The Open Orthopaedics Journal




ISSN: 1874-3250 ― Volume 13, 2019

The Use of Preoperative Epoetin-α in Revision Hip Arthroplasty



Lawrence A Delasotta*, 1, Ashwin Rangavajjula2, Michael L Frank 3, Jamie Blair 4, Fabio Orozco 2, 5, Alvin Ong 2, 5
1 Temple University, Department of Surgery, Philadelphia, PA 19140, USA
2 Thomas Jefferson University, Philadelphia, PA 19107, USA
3 The Richard Stockton College of New Jersey, Pomona, NJ 08240, USA
4 Egg Harbor Township, New Jersey 08234, USA
5 The Rothman Institute, AtlantiCare Regional Medical Center, USA

Abstract

Purpose:

To evaluate the efficacy of preoperative epoetin-α on the revision hip arthroplasty patient. We hypothesized that epoetin-α will reduce blood transfusion. A pertinent review of the literature is provided.

Methods:

Forty-six patients were retrospectively reviewed. Sixteen patients received epoetin-α. Patients were case matched by age, preoperative hemoglobin, surgery, gender, and BMI. The clinical triggers for blood transfusion during or after the procedure were determined based on peri- and postoperative hemoglobin levels, ASA score, and/or clinical symptoms consistent with anemia. Blood salvage was not used.

Results:

Blood transfusion and length of stay were decreased in the epoetin-α group. Hemoglobin in the intervention group increased from 12.0 to 14.5, preoperatively. Patients who received epoetin-α were 0.78 (RR=0.225) times as likely to receive a transfusion. Number Needed to Treat (NNT) to avoid one allogeneic transfusion was 1.84. Age, Gender, BMI, ASA, total and hidden blood loss, preoperative Iron supplements, preop Hct, preop PLT, PT, PTT, and INR were similar. One (6.0%) patient developed an uncomplicated deep venous thrombosis in the intervention group.

Conclusions:

The mildly anemic revision hip arthroplasty patient is at increased risk for transfusion. Epoetin-α increased preoperative hemoglobin counts and reduced transfusions in this study; it also decreased patient length of hospital stay likely allowing for an earlier readiness to resume normal activities and/or meet short-term milestones. A randomized study to evaluate the direct and indirect costs of such a treatment methodology in the mildly anemic revision patient may be warranted.

Keywords: Anemia, orthopedic surgery, autologous blood donation, blood transfusion, epoetin-α, revision total hip arthroplasty.


Article Information


Identifiers and Pagination:

Year: 2012
Volume: 6
First Page: 179
Last Page: 183
Publisher Id: TOORTHJ-6-179
DOI: 10.2174/1874325001206010179

Article History:

Received Date: 3/2/2012
Revision Received Date: 30/3/2012
Acceptance Date: 3/4/2012
Electronic publication date: 11/5/2012
Collection year: 2012

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© Delasotta et al.; Licensee Bentham Open.

open-access license: This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.


* Address correspondence to this author at 3401 N. Broad Street, Parkinson Pavilion, Suite 400, Philadelphia, PA 19140, USA; Tel: 215-707-3632; Fax: 215-707-1915; E-mail: lawrencedelasotta@gmail.com




INTRODUCTION

Revision hip arthroplasty is associated with increased transfusion needs [1 Bridgens J, Evans C, Dobson P, Hamer A. Intraoperative red blood-cell salvage in revision hip surgery A case-matched study Clin Orthop Relat Res 2007; 89(2): 270-5.]. A typical patient loses 4.0 g/dL, and receives three units [2 Callaghan JJ, O'Rourke MR, Liu SS. Blood management: issues and options J Arthroplasty 2005; 20: 51-4.] – such units have been of allogeneic or of autologous origin. However, both treatment modalities can lead to significant clinical morbidity.

Preoperative autologous donation has been used to prevent allogeneic transfusions. However, recent studies found that it may be less efficacious than anticipated. For instance, it can induce anemia, and thus may not be indicated when baseline hemoglobin levels (≤13.0 g/dl) are low [3 Pierson JL, Hannon TJ, Earles DR. A blood-conservation algorithm to reduce blood transfusions after total hip and knee arthroplasty J Bone Joint Surg Am 2004; 86-A(7): 1512-8.]. In contrast, recent studies suggest that the primary hip arthroplasty patient may benefit from preoperative epoetin-α more so than autologous donation [4 Moonen AF, Thomassen BJ, Knoors NT, van Os JJ, Verburg AD, Pilot P. Pre-operative injections of epoetin-alpha versus postoperative 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.]. Lastly, epoetin-α was efficacious in numerous fields of medicine and surgery; one of which was orthopaedic trauma [5 Wilson J, Yao G, Raftery J, et al. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer especially that attributable to cancer treatment Health Technol Assess 2007; 11(13): 1-220.]. To the knowledge of these authors, there has been one study that evaluated the use of preoperative epoetin-α in the revision hip patient [6 Noordin S, Waters TS, Garbuz DS, Duncan CP, Masri BA. Tranexamic acid reduces allogenic transfusion in revision hip arthroplasty Clin Orthop Relat Res 2011; 469(2): 541-6.].

The purpose of this study is to assess the effect of preoperative epoetin-α injection on the mildly anemic patient - a population thought to hold a four-fold and fifteen-fold transfusion rate increase over those with levels between 13.0-15.0g/dl and >15g/dl, respectively [7 Bierbaum 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 1999; 81(1): 2-10., 8 Salido JA, Marin LA, Gomez LA, Zorrilla P, Martinez 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): 216-0.]. Our hypothesis is that epoetin-α injection will reduce transfusions. A pertinent review of the literature is provided.

METHODS

Following Institutional Review Board (IRB) approval, we performed this retrospective analysis. Between January 2007 and May 2010 there were 46 patients who met our inclusion and exclusion criteria. All of our patients received revision hip surgery for prosthesis wear out and/or loosening. All surgical procedures were elective. The following cases were excluded from the study: control subjects with pre-operative hemoglobin values less than 10 g/dL or greater than 13g/dL, patients with hematological diseases or coagulation disorders, a prior history of deep venous thrombosis or pulmonary embolus, and subjects who received a postoperative drain. We termed patients with a hemoglobin level at or below 13g/dL and at or above 10g/dL mildly anemic.

For initial hemoglobin levels (obtained a month prior to surgery) >13g/dL and ≤14g/dL, a pre-operative autologous collection was offered. When a hemoglobin level was ≥10 and ≤13 g/dL, then three weekly doses of epoetin-α were considered. All risks associated with epoetin-α use were discussed. Patients that did not receive epoetin-α treatment were patient matched according to age, gender, body mass index, and ASA score. 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 identical. All surgeries were completed under combined spinal-epidural anesthesia. A hardinge approach utilizing the old incision was performed on all patients. All THAs were non-cemented. Neither cell saver nor drains were used - at our institution, it is not a routine practice to utilize drains during THA without an indication. Through 4-weeks postop, proper anticoagulant (either oral warfarin or subcutaneous enoxaparin) was administered to the patient. The target INR for all patients was 2.0-2.5. The first dose of prophylactic antibiotic (1 gram IV cefazolin or vancomycin for allergic patients) was administered within one hour prior to incision and then continued for the first 24 hours after surgery. The clinical triggers for blood transfusion during or after the procedure were determined based on an intraoperative hemoglobin level ≤8, or symptoms consistent with anemia.

We used a chi-square test for the proportions of cases receiving blood, and Student’s t-test and Chi-square 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 demographic data for the two cohorts are reported in Table 1. The records of 46 patients were reviewed, and no difference was found in demographic data between cohorts for age, gender, ASA, or BMI. There were no differences in patient blood values for preoperative PT, PTT, INR, or platelet count (p>0.05).

Table 1

Demographic Data for Hip Revision Patients




The average postoperative total blood loss (TBL), hidden blood loss (HBL), and calculated blood loss (CBL) are provided in Table 2. The average estimated blood loss was lower in the group of patients receiving epoetin-α (p=0.019). There was no difference in the median estimated blood loss. There was no difference in the average quantity of transfused blood.

Table 2

Blood Data for Hip Revision Study Patients




The average use of 2.88 doses of epoetin-α decreased the number of patients requiring transfusion. The discharge hemoglobin was higher in the intervention group. At the time of hospital admission the mean hemoglobin level was higher in the epoetin-α group. The mean duration of surgery was similar for both cohorts. There was a shorter length of hospital stay for patients who received epoetin-α (Table 2).

The index revision surgery was defined as any procedure in which at least acetabular, femoral, or liner/head components were exchanged. In the epoetin-α cohort, 12 (75%) patients had an acetabular revision. Three patients (18.8%) had a liner/head exchange, and 1 (6.3%) had a femoral component revision. In the control cohort, 21 (75%) of patients had an acetabular revision. Six patients had a liner/head exchange (21.4%), and 2 had a femoral revision (3.6%) (Table 3).

Table 3

Components for Hip Revision Study Patients




There was a single cardiovascular complication in this cohort. One of the patients in the intervention group (epoetin-α) developed an uncomplicated deep venous thrombosis diagnosed by ultrasound. The patient was treated as an outpatient. No further complications were noted.

In the epoetin-α group, 17.6% of the patients (3 of 17) required blood transfusion. This was significantly lower than the control group where 75.8% of the patients (22 of 29) received at least one unit of blood (p=0.0003) (Table 2). The relative risk of the epoetin-α treatment regimen was 0.225 (0.176/0.719). Number Needed to Treat (NNT) to avoid one allogeneic transfusion was 1.84 (1/(0.719-0.176)) (Table 2).

DISCUSSION

While preoperative epoetin-α injection has been shown to reduce peri- [9 Laupacis A, Fergusson D. Erythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials. The International Study of Peri-operative Transfusion (ISPOT) Investigators Transfus Med (Oxford England) 1998; 8(4): 309-17.] and postoperative transfusions in primary hip replacements, there has been one report, to the knowledge of these authors, of its effect on the revision hip patient [6 Noordin S, Waters TS, Garbuz DS, Duncan CP, Masri BA. Tranexamic acid reduces allogenic transfusion in revision hip arthroplasty Clin Orthop Relat Res 2011; 469(2): 541-6.]. Our patients who received epoetin-α were transfused less, had an elevated preoperative and discharge hemoglobin level, and a shorter hospital length of stay. Patients who received epoetin-α were 0.78 (RR=0.225) times as likely to receive a transfusion. Number Needed to Treat (NNT) to avoid one allogeneic transfusion was 1.84. There was one blood-related study cohort complication of deep venous thrombosis (6.0%) in a patient that was not transfused.

Noordin et al. studied revision THA patients. They noted that the transfusion rate for epoetin-α was no different than for a matched control group. However, not only did Noordin et al. use a different epoetin-α drug regimen, dose schedule, and study inclusion criteria, but they also used a control cohort that consisted of emergent surgery for periprosthetic fractures or infections. Additionally, their study group patients had a lower ASA score as well as a decreased rate of comorbidities than their blood utilization program patients [6 Noordin S, Waters TS, Garbuz DS, Duncan CP, Masri BA. Tranexamic acid reduces allogenic transfusion in revision hip arthroplasty Clin Orthop Relat Res 2011; 469(2): 541-6.]. Our study differs because we patient-matched our cohorts (age, BMI, gender, ASA) to decrease the inherent design flaws of a retrospective study. As such, we believe this study suggests that epoetin-α may be an efficacious option to reduce blood transfusions in the revision hip arthroplasty patient [10 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., 11 Faris PM, Ritter MA, Abels RI. The American Erythropoietin Study Group. The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation J Bone Joint Surg Am 1996; 78(1): 62-72.].

Moonen et al. [4 Moonen AF, Thomassen BJ, Knoors NT, van Os JJ, Verburg AD, Pilot P. Pre-operative injections of epoetin-alpha versus postoperative 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.] conducted a randomized trial that compared two cohorts of 50 patients each with mild anemia (10≥Hb≤13g/dL) who underwent either primary total hip or knee arthroplasty. The group randomized to receive a preoperative epoetin-α injection had a decreased blood transfusion frequency; however, the cost of the epoetin-α intervention exceeded that of the autologous re-transfused blood group. Another randomized trial by Slappendel et al. [12 Slappendel R, Weber EW, Hemon YJ, et al. Patients with and without rheumatoid arthritis benefit equally from preoperative epoetin-alpha treatment Acta Orthop 2006; 77(4): 677-83.] evaluated 695 patients with preoperative hemoglobin values of 10–13 g/dL who underwent elective orthopedic surgery – of which 113 patients had rheumatoid arthritis (RA). Their randomized cohorts consisted of either preoperative epoetin-α injection with standard care or standard care alone. They concluded that RA patients benefitted from preoperative epoetin-α treatment in combination with iron supplementation.

Gonzalez-Porras et al. [13 Gonzalez-Porras JR, Colado E, Conde MP, Lopez T, Nieto MJ, Corral M. An individualized pre-operative blood saving protocol can increase pre-operative haemoglobin levels and reduce the need for transfusion in elective total hip or knee arthroplasty Transfus Med 2009; 19(1): 35-42.] studied 305 patients who either underwent elective THA or TKA. The patients were individually assigned to one of five strategies: (1) no pre-operative intervention; (2) oral iron therapy; (3) intravenous iron therapy; (4) recombinant human epoetin-α with intravenous iron; and, (5) pre-operative autologous donation plus oral iron. They noted that preoperative autologous donation caused a reduction in hemoglobin levels. Furthermore, a multivariate subgroup analysis designed to evaluate postoperative transfusion risk factors determined that decreased weight and/or preoperative hemoglobin levels as well as the lack of a blood protocol strategy independently increased transfusion needs [13 Gonzalez-Porras JR, Colado E, Conde MP, Lopez T, Nieto MJ, Corral M. An individualized pre-operative blood saving protocol can increase pre-operative haemoglobin levels and reduce the need for transfusion in elective total hip or knee arthroplasty Transfus Med 2009; 19(1): 35-42.].

Garvin et al. found blood loss was greater for revision THA femoral components than for acetabular in 147 patients [14 Garvin KL, Feschuk CA, Sekundiak TD, Lyden ER. Blood salvage and allogenic transfusion needs in revision hip arthroplasty Clin Orthop Relat Res 2005; 441: 205-9.]. Furthermore, Zarin et al. found that when femoral and acetabular components were revised together blood loss was highest; whereas either component revised alone had no difference [15 Zarin J, Grosvenor D, Schurman D, Goodman S. Efficacy of intraoperative blood collection and reinfusion in revision total hip arthroplasty J Bone Joint Surg 2003; 85(11): 2147-51.]. Our study was not powered for such an analysis, but we identified for our controls that 90% of revised acetabular components required a transfusion, whereas for our study patients 8.3% of acetabular components required one.

Our study demonstrated that three weekly doses of 40,000 units of epoetin-α increased preoperative hemoglobin levels. Furthermore, for every 1.84 patients treated with epoetin-α, we were able to prevent one transfusion. We also believe that epoetin-α may be a more patient friendly and cost-effective treatment option for preoperative anemia [16 Faris PM, Ritter MA. Epoetin alfa A bloodless approach for the treatment of perioperative anemia Clin Orthop Relat Res 1998; (357): 60-7.]. For example, predonation of autologous blood can be an inefficient process since approximately 40-56% of it may be wasted [17 Billote D, Glisson S, Green D, Wixson R. A prospective randomized study of preoperative autologous donation for hip replacement surgery J Bone Joint Surg Am 2002; 84(8): 1299-304., 18 Hatzidakis A, Mendlick M, Mckillip T, Reddy R, Garvin KL. Preoperative autologous donation for total joint arthroplasty.an analysis of risk factors for allogenic transfusion J Bone Joint Surg Am 2000; 82(1): 89-100.]. It also carries a risk for compartment syndrome, contamination, febrile and/or septic reactions, clerical error, and inflammatory processes [19 Woronoff-Lemsi MC, Arveux P, Limat S, Morel P, Le Pen C, Cahn JY. Erythropoietin and preoperative autologous blood donation in the prevention of hepatitis C infection: necessity or luxury? Transfusion 1999; 39(9): 933-7.]. Furthermore, it is known to induce a phlebotomy related anemia [3 Pierson JL, Hannon TJ, Earles DR. A blood-conservation algorithm to reduce blood transfusions after total hip and knee arthroplasty J Bone Joint Surg Am 2004; 86-A(7): 1512-8.]. Therefore, we try to avoid its use.

Moonen et al. [4 Moonen AF, Thomassen BJ, Knoors NT, van Os JJ, Verburg AD, Pilot P. Pre-operative injections of epoetin-alpha versus postoperative 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.] reported that epoetin-α injection, supplemented by ferrofumerate tablets, increased the cost per patient when compared with a re-transfusion system. Their result was based on a direct cost analysis in Euros. However, the scarcity of and risk associated with allogeneic blood, potential transfusion error, administrative cost of testing, storing, and transfusing blood also need to be considered in an analysis. Furthermore, length of stay and patient satisfaction, among others should be considered. We recommend pre-op iron, folic acid, vitamin B12, and multivitamin use to all our patients undergoing elective surgery.

According to Sehat KR et al, there may be hidden blood loss into the soft tissue and joint of an arthroplasty patient. We did not detect a difference, but our study was likely not powered to do so; however, our average total and hidden blood losses were elevated when compared to the primary THA patient [20 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-.]. Importantly, the total and hidden blood loss is not a perfect measure; a part of its flaw is that the estimated blood loss intra- and postoperatively is a subjective measure based off a non-standardized process. One study presented their results utilizing the median value for total and hidden blood loss due to the numerous outliers present [21 Liu X, Zhang X, Chen Y, Wang Q, Jiang Y, Zeng B. Hidden blood loss after total hip arthroplasty J Arthroplasty 2011; 26(7): 1100-5.]. Therefore, we found it difficult to compare our blood loss results to those published. However, one interesting finding derived from such calculations is that a total hip arthroplasty has a lower hidden blood loss than total knee arthroplasty [20 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-.]. The change in hemoglobin from pre- to postoperatively in our study cohort was 12 to 14.5g/dL. Such a change was similar to those recorded by Sehat KR et al. who noted that a THA without re-infusion had a change of 3.3 g/dL and 2.8 g/dL with re-infusion. These authors consider this to be clinically significant since postoperative hemoglobin levels have been shown to correlate with patient readiness to resume normal activities after elective arthroplasty. Furthermore, it is known that short-term milestones are reached more rapidly if patients participate in inpatient rehabilitation immediately after surgery [22 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.].

There is a thought that epoetin-α may increase the occurrence of cardiovascular system side effects. However, there are also studies that link the drug with an anti-apoptotic activity that in preclinical and small clinical studies has been shown to protect cells from hypoxic and ischemic events [23 Coleman T, Brines M. Science review: Recombinant human erythropoietin in critical illness: a role beyond anemia? Crit Care 2004; 8(5): 337-41.-25 Brines M, Cerami A. Discovering erythropoietin's extrahematopoietic functions: biology and clinical promise Kidney Int 2006; 70(2): 246-50.]. It is possible that the anti-apoptotic activity of it may improve or prevent the outcome of an adverse event. However, cancer and chronic renal failure trial patients had an increased risk of thrombotic complications and death [26 Henke M, Laszig R, Rube 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.-28 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.]. Our protocol for epoetin-α administration had one blood-related complication. One patient developed an uncomplicated deep venous thrombosis (6%). It is standard in our orthopedic practice to transfuse patients based on anemic symptoms, or a hemoglobin count less than 8. All patients received the same postoperative treatment course that consisted of anti-thromboprophylaxis, early ambulation, and physical therapy. Additionally, no study patient had an ischemic event.

There were limitations to our study. The patient enrollment in the epoetin-α program was strictly voluntary, and the retrospective nature of our analysis invites the possibility of a confounding variable; however, we patient-matched on age, gender, BMI, ASA score, and procedure. Also, our study patients, on average, used more supplements preoperatively. Therefore, it is possible that we captured the effect of not only epoetin-α but also the vitamins; however, it is unlikely that the difference had a true clinical effect. Although estimated blood loss (EBL) was significantly different between our cohorts, we believe it was due to a few outliers present in the control group. Furthermore, the median estimated blood loss in the study and control groups were 150 and 200ml, respectively. Our series included a consecutive group of patients that received epoetin-α. Additionally, spinal anesthesia is thought to decrease perioperative loss when compared to general anesthesia [29 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-.]. Most of our patients underwent spinal anesthesia, but a few required general. Also, we did not include patients with a prior thromboembolic history because they are inherently at increased risk of clotting. Lastly, the trigger for transfusions is generally physician dependent. To account for this, we included cases performed by two surgeons only who have similar transfusion triggers as stated previously.

In conclusion, the present study demonstrates that the mildly anemic revision hip arthroplasty patient is at increased risk for transfusion. It also may suggest that epoetin-α could decrease the need for blood transfusion and/or decrease the length of hospital stay for the mildly anemic patient allowing earlier return to normal activities and/or to meet short-term milestones [22 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.]. A randomized study to evaluate the direct and indirect costs of such a treatment methodology in the mildly anemic revision hip patient may be warranted.

CONFLICT OF INTEREST

Declared none.

ACKNOWLEDGEMENT

Declared none.

REFERENCES

[1] Bridgens J, Evans C, Dobson P, Hamer A. Intraoperative red blood-cell salvage in revision hip surgery A case-matched study Clin Orthop Relat Res 2007; 89(2): 270-5.
[2] Callaghan JJ, O'Rourke MR, Liu SS. Blood management: issues and options J Arthroplasty 2005; 20: 51-4.
[3] Pierson JL, Hannon TJ, Earles DR. A blood-conservation algorithm to reduce blood transfusions after total hip and knee arthroplasty J Bone Joint Surg Am 2004; 86-A(7): 1512-8.
[4] Moonen AF, Thomassen BJ, Knoors NT, van Os JJ, Verburg AD, Pilot P. Pre-operative injections of epoetin-alpha versus postoperative 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.
[5] Wilson J, Yao G, Raftery J, et al. A systematic review and economic evaluation of epoetin alfa, epoetin beta and darbepoetin alfa in anaemia associated with cancer especially that attributable to cancer treatment Health Technol Assess 2007; 11(13): 1-220.
[6] Noordin S, Waters TS, Garbuz DS, Duncan CP, Masri BA. Tranexamic acid reduces allogenic transfusion in revision hip arthroplasty Clin Orthop Relat Res 2011; 469(2): 541-6.
[7] Bierbaum 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 1999; 81(1): 2-10.
[8] Salido JA, Marin LA, Gomez LA, Zorrilla P, Martinez 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): 216-0.
[9] Laupacis A, Fergusson D. Erythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials. The International Study of Peri-operative Transfusion (ISPOT) Investigators Transfus Med (Oxford England) 1998; 8(4): 309-17.
[10] 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.
[11] Faris PM, Ritter MA, Abels RI. The American Erythropoietin Study Group. The effects of recombinant human erythropoietin on perioperative transfusion requirements in patients having a major orthopaedic operation J Bone Joint Surg Am 1996; 78(1): 62-72.
[12] Slappendel R, Weber EW, Hemon YJ, et al. Patients with and without rheumatoid arthritis benefit equally from preoperative epoetin-alpha treatment Acta Orthop 2006; 77(4): 677-83.
[13] Gonzalez-Porras JR, Colado E, Conde MP, Lopez T, Nieto MJ, Corral M. An individualized pre-operative blood saving protocol can increase pre-operative haemoglobin levels and reduce the need for transfusion in elective total hip or knee arthroplasty Transfus Med 2009; 19(1): 35-42.
[14] Garvin KL, Feschuk CA, Sekundiak TD, Lyden ER. Blood salvage and allogenic transfusion needs in revision hip arthroplasty Clin Orthop Relat Res 2005; 441: 205-9.
[15] Zarin J, Grosvenor D, Schurman D, Goodman S. Efficacy of intraoperative blood collection and reinfusion in revision total hip arthroplasty J Bone Joint Surg 2003; 85(11): 2147-51.
[16] Faris PM, Ritter MA. Epoetin alfa A bloodless approach for the treatment of perioperative anemia Clin Orthop Relat Res 1998; (357): 60-7.
[17] Billote D, Glisson S, Green D, Wixson R. A prospective randomized study of preoperative autologous donation for hip replacement surgery J Bone Joint Surg Am 2002; 84(8): 1299-304.
[18] Hatzidakis A, Mendlick M, Mckillip T, Reddy R, Garvin KL. Preoperative autologous donation for total joint arthroplasty.an analysis of risk factors for allogenic transfusion J Bone Joint Surg Am 2000; 82(1): 89-100.
[19] Woronoff-Lemsi MC, Arveux P, Limat S, Morel P, Le Pen C, Cahn JY. Erythropoietin and preoperative autologous blood donation in the prevention of hepatitis C infection: necessity or luxury? Transfusion 1999; 39(9): 933-7.
[20] 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-.
[21] Liu X, Zhang X, Chen Y, Wang Q, Jiang Y, Zeng B. Hidden blood loss after total hip arthroplasty J Arthroplasty 2011; 26(7): 1100-5.
[22] 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.
[23] Coleman T, Brines M. Science review: Recombinant human erythropoietin in critical illness: a role beyond anemia? Crit Care 2004; 8(5): 337-41.
[24] Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin JAMA 2005; 293(1): 90-5.
[25] Brines M, Cerami A. Discovering erythropoietin's extrahematopoietic functions: biology and clinical promise Kidney Int 2006; 70(2): 246-50.
[26] Henke M, Laszig R, Rube 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.
[27] Leyland-Jones B, Semiglazov V, Pawlicki M, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study J Clin Oncol 2005; 23(25): 5960-72.
[28] 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.
[29] 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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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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