The ERAS trial (http://www.clinicaltrials.gov, registration number: NCT03517098) is a prospective, randomized controlled trial that test the superiority of ERAS pathway to current clinical practice in term of reduction of LOS. It will be conducted under the regulations of the Declaration of Helsinki. Following the CONSORT statement (http://www.consort-statement.org/), a brief flow diagram of the ERAS trial is summarized in Figure 1, and a checklist of Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) is provided in Figure 2.
This trial is supported by grant from Key research and development (R&D) Program of Science & Technology Department of Sichuan Province (2019YFS0224) and the National Natural Science Foundation of China (81502722). There is no conflict of interests in the whole process of study execution. A training manual will be produced to educate and train the study team, including orthopedic surgeons, anesthesiologists, nurses and clinical research coordinators before starting the trial.
Sample size calculation
Our primary hypothesis is that the application of the ERAS pathway would reduce the length of stay (LOS) in hospital when compared to the current non-ERAS practice in total joint arthroplasty (TJA). According to retrospective analysis of LOS of in hospital of TJA in 2014 (when ERAS pathway was just proposed) and 2016 (ERAS pathway was applied in about 50% of patients) in Department of Orthopedics, West China Hospital of Sichuan University, the mean LOS of THA were 10±1.5 days in 2014 and 8.6 ±1.1 days in 2016, and the mean LOS of TKA were 12.1±2.1 days in 2014 and 8.9 ±1.5 days in 2017, respectively. For THA, assuming the difference between two groups at a 5% significance level and a power of 0.90, 17 patients in each group are required, and for TKA, assuming the difference between two groups at a 5% significance level and a power of 0.90, only 7 patients in each group are required for a comparison within the group. Considering an estimated 20% dropout rate, there should be 42 patients in each group for THA and 20 patients in each group for TKA, and totally 62 patients are required in this study . For a better application of the ERAS pathway in orthopedic surgeon and anesthesiologist, we increase the sample size to 160 subjects in each group for THA and TKA, and a total of 640 subjects will be included. We plan to enroll 320 patients undergoing TKA to participate in this trial on the first step, and enroll 320 patients undergoing THA after completion of it. Primary comparison will be performed separately for TKA and THA.
A total of 640 patients undergoing elective arthroplasty, 320 in THA and 320 in TKA, will be enrolled at eight hospitals in China. Subjects will be enrolled and operated in the same individual hospital even under potentially different conventional clinical practice.
Randomization and blinding
We will use the Central Randomization System (CRS) to screen and randomize the subjects. We will include eight hospitals as participating centers and the centers will be stratified first to guarantee balance between arms within each hospital. According to the sequence of time that the subjects are enrolled, after entering the screen number and the subject’s information, the computer-based randomized number prepared in the internet and allocated group could be retrieved on the website of the CRS. While the subjects, the staffs who are responsible for follow-up, and the statisticians will be blinded to the treatment assignment, the investigators, research assistants, and the responsible physicians will not be blinded.
Study organization and quality control
The principal investigator, study coordinators, and the Office of Scientific Research at West China Hospital are jointly responsible for all aspects of the study protocol and relevant amendments. The implement of the study, the data completeness and accuracy will be supervised by Department of Anesthesiology, West China Hospital. The data safety and monitoring board (DSMB), including an orthopedic surgeon, an anesthesiologist, a statistician, a physician, and a member from the Office of Scientific Research who are not unrelated to this trial, will be involved for the entire duration of the trial to review all investigational data for accuracy and completeness periodically to ensure protocol compliance, and to make the decision to stop the trial if there are abnormal frequencies of safety issue, or the safety of participant were not guaranteed because of serious complication. Dr. Ren Liao, associated professor of Department of Anesthesiology, West China Hospital, will be the alert personnel of serious complications to report to DSMB, and be responsible for site monitoring. Data collection and follow-up will be performed by clinical research coordinators. There will be no preliminary analysis will be performed before the completion of the study.
- Patients undergoing primary TKA and THA, with both genders.
- Age above 18 years.
- Able to communicate, especially have the ability to express and totally understand an informed consent.
- Refuse to sign consent.
- Pregnancy or lactating female patients
- History or family history of malignant hyperthermia.
- Known allergy to propofol, desflurane or any other anesthetic agent.
- History of substance abuse.
- History of postoperative delirium.
- Impairment of cognitive function or communication.
- Active participation in another trial where the primary endpoint follow-up is ongoing.
- Unwillingness or inability to comply with protocol procedures.
The ERAS group: Patients will be treated according to the ERAS pathway, which is elaborated below.
ERAS pathway for orthopedic surgeons:
(1) Preoperative fasting time: 8 hours for consumption of fats and protein food, 6 hours for starchy food or non-human milk, and 2 hours for clear liquids before operation.
(2) Intravenous 20mg/kg of tranexamic acid will be given 15 minutes prior to incision.
(3) No indwelling urine catheters.
(4) No tourniquet used for TKA.
(5) No drainage tube after surgery.
(6) Give low molecular heparin subcutaneously 6 hours after the operation.
ERAS pathway for anesthesiologists:
(1) Before anesthesia induction, ECG, noninvasive blood pressure, pulse oximetry, and capnogram will be continuously monitored for every patient.
(2) Intravenous 10 mg of dexamethasone immediately before anesthesia induction.
(3) Anesthesia will be induced with 0~0.2μg/kg of sufentanil or 0~2μg/kg of fentanyl, 0.3mg/kg (for THA) or 0.15mg/kg (for TKA) of cis-atracurium, and 1mg/kg of propofol. Endotracheal intubation of insertion or laryngeal mask will be performed when the BIS value decreased to 50.
(4) Anesthesia will be maintained by titrating continuous remifentanil infusion at range of 0.15-0.3 μg/kg.min with continuous infusion of propofol of 2~4mg/kg/hr, or keeping end- tidal desflurane (Et-Des) level at 5 – 7% or sevoflurane (Et-Sev) level at 1.5 – 2.5%. The BIS value will be kept between 40 to 60 during the procedure.
(5) Incision site will be infiltrated with 40-50ml of 0.2% ropivacaine at the end of operation for postoperative analgesia, and no patient controlled intravenous analgesia devices will be applied post-operatively.
The non-ERAS (Control) group: Patients undergoing THA or TKA will receive conventional care according to the individual participating center. There is no standard protocol for pre-operative management, including the fasting guidelines, no restriction of choices of anesthetic techniques and intra-operative medications, as well as postoperative analgesia, and indwelling urinary catheter.
For all the subjects enrolled in the study, no matter which group they are allocated, the decisions regarding whether or not to place the urinary catheter or drainage tube, or to use tourniquet, or to perform any other medical treatment should be made by the individual responsible physician, based on his clinical judgment. For example, if a patient is allocated to ERAS group, but he develops urinary retention peri-operatively, as the result, the urinary catheter could be retained. In such case, we will make a record, and the patient will still be followed up and his data will be collected and analyzed in ERAS group as per other subject in the same group.
The primary outcome is Length of stay (LOS) in hospital, which is defined as time frame from the day of hospital admission to discharge from the hospital (unit: days).
i. Postoperative LOS, which is defined as time frame from the day of operation to discharge from the hospital (unit: days).
ii. All-cause mortality by 30 days after operation.
iii. In-hospital complications, which are divided into five grades:
a) Grade Ⅰ：Recovery after temporary treatment, e.g., postoperative nausea and vomiting (PONV), postoperative anxiety, insomnia.
b) Grade Ⅱ：Prolonged hospitalization, e.g., pulmonary infection requiring antibiotics or other treatment, surgical wound infection requiring wound debridement.
c) Grade Ⅲ：Life threatening complications requiring intense treatment during hospitalization, and resulting in good functional recovery e.g., dialysis therapy for acute renal insufficiency, mechanical ventilatory support for respiratory failure, or postoperative bleeding requiring re-operation.
d) Grade Ⅳ：Life threatening complications resulting in significantly decreased quality of life, e.g., myocardial infarction, stroke that left with paralytic limbs.
e) Grade Ⅴ：All-cause mortality by 30 days after operation, which is defined as a secondary outcome.
iv. Mobilization time, which is defined as the time frame from the end of operation to able to walk without external assistance (unit: hours).
v. Numerical rating scales (NRS) scores at rest during 3 days after operation.
vi. NRS scores during mobilization or physical therapy during 3 days after operation.
vii. Postoperative sufentanil or other analgesics requirement during 3 days after operation.
viii. Total in-hospital cost.
ix. Readmission rate by 30 days after discharge from the hospital.
We plan to execute this trial by two steps, that is, we test the hypothesis in TKA first and then in THA, and the primary comparison will be performed separately for TKA and THA. An intent-to-treat analysis will be performed to analyze all primary and secondary outcomes by using SPSS18.0 software (Statistic Package for Social Science, SPSS, Inc., Chicago, IL, USA). The baseline continuous variables will be summarized using mean ± standard deviation or median [Interquartile range] for continuous variables as appropriate. Categorical variables will be summarized using frequency (percentage).
Primary outcome: normality will be assessed for the primary outcome LOS. Appropriate transformation will be made if there is an assumption violation. We will use independent two-sample t-test to compared the LOS between the two groups. A p-value smaller than 5% will be considered as significant. For the primary outcome, we will also perform a sensitivity analysis using an analysis of covariance model (ANCOVA) with LOS as the response variable, treatment group as the main factor adjusting for potentially imbalanced baseline characteristics and center effect.
For the primary outcome, we will also perform subgroup analysis based with subgroups defined by each of the age (<65, ≥65), gender (Male, Female), and ASA class (I~II, III or higher). Analyses will be performed for each subgroup in a similar way to the primary analysis.
For the secondary outcomes, the continuous variables (postoperative LOS, mobilization time, NRS etc.) will be assessed for normality. Two-sample t-test or Wilcoxon rank sum test will be used for comparison depending on the normality test result. For categorical outcomes, odds ratio will be calculated and tested using Chi-square test. A P value<0.05 will be considered statistically significant. We will use Kaplan-Meier plot to describe the mortality and compared the mortality at 30 days using a logrank test for fixed time points.