Tranexamic Acid Decreases Incidence of Blood Transfusion in Simultaneous Bilateral Total Knee Arthroplasty

    Tranexamic Acid Decreases Incidence of Blood Transfusion in Simultaneous Bilateral Total Knee Arthroplasty Deren Bagsby M.D., Christopher Samujh M.D., Jacqueline Vissing BS, Janene A. Empson RN, ONC, Donald L. Pomeroy MD, Arthur Malkani M.D PII: DOI: Reference:

S0883-5403(15)00552-5 doi: 10.1016/j.arth.2015.06.040 YARTH 54581

To appear in:

Journal of Arthroplasty

Received date: Revised date: Accepted date:

18 February 2015 24 May 2015 15 June 2015

Please cite this article as: Bagsby Deren, Samujh Christopher, Vissing Jacqueline, Empson Janene A., Pomeroy Donald L., Malkani Arthur, Tranexamic Acid Decreases Incidence of Blood Transfusion in Simultaneous Bilateral Total Knee Arthroplasty, Journal of Arthroplasty (2015), doi: 10.1016/j.arth.2015.06.040

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ACCEPTED MANUSCRIPT Tranexamic Acid Decreases Incidence of Blood Transfusion in Simultaneous

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Deren Bagsby, M.D. 1 Christopher Samujh, M.D. 2 Jacqueline Vissing, BS 2 Janene A. Empson, RN, ONC 2 Donald L. Pomeroy, MD 2 Arthur Malkani, M.D 2 1. Department of Orthopaedic Surgery Indiana University School of Medicine 541 Clinical Drive, Suite 600 Indianapolis, IN 46202-5111 2. Department of Orthopedic Surgery University of Louisville School of Medicine 550 S. Jackson St., 1st Floor ACB Louisville, KY 40202 Corresponding Author Arthur Malkani, MD Department of Orthopedic Surgery University of Louisville School of Medicine 550 S. Jackson St., 1st Floor ACB Louisville, KY 40202 Phone: 502-852-5319 Fax: 502-852-7227 Email: [email protected]

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Bilateral Total Knee Arthroplasty

ACCEPTED MANUSCRIPT Abstract Blood management for simultaneous bilateral total knee arthroplasty (TKA)

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patients is more challenging than in unilateral arthroplasty. We examined if

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administration of tranexamic acid (TXA) to patients undergoing simultaneous bilateral TKA would reduce blood loss and decrease allogeneic blood transfusion

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requirements. A retrospective review of 103 patients, 57 in the control and 46 in the

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TXA group, was performed. There was a higher postop day 1 hemoglobin in patients receiving TXA (2.95 ± 1.33 versus 4.33 ± 1.19, p < 0.0001). There was also a

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decrease in the transfusion incidence with administration of TXA (17.4% versus

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57.9%, p < 0.0001). In conclusion, we have shown that TXA is an effective tool in reducing the transfusion rates by almost 70% in simultaneous bilateral total knee

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arthroplasty.

Keywords: Tranexamic acid; total knee arthroplasty; simultaneous bilateral; blood

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loss; transfusion; anemia

ACCEPTED MANUSCRIPT Introduction Total knee arthroplasty (TKA) procedures have continued to increase over

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the past decade due to its overwhelming effectiveness for the treatment of end-stage

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knee arthritis. This procedure is generally well tolerated with good outcomes, however, TKA is also associated with blood loss, at times necessitating allogenic

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blood transfusions1,2.Allogeneic blood transfusions have associated costs, the risk of

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transmitting blood borne pathogens, and of inducing an immune-modulatory response, which is a well-associated risk factor for peri-prosthetic joint infection3,4.

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Pharmacologic blood conservation strategies aimed at reducing the need for blood transfusion include preoperative autologous donation, preoperative use of

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erythropoietin, intraoperative hemo-dilution, administration of thrombotic agents

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to the wound, and postoperative reinfusion drains2,5. Additionally, the use of a

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tourniquet ensures a dry surgical field and minimal intraoperative bleeding, but it augments fibrinolysis stimulated by surgical trauma, which enhances release of

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plasmin at the site of vascular damage6-9. To further decrease perioperative bleeding and transfusions, pharmacologic agents have been introduced to minimize bleeding through the inhibition of blood clot degradation The use of tranexamic acid (TXA) to further decrease blood loss has increased in popularity with several studies documenting its efficacy at reducing blood loss and transfusion requirements in unilateral TKA6,10-17. Transexamic acid is a synthetic analog of the amino acid lysine and acts by competitively blocking the lysine-binding site of plasminogen, leading to inhibition of fibrinolysis. However, there is limited literature regarding the use of TXA in patients undergoing

ACCEPTED MANUSCRIPT concurrent bilateral TKA18-23. Blood management for simultaneous bilateral TKA patientsis considered more challenging than in unilateral arthroplasty. These

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patients have higher transfusion requirements and are more likely to benefit from

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anti-fibinolytic therapy. In bilateral TKA, transfusions are needed in up to 76% of patients, with an average of 2.6 units of packed red blood cells (pRBC) transfused

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per patients24. The purpose of this study was to determine if administration of

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intravenous TXA to patients undergoing simultaneous bilateral TKA would help reduce perioperative blood loss and decrease allogeneic blood transfusion

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requirements. Secondary outcome measures were postoperative complications, including those that occur as a result of allogeneic blood transfusions, and the safety

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of TXA.

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Method and Materials

After obtaining institutional review board approval, a retrospective review of

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our database and the electronic medical records was undertaken. We selected all patients who underwent bilateral simultaneous TKA secondary to osteoarthritis. All arthroplasties were performed at the same institution using a standardized surgical technique, and standardized prosthesis design. Patients received a combined femoral and sciatic nerve block plus total intravenous anesthesia (TIVA), which is a method of providing a general anesthetic without the use of inhalation agents. Patients with contraindication to TIVA received a combined femoral and sciatic nerve block with traditional general anesthesia using inhalation agents.

ACCEPTED MANUSCRIPT All patients in this study were given tranexamic acid unless they met one or more of the contraindications described by the manufacturer. A pneumatic

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tourniquet was utilized in all cases which was inflated prior to skin incision and

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deflated immediately prior to closure. A midline skin incision was followed by either a subvastus or medial parapatellar arthrotomy. Patients were given one

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intravenous 10 mg/kg dose of tranexamic acid (Cyclokapron, Pfizer; New York, NY),

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10 minutes prior to tourniquet deflation, as per our protocol. Closure was performed after hemostasis was achieved with electrocautery. All patients received

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drains, which were removed on postoperative day (POD) #2. Physical therapy and continuous passive motion machines were started on

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POD #1. All patients were started on low molecular weight heparin for DVT

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prophylaxis unless they were on another preoperative medication for

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cardiovascular disease. Postoperative hemoglobin (hgb) values were recorded routinely as part of a CBC on the morning of POD #1 and compared to a

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preoperative hemoglobin value 1–2 weeks prior to the surgery. A contemporary blood management protocol was applied in all patients. Our institution’s Blood Bank department set the guidelines for blood transfusion. Patients were considered for allogeneic blood transfusion, in the form of pRBC, if their hemoglobin was less than 8 g/dl and symptomatic (defined as syncope, lightheadedness, short of breath, fatigue, palpitations). Thromboembolic complications included deep vein thrombosis (DVT) and pulmonary embolism (PE). Rate of DVT or PE was determined by confirming radiological studies (venous doppler, chest CT, V/Q scans), ordered when clinical suspicion warranted such tests. Baseline patient

ACCEPTED MANUSCRIPT demographics including age, gender, and body mass index were recorded and compared between both groups.

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The primary outcome measured was the transfusion rate and the difference

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between the preoperative hgb and the postoperative day 1 hgb. Patients who were transfused intra-operatively were excluded from the study. The secondary

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outcomes were number of units transfused, estimated blood loss, rate of DVT/PE,

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and associated perioperative complications. Peri-operative complications were defined as contracture requiring manipulation under anesthesia, infection requiring

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irrigation and debridement, aseptic loosening requiring revision, reflex sympathetic dystrophy, and nerve palsy. Transfusion associated complications were defined as

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transfusion related acute lung injury, hemolytic reactions, transfusion associated

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bacterial sepsis, or confirmed blood pathogen infection.

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All analyses comparing the two groups were performed using Microsoft Excel 14.4.7. Two-sided independent t-test was used to compare all normally

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distributed continuous variables. Fischer’s exact test was used to compare all categorical variables. Statistical significance was defined as p< 0.05.

Results There were 103 patients; 57 in the control and 46 in the TXA group. There were no differences seen between the two groups in any parameter, except a higher BMI (34.48± 8.71 versus 30.79±6.14, p = 0.01) was seen in the TXA group. Additionally, there was a strong trend towards a higher pre-operative hgb (g/dL) in the control group (14.24 ± 1.28 versus 13.75 ± 1.45, p = 0.06), though this was not

ACCEPTED MANUSCRIPT statistically significant. We observed a statistically significantly higher hgb(g/dL)on POD#1 (10.8± 1.48 versus 9.91± 1.27, p = 0.001) in patients administered TXA

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which was supported by the finding of a reduced calculated hgb(g/dL)drop in these

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patients from preoperative to POD#1 (2.95 ± 1.33 versus 4.33 ± 1.19, p < 0.0001).

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Overall, 61 units were transfused in the control (1.1 units/patient) group compared with 17 units in the TXA (0.37 units/patient) group (p < 0.001).There was a

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statistically significantly decrease in the transfusion incidence in patients that received TXA (17.4% versus 57.9%, p < 0.0001). This accounted for an approximate

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70% reduction in the total incidence of transfusion in patients receiving TXA.

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Furthermore, the average number of units transfused both intra-operatively (0 ± 0 versus 0.07 ± 0.21) and post-operatively (0.37 ± 0.88 versus 1.00 ± 1.04) was

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reduced with the use of TXA (p=0.04 and p=0.0001, respectively).

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There were no differences in post-operative thromboembolic complications between the control group and treatment group, (4.3% versus 1.8%, p = 0.59).

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There were two patients in the control group and one patient in the treatment group that developed a thromboembolic complication. All 3 patients had both a ultrasound confirmed DVT and a CT confirmed PE. There was no difference in general post-operative complications (19.6% versus 19.3%, p = 0.97). In the TXA group, 4 patients had contractures requiring a manipulation under anesthesia, 2 had unilateral aseptic loosening requiring a revision, 2 had unilateral infections requiring irrigation and debridement with polyethylene liner exchange, and 1 had bilateral peroneal nerve palsy. In the control group, there were 3 patients with contractures requiring manipulation under anesthesia, 3 with reflex sympathetic

ACCEPTED MANUSCRIPT dystrophy treated with medication, 2 with unilateral aseptic loosening requiring revision, 2 with unilateral infection requiring irrigation and debridement with

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polyethylene liner exchange, and 1 with an intraoperative non-displaced medial

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condyle fracture. No transfusion related complications were seen in either group.

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Discussion

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Osteoarthritis is not a unilateral disease, as approximately 10% of patients who undergo unilateral TKA will have contralateral TKA surgery within 1

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year25.From 1990 to 2004, use of simultaneous bilateral TKA more than doubled for the entire population,almost tripling among females26. Supporters of single stage

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bilateral TKA cite numerous benefits, including: low complication rates, high patient

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satisfaction scores,reduction of potential risks including nerve palsy, vascular injury,

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muscle damage and postoperative swelling/stiffness, reduced length of hospital stay, better consequences of physical therapy, and lower costs27-35.Furthermore,

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bilateral TKA has demonstrated similar or better results for range of motion, Oxford Knee Score, Knee Society score, survivorship at 7 and 10 years, 36- and 12-Item Short Form Health Survey, and Western Ontario and McMaster Universities Arthritis index, when compared to staged unilateral surgery28,30,36-39. However, others have shown that bilateral TKA performed during the same anesthetic session is associated with higher systemic complication rates, increased risk of cardiac complications, and increased morbidity and mortality24,28,36-38,4044.Memtsoudis

et al demonstrated an increase of in hospital morbidity 0.3% to 0.5%,

while Parvizi et al showed an increased 30-day mortality rates from 0.17% to

ACCEPTED MANUSCRIPT 0.49%40,45. A primary component of this increased risk is the greater incidence of myocardial ischemia, which is 4 to 6 times more frequent in single staged bilateral

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TKA compared with unilateral24,44. This complication isstrongly correlated with the

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increased incidence of post-operative anemia, which can result in a 17 fold increased risk of allogeneic blood transfusions after simultaneousbilateral TKA37,45-

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48.

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Allogeneic blood transfusions are a major concern following TKA, even more so with bilateral simultaneous TKA. Blood loss causing anemia may produce

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hypotension, fatigue, weakness, and loss of balance that can result in delayed mobilization and extended length of hospital stay, blood transfusion, and increased

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cost49-51.The need for transfusion is concerning as increasing data suggest that both

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bleeding and resultant transfusions are associated with an increased risk of adverse

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outcomes.The increased requirement of blood transfusion in simultaneous bilateral TKA patients predisposed them to these increased postoperative

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morbidities.Allogeneic blood transfusions are associated with heightened risk of transfusion related acute lung injury, hemolytic reactions, volume overload, thromboembolism,immune sensitization,increased postoperative bacterial infection, and transfusion associated sepsis52-57.Albeit small, there is still a finite chance of disease transmission and transfusion reaction can complicate the patient’s postoperative course substantially. Concerns of patients and clinicians regarding blood safety have generated enthusiasm for the use of technologies intended to reduce the use of allogeneic blood.Alternative strategies, both pharmacologic and non-

ACCEPTED MANUSCRIPT pharmacologictreatments, for reducing blood loss have been developed. Despite blood-sparing techniques such as cell salvage, normo-volemichemo-dilution, and

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surgical hemostasis, bleeding requiring transfusion is still frequently encountered

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peri- and post-operatively.

Many recent prospective randomized clinical trials and meta-analysis have

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reported TXA to be effective and safe in reducing allogenic blood transfusion and

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blood loss, without increasing thromboembolic complications, in unilateral total knee arthroplasty10-13. Additionally, a Cochrane review including 21 trials of

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tranexamic acid compared with controls in total hip and knee replacement, including 993 patients, demonstrated that tranexamic acid significantly reduces

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allogeneic blood transfusions but 56% and total amount of blood lost during

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perioperativeperiod by an average of 440mL59.Most of the external blood loss in

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TKA occurs in the first few hours postoperatively after removal of the tourniquet, when the TXA would be most effective. With the use of tranexamic acid for patients

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undergoing total knee arthroplasty, fewer patients are at risk for transfusion and related complications, because risk is calculated per unit of transfusion12.While it has been shown that TXA is effective at reducing measured loss, it does not significantly reduce the hidden loss, which may explain why there is still a requirement for allogeneic transfusion, albeit diminished18. There is a growing body of evidence that TXA, when used in simultaneous bilateral TKA, has a substantial impact on blood loss and decreases the need for post-operative transfusion.Kakar et al demonstrated a decreased total blood loss of 54% and decreased transfusion rate by 85% in 13 simultaneous bilateral TKA

ACCEPTED MANUSCRIPT patients in New Dehli60.In a prospective randomized double blind study, MacGillivray et al demonstrated decreased mean blood loss and transfusions

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volumes when TXA used in 20 patient groups undergoing simultaneous

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BKA19.Hedge et al, using a prospective comparative study of multiple 30 Indian patient groups, showed similar benefit of using TXA without difference in

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intravenous or intra-articular routes of administration22.Dhillon and colleagues

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found that TXA administered to 52 Indian patients undergoing single staged bilateral TKA reduced blood loss and decreased allogeneic blood transfusion

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requirements from 100% to 52% compared to their 56 controls20.Karam et al showed that intravenous TXA in 87 simultaneous bilateral TKA patientsresulted in

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reduced transfusion requirements23.Kim et al demonstrated no difference in total

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blood loss but a significant reduction in the allogeneic transfusion rate, 7% vs 27%,

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in 146 simultaneous bilateral TKA patients in Korea21. In this study, we retrospectively reviewed 103 primary total knee

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arthroplasties to assess the effectiveness of TXA in reducing blood loss and transfusion requirements.Our results show a statistically significant difference in postoperative hgb, change in hgb, and transfusion rate when TXA is utilized. We feel the drop in transfusion incidence is directly attributable to the use of TXA as that was the only variable changed between these two groups. While Yeager et al reported that patients who underwent bilateral TKA were at a higher risk of developing DVT or PE, and anti-fibrinolytics carry a theoretical increased risk of clotting, we found no difference in our rates of symptomatic DVT and PE33. The lack of significant excessive risk of venous thromboembolism with the use of anti-

ACCEPTED MANUSCRIPT fibrinolytics could be due to the systematic use of appropriate venous thrombosis prophylaxis. Equivocal rates to controls are similar to what has been demonstrated

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in large unilateral TKA meta-analysis12,13.

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While the literature on TXA is abundant, there is a lack of studies related to simultaneous bilateral TKA using tranexamic acid. To the author’s knowledge, this

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is one of the largest reported series from a single American institution detailing the

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impact of TXA on blood loss and transfusion for bilateral total knee arthroplasty. Our results confirm previously published studies in bilateral TKA showing a

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reduction in blood loss, higher postoperative hgb levels, and a decrease in transfusion rate compared to control. These results are similar to a previous study

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that demonstrated a decreased transfusion rate in primary unilateral TKA to almost

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zero with TXA61. The inability of TXA to reduce transfusion rates in simultaneous

patients.

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bilateral TKA further demonstrates the difficulty in blood management in these

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We acknowledge the retrospective nature of this review and the limitations that come with that, including the non-randomized design, not allowing for complete control of the perioperative variables such as demographics and comorbidities.However, this was a consecutive series as the same institutionand matched for variables felt most likely to influence outcomes.We did not evaluate blood drainage since diminishing allogenic blood transfusion was our main objective. Additionally, it is recognized that blood collected in intra-articular drains will not be an accurate reflection of total blood loss, due to covert accumulation in the tissues18,62,63.Routine duplex ultrasonographic screen for DVT was not

ACCEPTED MANUSCRIPT performed in our cohort, as patients with any signs or symptoms of thromboembolism are systematically evaluated. Therefore, it is possible that we

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missed a subclinical DVT or PE in these patients. We recognize that a much larger

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sample size would be required to determine any increased risk of DVT or PE with this protocol. Nevertheless, there was no statistical difference in symptomatic DVT

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or PE within the two groups.Despite these limitations, the strengths of this study

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include a homogenous design, which lacked confounding variables; it focused on a

a similar surgical technique.

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relatively large number of consecutive patientstreated at the same institution, using

In conclusion, we found that intravenous TXA administeredprior to

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tourniquet deflation in patients undergoing bilateral TKA results in reduced blood

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loss and need for transfusion. This diminished blood loss was statistically and

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clinically significant, with an almost 70% reduction in our transfusion rate.We believe that TXA is an effective tool in reducing the transfusion rates and its

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associated risks. Further works needs to be performed on the ideal dose and timing of TXA in patients undergoing simultaneous bilateral total knee arthroplasty to further decrease the transfusion incidence.

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ACCEPTED MANUSCRIPT Table 1. Patient and Outcome Variables

M F

p 0.39

23 (50%) 23 (50%) 34.48 +/- 8.71 169 +/- 24 121 +/- 23 82 +/- 21 3.61 +/- 1.08

28 (49.1%) 29 (51.9%) 30.79 +/- 6.14 175 +/- 20 125 +/- 17 92 +/- 14 3.28 +/- 0.90

0.99

PT

Thromboembolic Complications

33 (57.9%) 24 (42.1%) 0.07 +/- 0.21 1.0 +/- 1.04 222.81 +/- 78.19 14.24 +/- 1.28 9.91 +/- 1.27 4.33 +/- 1.19

+ -

2 (4.3%) 44 (95.7%)

3 (5.3%) 54 (94.7%)

0.98

+ -

2 (4.3%) 44 (95.7%)

1 (1.8%) 56 (98.2%)

0.59

+ -

9 (19.6%) 37 (80.4%)

11 (19.3%) 46 (80.7%)

0.97

MA

ED

Intra-Operative Transfusion (units) Post-Operative Transfusion (units) Estimated Blood Loss (mL) Preoperative Hgb (g/dL) Postoperative Day 1 Hgb (g/dL) Change in Hemoglobin (g/dL) Thrombotic Risk factors

0.01 0.15 0.25 0.09 0.08

8 (17.4%) 38 (82.6%) 0 +/- 0 0.37 +/- 0.88 229.89 +/- 111.5 13.75 +/- 1.45 10.8 +/- 1.48 2.95 +/- 1.33

NU

+ -

SC

RI P

BMI Anesthesia Time (minutes) Operative Time (minutes) Tourniquet Time (minutes) Length of Stay (Days) Patients Transfused

Control (n = 57) 61.72 +/- 8.76

T

Age (years) Gender

TXA (n = 46) 60.37 +/- 6.77

< 0.0001 0.04 0.001 0.73 0.065 0.001 < 0.0001

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Postoperative Complications