Study design
Our study was a prospective, single-center, double-blinded, randomized, controlled trial. The study protocol was approved by our institutional review board and is registered in the Chinese Clinical Trial Registry (ChiCTR-OPC-17013503). Written informed consent and research authorization for participation in this study were obtained from each patient before surgery.
Study population
This trial included patients (age 18–80 years) undergoing simultaneous bilateral TKAs with osteoarthritis (OA)/rheumatoid arthritis (RA) from July 2017 to July 2018 in our hospital. Patients scheduled for unilateral TKA, staged bilateral TKA, or revision TKA were excluded. In addition, patients with contraindications to any of the study drugs due to an allergy, renal insufficiency, a history of cardiac disease, deep vein thrombosis, or surgery of the knee joint were excluded.
Among the 74 prospective cases, 60 met the study inclusion criteria and received the trial intervention. The preoperative diagnosis was osteoarthritis of the knee in all patients. The operating surgeon, operating staff, patients, physiotherapists, anesthetists and data collectors remained blinded for the study duration.
Interventions
In the operating room immediately preoperatively, the right or left knee was allocated to receive the MCPI with or without steroids using the envelope method. The circulating nurse performed the envelope selection before mixing the cocktail injection so that neither the patient nor the other staff knew the treatment details.
In the control knee, a 60-mL MCPI with (ropivacaine 200 mg/20 ml (AstraZeneca AB, Sweden), morphine 10 mg/1 ml, flurbiprofen axetil injection 50 mg/5 ml (Beijing Tide Pharmaceutical Co., Ltd., China), adrenaline 0.25 mg (1:1000), tranexamic acid 2000 mg/20 ml (Guangzhou Baiyunshan Pharmaceutical Co., Ltd., China), and 14 mL of normal saline solution) was prepared in three 20-mL syringes.
In the intervention knee, the 60-mL MCPI was the same as in the control knee, except Betamethasone 7 mg/1 ml (Schering-Plough Labo N.V., Belgium) was added to it.
The first 20 mL of the cocktail was injected into the posterior aspect of the capsule and structures of the knee joint immediately before implanting the prosthesis. After implantation, the remaining 40 mL of mixture was injected into the extensor mechanism, synovium, anterior capsule, pes anserius, retinaculum, periosteum, iliotibial band, and collateral ligaments.
Surgical procedures
All TKAs were performed under a tourniquet control inflated to 250 mm Hg by a senior orthopedic surgeon (JL). A medial parapatellar approach was utilized in all knees, and either a G-II PS (Smith & Nephew, Memphis,USA) or Nexgen PS (Zimmer, Limerick, Ireland) was inserted. Postoperatively, a standardized rehabilitation protocol was implemented. This included ROM exercises commencing on day one, with additional rehabilitation performed either on the ward or in the physiotherapy department until discharge. Postoperative chemical and mechanical thromboprophylaxis was instituted in all patients and consisted of thromboembolic deterrent stockings (TEDS) along with daily low molecular weight heparin subcutaneous injection until discharge. Vacuum wound drainage was applied in every patient with drain clamping for 4 hours, which was removed 48 hours later.
Intravenous second-generation cephalosporin (Cefuroxime 1.5 g, Glaxo Smith Kline, UK) was given preoperatively and every 12 hours for the first 24 hours postoperation. We gave 1 g of tranexamic acid intravenously (Guangzhou Baiyunshan Pharmaceutical Co., Ltd.,Guangzhou, China) just before skin incision in addition to adding tranexamic acid to the MCPI.
Multimodal pain management protocol
Patients were given 40 mg parecoxib (Dynastat, Pfizer, USA) diluted to 5 mL with 0.9% normal saline every 12 hours postoperation for 3 days followed by an oral NSAIDs (60 mg of Loxoprofen Sodium Tablets Tid,Daiichi Sankyo, Japan). Patient-controlled analgesia (PCA) was used in all patients for 3 postoperative days with 1 mg morphine per press. There was no background or loading infusion of morphine. For rescue analgesia, aminophenol oxycodone (Mallinckrodt Inc., US) was used when necessary.
Outcome Measurements
Primary outcome
Staff who were unaware of the treatment group to which either knee had been assigned conducted all assessments. The intensity of pain was rated using a 100 mm horizontal visual analog scale (VAS) in 100 mm increments, in which 0 mm represented no pain and 100 mm represented extreme pain. Time zero was defined as the time when the patients were awake at the postanesthesia care unit (PACU). Primary outcome measures included the VAS pain score at rest (preoperatively, time zero; postoperatively 6 h, 12 h, 24 h, day 2 and day 3), the VAS pain score in motion (postoperative 6 h, 12 h, 24 h, day 2 and day 3);
Secondary outcomes
The secondary outcomes were : 1)ROM of the knee during physical therapy (preoperatively and on postoperatively days 1, 3, 5, and 3 months);2༉thigh swelling of each leg[17] (2 points: the thigh girth at the patella superior border and at 5 cm proximal from the patella superior border; preoperatively and on postoperative days 1, 2, and 3)༛3༉HSS score (preoperatively and at 3 months postoperatively༛4༉thigh skin temperature of each leg (5 cm proximal from the patella superior border; preoperatively and on postoperative days 1, 2, and 3) and 5༉adverse events during the course of the trial, including wound complications, surgical site infection, peroneal nerve palsy, and deep venous thrombosis (DVT).
Sample size calculation
It was reported that a reduction of 20 points in the VAS pain scale score to be a clinically relevant difference[18]. To allow a dropout rate of 20% (8 participants), 51 patients were needed per group to detect a mean difference (and standard deviation) of 20 ± 33 points in the VAS pain scale score with a 2-sided 5% significance level and 80% power.
Statistical analysis
For statistical analysis, the Statistical Package for Social Sciences (SPSS Inc, IBM, version 22) was used. Statistical advice was gained before the planning of the study. For continuous variables, data are presented as the mean and the range and were compared between the groups using Student’s t tests. For categorical variables, data are summarized as the frequency and proportion. Proportions were compared between the groups using a Fisher exact test for univariate analysis.
Patient and Public Involvement:
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The study protocol was discussed with patients in our department and got suggestions before getting the IRB approval.
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Patients were not involved in the recruitment to and conduct of the study.
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The preliminary results had been disseminated to study participants via E-mail or written letter
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The burden of the intervention were informed and assessed by patients themselves before participating in the trial.
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Patient advisers had been thanked in the contributorship statement/acknowledgements.