Study design
This was a single-center, single blind randomized controlled trial. This study was conducted at the Department of Orthopedics in Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine and registered in the Chinese Clinical Trial Registry (ChiCTR1900025013). The Institutional Review Board (Ethics Committee of Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine) give permission for our study. According to the Standards of Reporting Trials (CONSORT) recommendations for randomized controlled trials[20], and all participants gave their written informed consent before recruitment.
Sample size calculation
The sample size was calculated on the basis of the difference in the amount of HBL dependent on TXA therapy. The overall standard deviation is σ = 250, and the allowable error estimate is δ = 200. These values were estimated using the statistical formula
Predicting an estimated dropout rate of 10%, 104 subjects will be required to yield a power of 90% with a significance level of 0.05.
Patients
From September 2019 to May 2020, we consecutively screened patients aged 50–75 years old who underwent primary unilateral TKA for RA. Doppler ultrasound examination without deep vein thrombosis (DVT). Exclusion criteria included a diagnosis other types of arthritis than RA. Renal dysfunction, or severe cardiovascular or cerebrovascular diseases, and patients with prolonged use of oral anticoagulant drugs. Elimination criteria included acquired color vision disorder; active intravascular coagulation patients; and a history of seizures.
Randomized and drug delivery
All eligible patients were randomized into two groups using computer-generated randomization, which was prepared by the statistician who was not involved in the trial and the group data was saved by the statistician. Allocation was concealed in consecutively numbered, sealed, opaque envelopes. IV-TXA (1 g) was administered 10 min prior to skin incision by an anesthesiologist, and articular-injection TXA (1.5 g) was administered by the surgeon after cavity suture during the surgery. The patients were allocated into two groups, group A: one dose of IV-TXA (1 g) at 3 h post-operatively; group B: three doses of IV-TXA (1 g) at 3, 6, and 12 h post-operatively. Dose administration was performed by a nurse after surgery. The surgeon, anesthesiologist, and statistician were blinded to the trial. Only the nurses knew of the patient s’ enrolment.
Perioperative anti-rheumatic treatment
Methotrexate and hydroxychloroquine will be used during the perioperative period. Leflunomide will be discontinued one week before surgery. Use of other disease-modifying antirheumatic drugs will be discontinued two days before surgery, and restarted 1–2 days after gastrointestinal function recovery. The use of newer biologic agents such as tumor necrosis factor alpha will be discontinued 4 to 5 half-lives before surgery and restarted after wound healing and infection elimination[21,22].
Surgical procedure and postoperative management
For perioperative prophylaxis, cefazolin sodium antibiotics were administered 30 min before surgery, and 24–48 h after surgery. General anesthesia was performed by anesthetists. The blood pressure was controlled to within 80–100 mmHg / 60–70 mmHg throughout the procedure. The tourniquet was inflated to 100 mmHg above the systolic pressure before the incision and deflated after the closure of the incision. The surgery was performed by a single surgeon using the same technique. All patients received a surgeon-selected, cemented, posterior-stabilized prosthetic design with patellar resurfacing. These patients were not use drains and blood salvage after surgery. Postoperatively, the elastic bandage was compressed and bandaged on the surgery limb for 24 h. The patients were discharged on the post-operative day (POD) 14 when they met discharge criteria, which included no wound leakage, swelling, and pain, or infection, independent mobility.
During hospitalization, all patients received physical prophylaxis and chemoprophylaxis for venous thromboembolism. Patients were asked to performed equal length contractions of the femoral quadriceps and ankle pump movements, lower-extremity strength training, and range of motion exercises on the day after surgery. At 6 h after surgery, perioperative oral rivaroxaban (10 mg, once a day for 14 days) was prescribed to prevent thrombosis[23]. Blood transfusions were given when the post-operative Hb level less than 70 g/L or any organ dysfunction related to anemia regardless of Hb level.[24]
Outcome measurements
Perioperative hematocrit (Hct), Hb, coagulation index, and renal function were measured preoperatively, and on POD 1, 3, 7, and 14.
Nadler’s formula[25] was used to estimate patient blood volume (PBV) and the Gross[26] formula was used to calculate blood loss based on PBV and Hct drop.
Intraoperative blood loss (IBL) was estimated based on the amount of liquid in the negative pressure drainage bottle + amount of liquid in the gauze – amount of saline. A piece of gauze was soaked with approximately 20 mL of liquid.
PBV = K1 × height3 (m3) + K2 × weight (kg) + K3. Male: K1 = 0.3669, K2 = 0.03219, K3 = 0.6041. Female: K1 = 0.3561, K2 = 0.03308, K3 = 0.1833. Total red blood cell loss (TBL) = PBV × (Hctpre – Hctpost)/ Hctave, where Hctpre = initial pre-operative Hct level, Hctpost = lowest Hct postoperative, Hctave = average of Hctpre and Hctpost. HBL is defined as TBL minus IBL plus transfusion. Thus, HBL = TBL – IBL + transfusion.
Patients were monitored for adverse events (DVT, Wound complications, Infection, Acute renal failure). Transfusion rate and adverse events were assessed post-operatively during inpatient hospital stay.
Statistical analysis
Analyses were performed using SPSS Version 25.0 (IBM Corp., Armonk, New York). Continuous-variable data were evaluated for a normal distribution with the Shaprio-Wilk test. They were presented as the means ± standard deviations (SDs), and the difference between groups was compared using two independent sample t tests; Pearson’s chi-square test was used for categorical variables. A P -value of less than 0.05 was considered statistically significant.