Introduction

Total knee replacement (TKR) is one of the most performed procedures for knee osteoarthritis. An important concern is blood loss, which can range from 726 to 1,768 ml^1,2. It derives from soft tissues release, osteotomies on the femur and tibia, and dredging of the marrow cavity³, seriously impacting patients with co-morbidities and impaired hematopoietic ability, and often requiring blood transfusions and prolonged hospital stays, ultimately increasing health risks and economic costs. While transfusions may be necessary, they can cause anaphylactic reactions, circulatory overload, renal failure, lung injury, infection, immunosuppression, and death⁴. Blood management is, therefore, a key component in optimizing patient care.

Strategies to reduce bleeding include intra-articular injections of tranexamic acid (TXA)⁵, pharmacological agents^6,7, blood reinfusion systems, protocols for tourniquets and drains⁸, autologous platelet gels⁹, minimally invasive or computer-aided surgery^10,11, and continuous passive motion machines. TXA acts by inhibiting plasminogen activation, blocking its lysing-binding sites, and it was shown¹² to provide a significant bleeding reduction without disadvantages like systemic absorption of thromboembolic complications. Similar effects were reported for agents like bupivacaine, epinephrine, and norepinephrine¹³, administered locally during the surgical procedure.

In the last decade, those strategies have been combined into an evidence-based multimodal approach called “fast track” (FT), or “enhanced recovery” (ER). Its main concepts are: anesthesia, fluid therapy, pain therapy, and early post-operative mobilization^14,15. This approach shows¹⁶ a reduction of convalescence time, improved clinical results, reduction in morbidity and mortality, and reduction in length of stay, and it does not compromise patient safety or increased complication rates.

Further improvement is sought, especially for post-operative limb positioning. Traditionally, replaced knees have been placed in extension, with a compressive dressing to reduce bleeding. This has been found to be able to reduce post-operative flexion at 6 weeks follow-up and to minimally influence transfusion rates; therefore, knee flexion has been suggested^17,18. The rationale is that this position would reduce tension on the popliteal vein, increasing venous return, reducing venous pressure, and reducing hidden blood loss¹⁹. Moreover, the compression of soft tissues obtained in a flexed knee could decrease the space for bleeding and improve the postoperative range of motion (ROM)²⁰.

The optimal post-operative position is still under debate, along with the amount of time required for significant blood loss control. Hypothetically, deep flexion should provide greater bleeding control, but low compliance, wound complication, and residual deformities could be expected. On the contrary, lower degrees of flexion could be much more tolerated and have no influence on wound healing but may not reduce the need for transfusions. These protocols may require prolonged flexed positioning for up to 48 or 72 hours and are, therefore, incompatible with an FT regimen.

The main purpose of this paper was to compare three blood management protocols in patients who underwent TKA. The first hypothesis was that a combination of LIA (local infiltration analgesia), TXA, no drain, and a short (3 hours) post-operative high flexion regimen (group B) would drastically reduce blood loss and transfusion rate with respect to our standard protocol (group A). The secondary hypothesis was that a short (3 hours) postoperative high flexion regimen (group B) may be superior to a postoperative knee extension regimen (group C) when the other variables remain unchanged.

Materials and Methods

This is a case-control and observational study. The study was conducted according to the guidelines of the Declaration of Helsinki. All patients gave informed consent prior to enrollment. Approval of the Regional Ethical Committee was not deemed necessary by Hospital Direction since some of the proposed strategies were already practiced individually in our institution.

A Fast Track protocol for blood management was applied in our Institution in January 2018. The first consecutive patients undergoing primary TKA for disabling knee osteoarthritis were enrolled in this prospective observational monocentric study. Patients with revision surgery, a history of thromboembolism, bleeding disorders, renal failure, rheumatoid arthritis, or similar conditions were excluded. Patients with previous knee surgery, except for meniscectomy, were excluded as well. The study group was made up of 75 patients. A control group was created to review the same continuous number of previously operated patients, who, therefore, were treated with our standard blood management protocol. Lastly, in order to describe possible differences arising from a different post-operative limb positioning, a third group of 75 consecutive patients (respecting inclusion and exclusion criteria) was enrolled. The final population was made of 225 consecutive patients divided into three groups.

Group A – Control Group (n=74)

A standard blood management protocol was used in this group. A urinary catheter was placed in all cases. Non-selective epidural anesthesia was administered. In the preoperative phase, no premedication was given. No TXA was used either intravenously or intra-articularly. A tourniquet was used throughout the procedure. No LIA was administered. Two drains were placed (under and above the fascia) before wound closure. The limb was left extended with drains in place for 48 hours. A blood reinfusion system was always adopted; blood collected within the first five hours was re-infused. Patient ambulation and CPM (once a day, 20 minutes) were started after drain removal. Cryotherapy was used after each kind of mobilization and at least 5 times a day for 20 minutes. On day 3 or 4, patients were instructed and assisted in climbing and descending a ramp of stairs. Discharge from the hospital was set on days 5 to 6.

Group B – Fast Track Study Group, Knee Flexed (n=73)

This group represents the first cohort of patients undergoing our FT protocol. Urinary catheter was never used. Selective epidural anesthesia was administered, aiming to minimize the effect on the contralateral limb and detrusor muscle. Preoperative pre-medication with hydrocortisone sodium succinate (500 mg/5 mL) i.v. and TXA 1,000 mg i.v. were given half an hour before surgery. Intra-operatively tourniquet was used throughout the procedure. A second dose of 1,000 mg of TXA was given i.v. at tourniquet removal, and a third dose of 1,000 mg was injected intra-articular after capsule watertight closure diluted in 20 cc of saline. Before implantation of the prosthetic components, LIA was administered peri-capsularly and subcuticularly (Chirocaine 150 mg and Adrenalin 0.5 mg diluted in 25 cc of saline). The medullary canal was closed with bone cement. No drain was placed. After skin closure, the limb was placed for three hours in 110-120° flexion on a homemade jig (Figure 1). A single pill of methylprednisolone 16 mg was given the morning after surgery. At the removal of the jig, each patient was mobilized under assistance and instructed to walk with crutches and full weight bearing for a short distance (i.e., around the bed). A CPM machine was also applied, one time a day, for 20 minutes starting on day 1 postoperatively. Cryotherapy was used after each kind of mobilization and at least 5 times a day for 20 minutes. On day 2 or 3, patients were instructed and assisted in climbing and descending a ramp of stairs. Discharge from the hospital was set on day 4.

Figure 1. Patient’s operated leg on the custom-made flexion jig used in this study.

Group C – Fast Track Study Group, Knee Extended (n=73)

An identical FT protocol was applied in this group, only changing the variable of post-operative knee positioning. The patient’s knee was kept extended for three hours. After this, patients were allowed to mobilize and walk around the bed.

Each patient of the three groups had antibiotics (Cefazolin 2 gr, intravenously, 30 minutes before surgery and 1 gr the morning after surgery), fluid therapy (2 L/day of electrolytic saline during the first 24 hours and 1 L/day until the 48^th hour), and DVT-prophylaxis (sodium enoxaparin, 4,000 IU, subcutaneously; starting 12 hours after surgery, and then 1/day for 35 days).

Surgery was standardized and performed by the two senior authors (NC, DE). It consisted of a medial parapatellar approach to implant a cemented bi- or tri-compartmental knee prosthesis (Attune, DePuy, Warsaw, Indiana, USA).

Pre-Operative and Post-Operative Evaluation

Age at surgery, body mass index, percentage of males and females, pre-operative hemoglobin (g/dl), pre-operative hematocrit (%), and pre-operative blood volume were recorded and evaluated.

Primary outcome tools were hemoglobin and hematocrit values on days 1 and 2 after surgery, blood loss (ml), number of additional blood tests, number of blood transfusions, amount of transfused blood units, and length of hospitalization. Blood volume was calculated with Nadler’s formula²¹, while blood loss was calculated according to Gross’s formula²². The trigger for blood transfusion was set for hemoglobin lower than 8 g/dl in healthy patients and lower than 10 g/dl in patients with relevant heart disease.

Statistical Analysis

Statistical analysis was performed to compare each group for homogeneity and to compare pre- and post-operative variables of each group. Continuous and non-continuous values were compared using a Student’s t-test and Chi-square test, respectively. To improve the results, the ANOVA test was used to compare continuous variables, and the Chi-square (χ²) test was employed for categorical variables such as gender among the three groups. A p-value was considered significant if lower than 0.05.

Results

The study cohort consisted of 225 patients equally distributed into 3 groups. Five patients were excluded (one patient from group A had an incomplete set of data; one patient from group B and three patients from group C were unable to have TXA for deep vein thrombosis history and severe heart disease). Age, BMI, gender, preoperative hemoglobin values, hematocrit values, and estimated blood volume (according to Nadler’s formula) are reported in Table 1. Comparisons between groups for each item did not show any significant difference (p>0.05), demonstrating an appropriate homogeneity except for BMI and preoperative hematocrit.

Table 1. Pre-operative values for each group.

BMI=body mass index; Hb=hemoglobin; HCT=hematocrit; EBV=estimate blood volume. *: Student’s t-test; ^§: Chi-Square test.

Postoperative outcomes are shown in Table 2. Comparisons between the results of group A and group B showed statistical differences for all variables (p<0.05). Specifically, on the second postoperative day, there was a significantly higher hemoglobin drop and blood volume loss in group A (3.9 g/dl and 1,450 ml) compared to group B (2.6 g/dl and 892 ml). Moreover, patients in group A required a significant number of blood transfusions compared to patients in group B (13% vs. 0%). The length of hospital stays significantly decreased from 6.5 days to 6 days (p<0.05). Analysis was also confirmed with multigroup testing.

Comparisons between the results of group A and group C showed statistical differences for all variables (p<0.05). Specifically, on the second postoperative day, there was a significantly higher hemoglobin drop and blood volume loss in group A (3.9 g/dl and 1,450 ml) than in group B (2.5 g/dl and 886 ml). Moreover, patients in group A required a significant number of blood transfusions compared to group C (13% vs. 2.7%). The length of hospital stays significantly decreased from 6.5 days to 5.2 days (p>0.05).

Comparisons between groups B and C did not show statistical differences for any of the examined variables (p>0.05), but the length of hospital stay decreased from 6 days to 5.2 days (p>0.05).

Table 2. Results obtained comparing each post-operative regimen.

Hb=hemoglobin; HCT=hematocrit. *: Student’s t-test; ^§: Chi-Square test.

Discussion

This study describes a monocentric experience of blood management in TKR. The previous ordinary protocol (group A) was compared to a recently adopted “Fast Track” protocol (group B) with its slightly modified version in order to assess the most advantageous post-operative knee position (group C). The main strengths are the large cohort of consecutive patients evaluated and the standardization in surgical technique, prosthetic implants, and post-operative rehabilitation.

Results provided show that both FT groups (B and C) obtained significantly better values in terms of hemoglobin drop and need for blood transfusions, compared to group A. Similarly, a significant reduction in the length of hospital stay was seen, favoring the application of FT protocols, with an average reduction of 0.5 to 1.3 days compared to group A (Table 2). Instead, no statistically significant differences were found between groups B and C for hemoglobin drop, blood loss, or need for transfusions. Therefore, it can be assumed that a high post-operative knee flexion positioning (110-120°), kept for 3 hours, does not influence post-operative bleeding. The three-hour period of flexion was selected for a practical reason: it is a relatively short period of time that can allow for early mobilization and ambulation even for a patient operated on in the late afternoon. If a six-hour period of flexion were to be chosen, in fact, those patients operated on in the afternoon would not have been able to walk on the same day of surgery. Lastly, a statistically significant difference was observed in the length of hospital stay, among all groups. If this could be expected by comparing group A with B and C, it is somewhat unexpected comparing the two FT groups (6±0.8 days for group B vs. 5.2±0.8 days for group C). Since no difference in bleeding was seen among these two groups, the difference could be explained by increased confidence and familiarity developed by surgeons, physicians, and rehabilitators, while adopting FT protocols. Group C, in fact, being the latest group of consecutive patients, could suffer from a sort of “confidence bias”, which ultimately led to a reduction in hospitalization.

In terms of general outcomes, the reported results are in line with the published literature. Several studies²³ advocated the application of many of the strategies included in the FT regimen, especially for TXA, a synthetic antifibrinolytic agent which retards fibrinolysis and blood clot degradation. It was recommended for routine use in primary THA and TKA to reduce blood loss by several meta-analyses^24-26, and it was also shown to reduce total blood loss by intra-articular injection of a 30 mg/ml dose²⁷. Moreover, non-use of TXA was demonstrated to be a risk factor for blood transfusions²⁸ and the strongest independent risk factor among octogenarians and nonagenarians²⁹. But “Fast Track” protocols are a set of strategies working together as a whole. Comprehensive protocols, in fact, were demonstrated to be extremely helpful³⁰ even after revision surgeries³¹. Similar results were published by Rostund and Kehlet³², and by Holm et al³³ showing consistent pain relief, along with recovery of an appropriate health-related QoL, efficiency, functionality, and high patients’ satisfaction, which should be considered the ultimate goal of joint replacement. Even early mobilization is important to reduce the risk of thrombosis and to initiate rapid recovery, as demonstrated by several authors^34-36.

Regarding post-operative limb positioning, a debate is ongoing, and our results seem to suggest little to no influence on the overall outcomes. Knee flexion is thought to decrease the tension of the popliteal vein, increasing venous return and diminishing venous pressure, therefore leading to a lower hidden blood loss³⁷. This reduction was demonstrated to help to restore the functional ROM by diminishing the degree of joint effusion and swelling, allowing patients to perform simple quadriceps exercises earlier^38,39. Several protocols of knee flexion have been proposed^40-43. However, only those promoting 3 or 6 hours of flexion may be useful in an FT setting aimed at patients’ ambulation on the same day of surgery. There are few studies available in literature in which high knee flexion was adopted for a short period of time. Napier et al³⁹ did not find significant differences in blood loss and ancillary findings among the group with the knee in extension and the group with the knee kept flexed at 120° for 3 hours. Instead, they found a significant reduction of blood loss in patients who kept 120° flexion for 6 hours with respect to 3 hours or knee extended. There was no significant difference in blood transfusion among the three groups. This study, however, differed from ours in that TXA was not used, patient mobilization and ambulation were started on day 1 after surgery, and the threshold for blood transfusion was also different³⁹. Antinolfi et al⁴⁴ compared a control group, a flexion group (3 hours flexed at 90° and 3 hours flexed at 50°), and a TXA group (500 mg intra-articular at the end of TKR procedure). The authors⁴⁴ found no significant differences in blood loss and hemoglobin drop among the control and flexion group⁴⁴. However, there was a significant decrease in blood loss and an increase in hemoglobin values (only on day 1) for the TXA group with respect to other groups. In contrast to our study, drainage was used and kept for 48 hours, and the blood loss was considered as the actual amount of blood present in the drainage 44 instead of calculating it from the hematocrit values²². Panni et al²⁷ compared a flexion group (6 hours, 90°) and an extension group as well. They found a significant decrease in calculated blood loss (24 hours) and hemoglobin drop (24 and 72 hours) in the flexion group compared to the extension group. There were 5 transfusions in the extension group and 0 in the flexion group. Suction drainage was positioned and kept for 24 hours. All the patients had 1,000 mg TXA iv before skin incision²⁷. Madarevic et al⁴⁵ compared a flexion group (6 hours, 90°) and an extension group. They were unable to prove any statistical difference in blood loss (from suction drainage) and hemoglobin loss among the two groups. TXA was not used in this study⁴⁵.

Lastly, FT regimens have been associated with some complications. A little concern arose regarding the risk of wound and skin complications with high knee flexion. Yashar et al³⁷ studied continuous passive movement (CPM) with early flexion and reported an episode of skin necrosis among 104 patients having an accelerated CPM regimen. Skin necrosis has also been reported³⁸ with intra-articular injections of adrenaline (epinephrine) without using a drain post-operatively. However, a more recent study by Napier et al³⁹, did not show a single episode of wound breakdown or skin necrosis despite an early passive high knee flexion up to 6 hours post-operatively. Other authors showed how keeping the knee in a flexion position could induce a flexion contracture, reducing ROM and increasing wound complications due to a lower oxygen tension at the wound edges, delaying the healing of the wound⁴⁵. On the contrary, flexed knee position was also shown⁴⁶ to be effective in reducing blood transfusions and improving ROM by a recent metanalysis in which no complications of any sort were noted.

In this study, two major complications were observed, all regarding group A: a deep prosthetic infection, acute atrial fibrillation, and consequent heart failure, which required the patient to be moved into the intensive care unit. This female patient had a preoperative Hb of 11.1 g/dl and a second-day Hb of 9.8 g/dl. She received two blood units (the trigger was 10 g/dl in patients with known heart disease), but this was not enough to prevent atrial fibrillation and heart failure. No major complications occurred in groups B and C. Minor skin blistering was observed once in group B and twice in group C. No wound problems were observed in either group.

Limitations

This paper has some limitations. First, the comparison between groups A and B/C could have only a descriptive value because of the many different variables characterizing each group. However, there is not a single factor that can provide optimal post-operative bleeding control by itself. Therefore, a comparison between an old-fashioned yet widespread blood management protocol and newer approaches able to allow for early mobilization and recovery was deemed appropriate. Second, factors that may have had a role in bleeding, such as chronic drug therapies, smoke habits, comorbidities, surgical time, and tourniquet time, were not taken into account, although those were not seen as a limit for the application of one regimen or another. Third, pre-operative and post-operative ROM evaluations were not recorded, but the study was focused on bleeding control over the immediate post-operative timespan, and therefore, ROM was not considered a useful outcome tool.

Conclusions

In conclusion, our results support the application of a newer “Fast Track” comprehensive regimen for total knee replacement despite a more traditional protocol with drain application.

High knee flexion for three hours was not statistically superior to an extended limb position in terms of blood loss, need for blood transfusions, and complications. Therefore, the adoption of an FT protocol with an extended limb for three hours before ambulation is preferred.

Acknowledgments

The authors would like to deeply thank Dr. Matteo Barabani, Nurse Head and Coordinator of the Orthopaedic Unit, Casa di Cura “Villa Igea” Hospital, for his work and dedication.

Informed Consent

All patients gave informed consent prior to enrollment.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding

None.

Data Availability

Data sets are available in Excel format upon direct request to the corresponding author.

References

1. Hinarejos P, Corrales M, Matamalas A, Bisbe E, Cáceres E. Computer-assisted surgery can reduce blood loss after total knee arthroplasty. Knee Surg Sports Traumatol Arthrosc 2009; 17: 356-360.
2. Wong J, Abrishami A, El Beheiry H, Mahomed NN, Davey JR, Gandhi R, Syed KA, Ovais Hasan SM, De Silva Y, Chung F. Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint Surg Am 2010; 92: 2503-2513.
3. Sehat KR, Evans RL, Newman JH. 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: 561‑565.
4. Gillet P, Rapaille A, Benoit A, Ceinos M, Bertrand O, de Bouyalsky I, Govaerts B, Lambermont M. First-time whole blood donation: a critical step for donor safety and retention on first three donations. Transfus Clin Biol 2015; 22: 312-317.
5. Zhao-Yu C, Yan G, Wei C, Yuejv L, Ying-Ze Z. Reduced blood loss after intraarticular tranexamic acid injection during total knee arthroplasty: a meta-analysis of the literature. Knee Surg Sports Traumatol. Arthrosc 2014; 22: 3181-3190.
6. Kim TK, Chang CB, Koh IJ. Practical issues for the use of tranexamic acid in total knee arthroplasty: a systematic review. Knee Surg Sports Traumatol Arthrosc 2014; 22: 1849-1858.
7. Muñoz M, Ariza D, Garcerán MJ, Gómez A, Campos A. Benefits of postoperative shed blood reinfusion in patients undergoing unilateral total knee replacement. Arch Orthop Trauma Surg 2005; 125: 385-389.
8. Al-Zahid S, Davies AP. Closed suction drains, reinfusion drains or no drains in primary total knee replacement? Ann R Coll Surg Engl 2012; 94: 347-350.
9. Horstmann WG, Slappendel R, van Hellemondt GG, Wymenga AW, Jack N, Everts PAM. Autologous platelet gel in total knee arthroplasty: a prospective randomized study. Knee Surg Sports Traumatol Arthrosc 2011; 19: 115-121.
10. Fu Y, Wang M, Liu Y, Fu Q. Alignment outcomes in navigated total knee arthroplasty: a meta-analysis. Knee Surg Sports Traumatol Arthrosc 2012; 20: 1075-1082.
11. Wegrzyn J, Parratte S, Coleman-Wood K, Kaufman KR, Pagnano MW. The John Insall award: no benefit of minimally invasive TKA on gait and strength outcomes: a randomized controlled trial. Clin Orthop Relat Res 2013; 471: 46-55.
12. Nielsen CS, Jans Ø, Ørsnes T, Foss NB, Troelsen A, Husted H. Combined intra-articular and intravenous tranexamic acid reduces blood loss in total knee arthroplasty: a randomized, doubleblind, placebo-controlled trial. J Bone Joint Surg Am 2016; 98: 835-841.
13. Bierbaum BE, Callaghan JJ, Galante JO, Rubash HE, Tooms ER, Welch RB. An analysis of blood management in patients having a total hip or knee arthroplasty. J Bone Jt Surg 1999; 81: 2-10.
14. Khan SK, Malviya A, Muller SD, Carluke I, Partington PF, Emmerson KP, Reed MR. Reduced short-term complications and mortality following Enhanced Recovery primary hip and knee arthroplasty: results from 6,000 consecutive procedures. Acta Orthop 2014; 85: 26-31.
15. Wainwright TW, Gill M, McDonald DA, Middleton RG, Reed M, Sahota O, Yates P, Ljungqvist O. Consensus statement for perioperative care in total hip replacement and total knee replacement surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations. Acta Orthop 2020; 91: 3-19.
16. Schneider M, Kawahara I, Ballantyne G, McAuley C, Macgregor K, Garvie R, McKenzie A, Macdonald D, Breusch SJ. Predictive factors influencing fast track rehabilitation following primary total hip and knee arthroplasty. Arch Orthop Trauma Surg 2009; 129: 1585-1591.
17. Ong SM, Taylor GJ. Can knee position save blood following total knee replacement? Knee 2003; 10: 81-85.
18. Timlin M, Moroney P, Collins D, Toomey D, O’Byrne J. The 90/90 pillow reduces blood loss after knee arthroplasty: a prospective randomized case-control study. J Arthroplasty 2003; 18: 765-768.
19. Fu X, Tian P, Li ZJ, Sun XL, Ma XL. Postoperative leg position following total knee arthroplasty influence blood loss and range of motion: a meta-analysis of randomized controlled trials. Curr Med Res Opin 2016; 32: 771-778.
20. Li B, Wen Y, Wu H, Qian Q, Lin X, Zhao H. The effect of tourniquet use on hidden blood loss in total knee arthroplasty. Int Orthop 2009; 33: 1263-1268.
21. Nadler SB, Hidalgo JH, Bloch T. Prediction of Blood Volume in Normal Human Adults. Surgery 1962; 51: 224-232.
22. Gross JB. Estimating allowable blood loss: corrected for dilution. Anesthesiology 1983; 58: 277-280.
23. Hardy JF, Belisle S. Natural and synthetic antifibrinolytics: inert, poisonous or therapeutic agents? Can J Anaesth 1997; 44: 913-917.
24. Sehat KR, Evans R, Newman JH. How much blood is really lost in total knee arthroplasty? Correct blood loss management should take hidden loss into account. Knee 2000; 7: 151-155.
25. Alshryda S, Sarda P, Sukei KM, Nargol A, Blenkinsopp J, Mason JM. Tranexamic acid in total knee replacement: a systematic review and meta-analysis. J Bone Joint Surg Br 2011; 93: 1577-1585.
26. Gandhi R, Evans HM, Mahomed SR, Mahomed NN. Tranexamic acid and the reduction of blood loss in total knee and hip arthroplasty: a meta-analysis. BMC Res Notes 2013; 6: 184.
27. Panni AS, Cerciello S, Vasso M, Del Regno C. Knee flexion after total knee arthroplasty reduces blood loss. Knee Surg Sports Traumatol Arthrosc 2014; 22: 1859-1864.
28. Mello Pavao D, Heringer EM, Jorio Almeida G, Rocha de Faria JL, Sattamini Pires E, Albuquerque R, Branco de Sousa E, Labronici PJ. Predictive and protective factors for allogenic blood transfusion in total knee arthroplasty. A retrospective cohort study. J Orthop 2023 21; 40: 29-33.
29. Hanreich C, Cshner F, Krell E, Gausden E, Cororaton A, Gonzalez Della Valle A, Boettner F. Blood management following total joint arthroplasty in aging population: can we do better? J Arthroplasty 2022; 37: 642-651.
30. Maccagnano G, Pesce V, Noia G, Coviello M, Vicenti G, Vitiello R, Ziranu A, Spinarelli A, Moretti B. The effects of a new protocol on blood loss in total knee arthroplasty. Orthop Rev (Pavia) 2022; 14: 37625.
31. Winther SB, Foss OA, Wik TS, Davis SP, Engda M, Jessen V, Husby OS. 1-year follow-up of 920 hip and knee arthroplasty patients after implementing fast-track Good outcomes in a Norwegian university hospital. Acta Orthopaedica 2015; 86: 78-85.
32. Rostlund T, Kehlet H. High-dose local infiltration analgesia after hip and knee replacement—what is it, why does it work, and what are the future challenges? Acta Orthop 2007; 78: 159-161.
33. Holm B, Kristensen MT, Myhrmann L, Husted H, Andersen LO, Kristensen B, Kehlet H. The role of pain for early rehabilitation in fast track total knee arthroplasty. Disabil Rehabil 2010; 32: 300-306.
34. Husted H, Holm G, Jacobsen S. Predictors of length of stay and patient satisfaction after hip and knee replacement surgery: fast-track experience in 712 patients. Acta Orthop 2008; 79: 168-173.
35. Husted H, Otte KS, Kristensen BB, Orsnes T, Kehlet H. Readmissions after fast-track hip and knee arthroplasty. Arch Orthop Trauma Surg 2010b; 130: 1185-1191.
36. Husted H, Otte KS, Kristensen BB, Orsnes T, Wong C, Kehlet H. Low risk of thromboembolic complications after fast-track hip and knee arthroplasty. Acta Orthop 2010c; 81: 599-605.
37. Yashar AA, Venn-Watson E, Welsh T, Colwell CW Jr, Lotke P. Continuous passive motion with accelerated flexion after total knee arthroplasty. Clin Orthop Relat Res 1997; 345: 38-43.
38. Callaghan JJ, O’Rourke MR, Liu SS. Blood management: issues and options. J Arthroplasty 2005; 20: 51-54.
39. Napier RJ, Bennett D, McConway J, Wilson R, Sykes AM, Doran E, O’Brien S, Beverland DE. The influence of immediate knee flexion on blood loss and other parameters following total knee replacement. Bone Joint J 2014; 96-B: 201-209.
40. Ma T, Khan RJ, Carey Smith R, Nivbrant B, Wood DJ. Effect of flexion/extension splintage post total knee arthroplasty on blood loss and range of motion-a randomized controlled trial. Knee 2008; 15: 15-19.
41. Liu J, Li YM, Cao JG, Wang L. Effects of knee position on blood loss following total knee arthroplasty: a randomized, controlled study. J Orthop Surg Res 2015; 10: 69-73.
42. Zeng Y, Haibo S, Canfeng L, Yuangang W, Bin S. Effect of Knee Flexion Position and Combined Application of Tranexamic Acid on Blood Loss Following Primary Total Knee Arthroplasty: A Prospective Randomized Controlled Trial. Int Orthop 2018; 42: 529-535.
43. Bin L, Wen Y, Liu D, Tian L. The Effect of Knee Position on Blood Loss and Range of Motion Following Total Knee Arthroplasty. Knee Surg Sports Traumatol Arthrosc 2012; 20: 594-599.
44. Antinolfi P, Innocenti B, Caraffa A, Peretti G, Cerulli G. Post-operative blood loss in total knee arthroplasty: knee flexion versus pharmacological techniques. Knee Surg Sports Traumatol Arthrosc 2014; 22: 2756-2762.
45. Madarevic T, Tudor A, Sestan B, Santic V, Gulan G, Prpic T, Ruzic L. Postoperative blood loss management in total knee arthroplasty: a comparison of four different methods. Knee Surg Sports Traumatol Arthrosc 2011; 19: 955-959.
46. Li B, Wang G, Wang Y, Bai L. Effect of two limb positions on venous hemodynamics and hidden blood loss following total knee arthroplasty. J Knee Surg 2017; 30: 70-77.