The randomized controlled study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University in advance and registered in Chinese Clinical Trail Registry (No. ChiCTR-ONRC-14004247). All subjects were provided with written, informed consents. The protocol was designed and conducted in accordance with Consolidated Standards of Reporting Trails Statement (6). Inclusion criteria: patients between 18 and 75 years old who underwent selective unilateral TKA. Exclusion criteria included the following: 1) patients with American Society of Anesthesiologists (ASA) grade IV or V; 2) patients whose body mass index (BMI) was >35; 3) patients who had neuropsychological dysfunction; 4) patients who had bilateral knee replacement or knee surgery not interfering with articular joint cavity (such as wound debridement and suture) or the second knee revision surgery; 5) patients who had uncontrolled systemic infection; 6) patients who had severe coagulation disorders or active stomach ulcers or who were administered anticoagulants; 7) patients who had local infection at the site of the femoral nerve block or known allergic reactions to the local anesthetic drugs and other drugs used during surgery; and 8) patients who had intraoperative respiratory arrest or cardiac arrest.
Statistics Analysis System software (SAS) proc plan procedure was used to generate a random number. The number of every patient was concealed in opaque envelopes. The envelope was not opened until the patient was enrolled in this study.
Types of Anesthesia
General anesthesia was performed in participants. After rapid intravenous induction and subsequent intubation, controlled ventilation was provided. Heart rate, respiratory rate, temperature, pulse oximetry, and invasive arterial pressure were monitored. Anesthesia was maintained by sevoflurane (1% to 3%) with continuous intravenous infusion of propofol (25-75 µg/kg/min) and remifentanil (7-8 µg/kg/h) with microperfusion pump. Fluid therapy was administered at 5-10 ml/kg/h. Vasodilators, vasoconstrictors, and diuretics were used when necessary to maintain hemodynamic stability. A group of senior anesthesiologists performed anesthesia and analgesia for patients. Similarly, one team of senior surgeons performed the operation for patients.
Types of Postoperative Analgesia
In the CFNB group, anesthesiologists performed the femoral nerve block on the operated leg before induction of anesthesia. All patients extended their legs for block placement while lying on the operating room table. After sterile preparation, we used ultrasound to identify the puncture site, 1-2 cm lateral to the femoral artery and 2 cm distal to the inguinal ligament. After topical anesthesia with 2% lidocaine, we connected an insulated needle (20 G 45 mm, short bevel, 30°) (Contiplex Braun, Melsungen, Germany) to the nerve stimulator with the stimulating intensity of 1 mA at a rate of 2 Hz (Innervator, Fisher & Paykel, New Zealand). The needle was advanced at 30°-45° angle to the skin, until quadriceps femoral muscle twitches were elicited. When muscle contraction still occurred with 0.3 mA, the needle position was felt to be correct. Then, the patients were given an initial anesthetic dose with 10 ml of 2% lidocaine and 10 ml of 1% ropivacaine. The catheter remained in place for 10-15 cm. To confirm the correct position of the catheter, the cutaneous sensation in the area of the femoral nerve was assessed using a cold test (7). 30 minutes before the end of the operation, the catheter was connected to the femoral nerve catheter pump. Parameters of the pump were as follows: The loading dose was 5 ml of 0.15% ropivacaine, the background infusion rate was 5 ml/h, the dose of analgesic bolus was 5 ml, and the lockout time was 30 minutes.
In the PCIA group, intravenous access was established for PCIA 30 minutes before the end of surgery and then was connected to the patient-controlled analgesia pump. The regimen of the PCIA analgesia pump was as follows: 800 mg tramadol, 100 mg flurbiprofen axetil, and 5 mg dexamethasone and 0.9% saline into a total of 80 ml solution. The parameters of the analgesia pump were as follows: The loading dose was 2 ml, the background infusion rate was 1 ml/h, the dose of analgesic bolus was 2 ml, and the time of secure lockout was 15 minutes. All patients were given 4 mg ondansetron intravenously to prevent postoperative nausea and vomiting. In both groups, the analgesia pump was removed at 72 hours post-operatively.
Rescue Analgesia Protocol
Pain intensity was evaluated during the use of PCA and non-PCA periods. Rescue analgesia was used for patients whose numerical rating score (NRS) ≥4 (a scale contained number 1 to 10, 0 represents no pain and 10 represents worst possible pain). The first step was to adjust the parameters of the analgesia pump as follows: In the CFNB group, we increased the infusion rate by 1 ml/h each time (the maximum rate was 10 ml/h) or (and) increased the dose of analgesic bolus by 1 ml each time additionally after pain evaluation (the maximum dose was 10 ml); in the PCIA group, we increased the fusion rate by 0.1 ml/h each time (the maximum rate was 1.5 ml/h) or (and) increased the dose of analgesic bolus by 1 ml each time additionally after pain evaluation (the maximum dose was 5 ml, and the maximum daily dose of tramadol was 400 mg). Pain intensity was repeated 30 minutes later. If the NRS was still ≥4, ultrasound examination was performed in the CFNB group, and the location of the catheter was identified. If the catheter fell out or was displaced, the catheter would be extracted and counted as one with analgesic adverse events. Patients in the CFNB group were injected intravenously with non-opioid rescue analgesics: Parecoxib sodium 40 mg (80mg daily maximally was used) and (or) tramadol 1.5 mg/kg (400 mg daily maximally was used). Finally, the opioid rescue medication (Pethidine, intramuscular, 1 mg/kg) was used if the non-opioid medications were considered ineffective (NRS≥4) at 30 minutes after intravenous injection. Patients in the PCIA group were injected intramuscularly with Pethidine 1 mg/kg.
Baseline characteristics included pre-operative items: age, height, weight, gender, ASA grade, NRS, knee flexion, Western Ontario and McMaster Universities (WOMAC, a scale including 3 dimensions: pain, joint stiffness, and daily life ability to estimate joint function) score for knee and comorbidity; intra-operative items: surgery time, anesthesia time and tourniquet time.
NRS at rest (defined as the pain lying supine in bed) and in motion (defined as the most severe pain during passive motion and active exercise) were measured at 24 hours, 48 hours, 7 days and 6 months post-operatively; frequency and dose of rescue analgesic agents used during PCA were recorded; the surgical knee flexion were assessed at 7 days and 6 months post-operatively; anesthesia-related adverse events including incomplete analgesia at rest and in motion (defined as NRS for pain ≥4 before rescue therapy), over-sedation, nausea and vomiting, respiratory depression, muscle weakness, and CFNB-related adverse events including catheter dropout, local infection and hematoma of CFNB catheter; postoperative length of hospital stay (defined as the interval between surgery and discharge) were recorded; WOMAC score for knee function, and quality-adjusted life years (QALY, a scale in which death has a value of 0 and optimal health has a value of 1 to adjust each year of life for the health-related quality of life experienced, always is transformed from EuroQol-5D score) converted from the EQ-5D score (EuroQol-5D score, a scale includes 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, which were used to evaluate the quality of life) were assessed at 6 months after surgery.
Cost of PCA Analgesia
Cost in the PCIA group included the cost of drugs, pump devices, And cost in the CFNB group included the cost of drugs, pump devices and positioning the femoral nerve catheter (nerve stimulator and ultrasound equipment).
Direct cost: The direct medical cost in-hospital included the cost of medications, medical examinations, physical rehabilitation, nursing, and treating adverse events during hospitalization.
Indirect cost: The indirect cost was calculated as multiplying lost working days by the average daily income. The working days lost were defined as the interval between the beginning of hospital admission and the end of postoperative rehabilitation (8, 9).
Total cost: The total cost included direct medical cost and indirect cost.
The cost of hospitalization was based on the database of the Health Information Center of the First Affiliated Hospital of Chongqing Medical University. The average daily income was based on the database of Chongqing Municipality bureau.
Cost-Effectiveness Analysis and Cost-Utility Analysis
Cost-effectiveness analysis: The cost-effectiveness ratio (CER) of an intervention is calculated as the cost of the intervention divided by its effectiveness (10).
The PCIA or CFNB analgesic CER was calculated as dividing all of patients’ PCA analgesic cost by the effectiveness of analgesia. The effectiveness of analgesia was evaluated as complete analgesia (100% minus the incidence of incomplete analgesia). The total CER was calculated at 6 months after surgery as dividing all of patients’ total cost by the degree of joint function improvement defined as △WOMAC scores (calculated as pre-operative WOMAC scores minus post-operative WOMAC scores) (8-12).
Cost-utility analysis: The cost-utility ratio (CUR) of an intervention is the ratio of the cost of the intervention to the utility it produces in terms of the number of years lived in full health by the beneficiaries. Utility needs to be expressed by the QALY score converted from EQ-5D score for evaluating the quality of life. The CUR in our study was calculated as dividing the cost by the degree of quality of life improvement defined as △QALY score (calculated by post-operative QALY score minus pre-operative QALY score) of each patient.
The incremental cost-effectiveness ratio (ICER) is the ratio of the difference in cost and the difference in effect of two interventions. The ICER may be stated as (C1-C0)/(E1-E0)( C0 and E0 represent the cost and effect of one intervention, C1 and E1 represent the cost and effect of the other intervention) (7). In our study, C1 and E1 represented the cost and △QALY of the CFNB group, C0 and E0 represented the cost and △QALY of the PCIA group. The ICER indicated that cost needed to pay of the CFNB group to get one more QALY compared to PCIA group. Then ICER was compared to the cost effectiveness threshold to assess cost effectiveness. For example, $30,000 per QALY is suggested as a threshold ICER for a cost-effective intervention. Thus, any health intervention which has an incremental cost of more than $30,000 per additional QALY gained is likely to be rejected and any intervention which has an incremental cost of less than or equal to $ 30,000 per extra QALY gained is likely to be accepted as cost-effective(8-12).
Sample calculation was based on the analgesic efficacy in a pilot study, a 10% difference between PCIA and CFNB on the incidence of moderate-severe pain in motion at 3 months after the surgery. Considering the dropout rate of 15% and statistical power of 80% at the 0.05 significant level, 280 patients estimated were randomly divided into the CFNB group and the PCIA group as 1:1 ratio.
The normality test was performed for measuring data. Normally distributed continuous variables were expressed as means±SD, and Student's t-test was used for statistical analysis. Non-normally distributed variables were represented as median (quartile), and Wilcoxon test was used for comparison between groups. Categorical variables were represented by frequency (percent), and chi-square test was used for comparison between groups. Fisher’s exact test was used for categorical variables when the number of events was less than 5. Both intention-to-treat analysis (ITT analysis) and per-protocol set analysis (PPS analysis) were used in this study. ITT analysis was used in baseline characteristics (e.g.: age, ASA grade, NRS, WOMAC score); surgery time, anesthesia time and tourniquet time; and pre-operative conditions (hypertension, coronary artery disease). PPS analysis was used in other indicators. Statistical difference was assumed when P value <0.05. SAS 9.2 software was used for data analysis.