinois) was used. A p<0.05 was considered statistically significant.

RESULTS

The mean Hgb level at time of surgery was higher in patients who received preoperative epoetin-α (13.9 vs 12.44 g/dL) (p=0.0001). Epoetin-α increased the preoperative hemoglobin level from 12.6 to 13.9 (P=0.0001). The average duration of surgery was similar (103 vs 109 minutes) (p=0.18). The intervention cohort had a blood loss from pre- to immediately postop of 4.6g/dL. There was no difference in the hemoglobin level at time of transfusion (8.2 vs 8.5) (p=0.31). At discharge, there was no difference in Hgb level (8.95 vs 8.90 g/dL) (p=0.83). Patients receiving epoetin-α were transfused less (55% (11 of 20) vs 95% (18 of 20)) (p=0.012). There were no difference in number of units transfused (1.45 vs 1.3units) (P=0.60)). Thirty-six percent of transfusions occurred on postoperative day 1; thirty-six percent on postoperative day 2; twenty-seven percent occurred on postoperative day 3. There was no difference in day of transfusion. There was no difference in length of hospital stay (3.26 vs 3.25days) (p=0.95) (Table 2).

Table 2

Results. Note that Epoetin-α Increased hgb Counts Preoperatively and Decreased Transfusions




One of the patients in the control group developed cellulitis four days after surgery which was completely resolved with antibiotic treatment. Another patient in this group developed a myocardial infarction five days following knee replacement. One patient in the epoetin-α group (65 year old male) passed away seven months after surgery due to cardiac arrest. No other minor or major complication, either local or systemic, was recorded in either cohort.

DISCUSSION

The blood loss during a simultaneous bilateral total knee arthroplasty surgery is substantial, and most mildly anemic (Hgb 10-13) patients will require transfusion. Three preoperative subcutaneous injections of 40,000 U of epoetin-α were successful at increasing preoperative blood counts, and decreasing transfusion.

De Andrade et al. compared epoetin-α to a placebo in a primary total knee arthroplasty double-blind study and noted that patients with mild anemia (10-13g/dl) who received epoetin-α were transfused less [17de 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 (Belle Mead NJ) 1996; 25(8): 533-42.]. Stowell CP et al. found that weekly epoetin-α doses of 40,000 units raised hemoglobin levels from 12.3 g/dL to 13.8 g/dL, preoperatively. Their patients maintained higher levels peri- and postop compared to those receiving autologous blood [18Stowell CP, Chandler H, Jové M, Guilfoyle M, Wacholtz MC. An open-label, randomized study to compare the safety and efficacy of perioperative epoetin alfa with preoperative autologous blood donation in total joint arthroplasty Orthopedics 1999; 22(1): S105-12.]. Epoetin-α increased hemoglobin levels in this study (12.6 to 13.9g/dl) resulting in a 40% decrease in the overall effect on transfusion practice. However, there was no effect on decreasing inpatient length of stay as demonstrated previously [12Delasotta LA, Rangavajjula AV, Frank ML, Blair JL, Orozco FR, Ong AC. The Use of Epoetin-α in Revision Knee Arthroplasty Adv Orthop 2012; 2012: 595027., 13Delasotta LA, Rangavajjula A, Frank ML, Blair J, Orozco F, Ong A. The use of preoperative epoetin-α in revision hip arthroplasty Open Orthop J 2012; 6: 179-83.].

All cases were performed under tourniquet control, which along with postoperative fibrinolysis can increase blood loss after arthroplasty [19Risberg B. The response of the fibrinolytic system in trauma Acta Chir Scand Suppl 1985; 522: 245-71.-21Hiippala S, Strid L, Wennerstrand M, et al. Tranexamic acid (Cyklokapron) reduces perioperative blood loss associated with total knee arthroplasty Br J Anaesth 1995; 74(5): 534-7.]. Epoetin-α is believed to transiently increase as well as improve platelet function, which theoretically decreases total blood loss [22Tang WW, Stead RA, Goodkin DA. Effects of epoetin alfa on hemostasis in chronic renal failure Am J Nephrol 1998; 18(4): 263-73.]. This study did not calculate a hidden blood loss, but it did note that total blood losses during simultaneous knee arthroplasty were higher than primary knee, revision knee, and/or revision hip surgeries [23Sehat K, Evans R, Newman J. Hidden blood loss following hip and knee arthroplasty: correct management of blood loss should take hidden loss into account J Bone Joint Surg Br 2004; 86(4): 561-.]. The change in hemoglobin from pre- to postop in our intervention cohort was 4.6 g/dL without re-infusion; such a change appears comparatively higher than that recorded by Sehat KR et al. who noted that a primary knee arthroplasty without re-infusion had a change of 3.3 g/dL and 2.8 g/dL after re-infusion. Interestingly, the change in blood count may be hidden in soft tissue and the joint of an arthroplasty patient [23Sehat K, Evans R, Newman J. Hidden blood loss following hip and knee arthroplasty: correct management of blood loss should take hidden loss into account J Bone Joint Surg Br 2004; 86(4): 561-.] – which was demonstrated in two radio-labeled RBC studies that showed peri-operative blood loss into the soft tissue compartments [24Erskine JG, Fraser C, Simpson R, Protheroe K, Walker ID. Blood loss with knee joint replacement J R Coll Surg Edinb 1981; 26(5): 295-7., 25McManus K, Velchik M, Alavi A, Lotke P. Non-invasive assessment of postoperative bleeding in TKA patients with Tc-99m RNCs J Nucl Med 1987; 28: 565-67.]. Although this study suggests that mildly anemic patients benefit from three preoperative doses of epoetin-α, the substantial blood loss during this procedure suggests that the goal of ‘bloodless medicine’ may require an additional intervention.

To achieve ‘bloodless medicine’, augmenting epoetin-α use in this population with tranexamic acid may be an additional option. Tranexamic has been shown to prevent fibrinolysis, and Ortega-Andreu M et al. showed that two doses, given intraoperatively, demonstrated a decrease in postoperative blood loss and transfusion practice in a multimodal protocol during primary total knee arthroplasty [14Ortega-Andreu M, Pérez-Chrzanowska H, Figueredo R, Gómez-Barrena E. Blood loss control with two doses of tranexamic Acid in a multimodal protocol for total knee arthroplasty Open Orthop J 2011; 5: 44-8.]. Future study to evaluate the combination of these two treatment modalities may demonstrate decreased blood loss and transfusion allowing earlier participation in physical therapy and/or achieving milestones sooner [2Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms RE, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty J Bone Joint Surg Am 1999; 81(1): 2-10., 17de 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 (Belle Mead NJ) 1996; 25(8): 533-42., 26Munin MC, Rudy TE, Glynn NW, Crossett LS, Rubash HE. Early inpatient rehabilitation after elective hip and knee arthroplasty JAMA 1998; 279(11): 847-52.-28Nuttall GA, Santrach PJ, Oliver WC Jr, et al. A prospective randomized trial of the surgical blood order equation for ordering red cells for total hip arthroplasty patients Transfusion 1998; 38(9): 828-33.] in the mildly anemic simultaneous total knee arthroplasty population.

Epoetin-α has been shown, in selected patient groups, to decrease total cost during primary knee arthroplasty [29Couvret C, Laffon M, Baud A, Payen V, Burdin P, Fusciardi J. A restrictive use of both autologous donation and recombinant human erythropoietin is an efficient policy for primary total hip or knee arthroplasty Anesth Analg 2004; 99(1): 262-71., 30Green WS, Toy P, Bozic KJ. Cost minimization analysis of preoperative erythropoietin vs autologous and allogeneic blood donation in total joint arthroplasty J Arthroplasty 2010; 25(1): 93-6.]. One study showed it increased direct cost per patient when compared to a re-transfusion system [31Moonen AF, Thomassen BJ, Knoors NT, et al. Pre-operative injections of epoetin-alpha versus post-operative retransfusion of autologous shed blood in total hip and knee replacement: a prospective randomised clinical trial J Bone Joint Surg Br 2008; 90(8): 1079-83.]; however, the indirect costs were not analyzed and the authors noted that true cost-effectiveness could not be determined. Our experience using epoetin-α has been safe and effective at increasing cell counts. Furthermore, the weekly dosing regimen appears more patient friendly and cost effective to reported alternatives [32Faris PM, Ritter MA. Epoetin alfa. A bloodless approach for the treatment of perioperative anemia Clin Orthop Relat Res 1998; 357: 60-7.]. Furthermore, the elevated preoperative hemoglobin level may improve short-term outcomes [26Munin MC, Rudy TE, Glynn NW, Crossett LS, Rubash HE. Early inpatient rehabilitation after elective hip and knee arthroplasty JAMA 1998; 279(11): 847-52.].

Epoetin-α is thought to also have anti-apoptotic activity that can protect cells from hypoxic and ischemic events [33Coleman T, Brines M. Science review: Recombinant human erythropoietin in critical illness: a role beyond anemia? Crit Care 2004; 8(5): 337.-35Brines M, Cerami A. Discovering erythropoietin's extra-hematopoietic functions: biology and clinical promise Kidney Int 2006; 70(2): 246-50.]. Interestingly, cancer and chronic renal failure patients were noted to have an increased thrombosis rate and death [36Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial Lancet 2003; 362(9392): 1255-60.-38Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients J Natl Cancer Inst 2006; 98(10): 708-14.]. This study had one unrelated cardiovascular incident. A myocardial event occurred seven months postoperative unrelated to drug use. Furthermore, all patients received the same immediate postoperative treatment course that consisted of anti-thromboprophylaxis, early ambulation, and physical therapy.

No retrospective study design is without limitation. To increase similarity between patient groups, patient-matching occurred based on age, gender, procedure, BMI, and American Society of Anesthesiology (ASA) scores. Each cohort was a consecutive series of mildly anemic (10-13 g/dl) patients. Ninety percent of patients underwent spinal anesthesia in both cohorts, which is associated with decreased blood loss in the hypotensive patient [39Juelsgaard P, Larsen UT, Sørensen JV, Madsen F, Søballe K. Hypotensive epidural anesthesia in total knee replacement without tourniquet: reduced blood loss and transfusion Reg Anesth Pain Med 2001; 26(2): 105-.]. The study group reported increased pre-operative iron, folic acid, vitamin B12, and multivitamin use. Cases were performed by two senior surgeons who use identical indications for transfusion based on peri- and postoperative hemoglobin levels, ASA score (American Society of Anesthesiologists), and/or symptomatic anemia. Lastly, no difference in ASA scores or hemoglobin counts at the time of transfusion between cohorts were noted.

In conclusion, the mildly anemic patient is at high-risk for transfusion during simultaneous bilateral total knee arthroplasty. A three week dosing regimen of 40,000 U of epoetin-α increases the preoperative blood count and decreases transfusion. To achieve the goal of preventing transfusion in the mildly anemic simultaneous total knee arthroplasty patient, additional interventions are likely necessary to not only achieve ‘bloodless medicine’, but also increase participation in physical therapy, achieve milestones sooner, and decrease overall inpatient length of stay.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

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[15] Hewitt PE, Llewelyn CA, Mackenzie J, Will RG. Creutzfeldt–Jakob disease and blood transfusion: results of the UK transfusion medicine epidemiological review study Vox Sang 2006; 91(3): 221-30.
[16] Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in patients undergoing total knee arthroplasty: results of a meta analysis of randomized controlled trials Transfusion 2005; 45(8): 1302-7.
[17] 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 (Belle Mead NJ) 1996; 25(8): 533-42.
[18] Stowell CP, Chandler H, Jové M, Guilfoyle M, Wacholtz MC. An open-label, randomized study to compare the safety and efficacy of perioperative epoetin alfa with preoperative autologous blood donation in total joint arthroplasty Orthopedics 1999; 22(1): S105-12.
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[21] Hiippala S, Strid L, Wennerstrand M, et al. Tranexamic acid (Cyklokapron) reduces perioperative blood loss associated with total knee arthroplasty Br J Anaesth 1995; 74(5): 534-7.
[22] Tang WW, Stead RA, Goodkin DA. Effects of epoetin alfa on hemostasis in chronic renal failure Am J Nephrol 1998; 18(4): 263-73.
[23] Sehat K, Evans R, Newman J. Hidden blood loss following hip and knee arthroplasty: correct management of blood loss should take hidden loss into account J Bone Joint Surg Br 2004; 86(4): 561-.
[24] Erskine JG, Fraser C, Simpson R, Protheroe K, Walker ID. Blood loss with knee joint replacement J R Coll Surg Edinb 1981; 26(5): 295-7.
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[26] Munin MC, Rudy TE, Glynn NW, Crossett LS, Rubash HE. Early inpatient rehabilitation after elective hip and knee arthroplasty JAMA 1998; 279(11): 847-52.
[27] Guerin S, Collins C, Kapoor H, McClean I, Collins D. Blood transfusion requirement prediction in patients undergoing primary total hip and knee arthroplasty Transfus Med 2007; 17(1): 37-43.
[28] Nuttall GA, Santrach PJ, Oliver WC Jr, et al. A prospective randomized trial of the surgical blood order equation for ordering red cells for total hip arthroplasty patients Transfusion 1998; 38(9): 828-33.
[29] Couvret C, Laffon M, Baud A, Payen V, Burdin P, Fusciardi J. A restrictive use of both autologous donation and recombinant human erythropoietin is an efficient policy for primary total hip or knee arthroplasty Anesth Analg 2004; 99(1): 262-71.
[30] Green WS, Toy P, Bozic KJ. Cost minimization analysis of preoperative erythropoietin vs autologous and allogeneic blood donation in total joint arthroplasty J Arthroplasty 2010; 25(1): 93-6.
[31] Moonen AF, Thomassen BJ, Knoors NT, et al. Pre-operative injections of epoetin-alpha versus post-operative retransfusion of autologous shed blood in total hip and knee replacement: a prospective randomised clinical trial J Bone Joint Surg Br 2008; 90(8): 1079-83.
[32] Faris PM, Ritter MA. Epoetin alfa. A bloodless approach for the treatment of perioperative anemia Clin Orthop Relat Res 1998; 357: 60-7.
[33] Coleman T, Brines M. Science review: Recombinant human erythropoietin in critical illness: a role beyond anemia? Crit Care 2004; 8(5): 337.
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[36] Henke M, Laszig R, Rübe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial Lancet 2003; 362(9392): 1255-60.
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[38] Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients J Natl Cancer Inst 2006; 98(10): 708-14.
[39] Juelsgaard P, Larsen UT, Sørensen JV, Madsen F, Søballe K. Hypotensive epidural anesthesia in total knee replacement without tourniquet: reduced blood loss and transfusion Reg Anesth Pain Med 2001; 26(2): 105-.

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Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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