Patient and public involvement
The research question and outcome measures were developed from a desire to evaluate whether the effect of TEAS on improvement of immunosuppression of patients after receiving CABG. We seek to promote this clinical technique and provide theoretical basis for further improvement of this technology. Patients, however, were not directly involved in the design or conduct of this study.
Monocyte human leukocyte antigen (mHLA-DR)，as the primary endpoint of this clinical trial, will be detected to evaluate the improvement of postoperative immunosuppression.
Related indicators of immunosuppression include interleukin-6 (IL-6), reactive C (CRP), secondary infection (incision infection, lung infection, hematogenous infection and indwelled catheter infection).
The indicators of related mechanism study include high mobility group proteins-1 (HMGB1), regulatory T-cell (Treg) and CD4+ T-cell.
A prospective, single-centre, randomised, double-blinded, controlled trial will be conducted in patients undergoing CABG in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
The enrolled subjects are the patients scheduled to receive CABG under extracorporeal circulation. Participants will be recruited voluntarily according to the inclusion and exclusion criteria below.
- Aged 18-75 years, male and female;
- Patients diagnosed as coronary disease, scheduled to receive CABG;
- BMI: 18.5kg/m2<BMI≤30kg/m2；
- Graded as I-III by ASA;
- Patients firstly receiving CABG under extracorporeal circulation.
- Presence of surgical incision or scar at Zusanli acupoint (ST36) /Shenshu (BL23) acupoint;
- Patients with local skin infection at acupoint;
- Patients with nerve injury on upper or lower limbs;
- Patients with history of spinal surgery;
- Patients who have participated in other clinical trial in recent 4 weeks;
- Patients using pacemaker;
- Patients combined with pain before surgery who are using central analgesic drug or drug abuser (e.g., opioid) and dependent user;
- Patients combined with severe central nervous system disease or severe mental disease;
- Patients with alcoholic history;
- Patients who have received emergent coronary bypass operation due to acute myocardial infarction.
With mHLA-DR as primary endpoint of this clinical trial, the improvement of postoperative immunosuppression is evaluated. Peripheral blood is collected from the patient to test this indicator at the following time points: One day before surgery, Day 1 after surgery (one day after surgery), Day 3 after surgery (3 days after surgery), and Day 5 after surgery (5 days after surgery). Flow cytometry is used for determination.( Becton-Dickinson, New Jersey, U.S.)
- Related indicators of immunosuppression include interleukin-6 (IL-6), reactive C (CRP), secondary infection (incision infection, lung infection, hematogenous infection and indwelled catheter infection). The examination methods and time points are as follows:
- IL-6: ELASA kit (ABCAM, Shanghai, China), One day before surgery, Day 1, 3 and 5 after surgery;
- CRP: automatic biochemical analyzer (Beckman Coulter, Georgia, U.S.), One day before surgery, Day 1, 3 and 5 after surgery;
- Secondary infection: observe the incidence of incision infection, lung infection, hematogenous infection and indwelled catheter infection after the surgery.
- The indicators of related mechanism study include high mobility group proteins-1 (HMGB1), regulatory T-cell (Treg) and CD4+ T-cell. The examination methods and time points are as follows:
- HMGB1: ELASA kit (ABCAM, Shanghai, China), One day before surgery, Day 1, 3 and 5 after surgery;
- Treg (CD4+/CD25+ T-cell): flow cytometry(Becton-Dickinson, New Jersey, U.S.)，One day before surgery, Day 1, 3 and 5 after surgery;
- CD4+ T-cell: flow cytometry(( Becton-Dickinson, New Jersey, U.S.)，One day before surgery, Day 1, 3 and 5 after surgery;
Randomization and blinding
Stratified randomization will be used to assign the candidate subjects to 2 group according to age (elderly patients≥65 and adult patients<65). Computer generates random group numbers. It will be printed and placed in separate sealed envelopes. When receiving a subject who meets the inclusion criteria, the anaesthesiologist will assign the newly recruited subject to a group according to the number in the envelope. Nurse anaesthetists will perform TEAS or Sham TEAS for the patients. Both anaesthesiologists and patients will be blinded to the regimen. The anaesthesiologist will be notified of the study group by the nurse anaesthetist in case of emergency.
Current Sample size justification
Human leukocyte antigen of monocyte (mHLA-DR) is the primary endpoint to evaluate on the improvement of immunosuppression of patient after surgery. To compare two groups across four timepoints, we calculate the sample size based on the repeated measures ANOVA. With the assumptions of 5 percent Type I error rate, 80 percent power and medium effect size of 0.5, we will need 39 observations in each group to finish the study. Assuming that the dropout rate to be 10%, we will need to enroll 88 observations (44 observations per group).
We will describe normally distributed continuous data and skewed continuous data using mean [standard deviation] or median (percentile 25 to percentile 75). Categorical variables are expressed as number and fraction (%). The statistical methods will include descriptive statistics, Student’s t-test, Mann-Whitney U-test, chi-squared test, Fisher's exact test and repeated measures ANOVAs. All statistical analysis will be completed with SPSS 19.0 or other statistical software packages as needed, and the significance level will be set at 5%.
This study is a prospective, single-center, double-blind, randomized and controlled clinical trial to explore the effects of TEAS therapy on improvement of postoperative immunosuppression of patients receiving CABG (Fig. 1). The trial was designed following the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statement (see Additional file 1).
This trial will include 2 groups: the group of TEAS combined with general anesthesia (TEAS+GA), and the group of transcutaneous acupoint pseudo - electric stimulation combined with general anesthesia (Sham TEAS+GA). In each group, there will be 44 patients receiving CABG under extracorporeal circulation. The patients of TEAS+GA group will receive TEAS therapy in perioperative period, and the Sham TEAS+GA will receive none TEAS in perioperative period.
The trial will be from Dec. 1, 2017 to Dec. 31, 2019.
- Selection of acupoints: Zusanli acupoint (ST36) – Shenshu acupoint (BL23) (Fig. 2 and 3)
- Zusanli location: located at outside of the shank, 3 cun (10 cm) below Dubi acupoint (ST36) and a finger’s width (middle finger) to tibial front edge;
- Shenshu location: located below the spinous process of the second lumbar vertebra, 1.5 cun (5 cm) to the central line.
- Stimulation timing: Before anesthesia + Intraoperative + Postoperative (Figure 4)
- 30 mins before anesthesia: one stimulation for 30 mins;
- Intraoperative: stimulating in the whole course;
- Postoperative: 0-24h: 4 times of stimulation (30 mins per stimulation). Hour 5-6 after the surgery (the first time), Hour 11-12 after the surgery (the second time), Hour 17-18 after the surgery (the third time), Hour 23-24 after the surgery (the fourth time).
- TEAS parameter
- Frequency: 2/100 Hz alternative;
- Intensity: 15mA;
- Low-frequency electronic pulse therapeutic device G6805-2 (Huayi, Shanghai, China) (Figure 5):
- Current intensity: main difference between the study group and control group
- TEAS+GA group: the acupoints including Zusanli and Shenshu, were identified before electrical stimulation with surface electrodes (Figure 6). Selection of these acupoints was based on a consensus between the acupuncturists of the study.
- Sham TEAS+GA group: No electrical stimulation sensation is performed in the Sham TEAS group. In the Sham TEAS group, pseudo-stimulation is provided by deliberately connecting the electrodes to the incorrect output socket of the electroacupuncture device, and thus there is no flow of electric current. Patients could see the output light flashing but no current was transmitted throughout the procedure. Patients would be told that the stimulation frequency selected was not perceivable by human beings.
- Anesthesia protocol
- Medication before the anesthesia
- Morphine: 0.1mg/kg
- Anesthesia induction
- Sufentanil 0.3～5ug/kg
- Propofol TCI: 2.0～5ug/ml
- Dextromidine 0.5～0ug/kg/hr or midazolam 0.05～0.1mg/kg
- Lidocaine 1mg/kg (Maximum dose not higher than 50 mg)
- Rocuronium bromide 0.9～2mg/kg
- Maintenance of anesthesia
- Narcotic analgesics: common sufentanil by 0.2～5ug/kg by times (i.v) or remifentanil by 0.05～0.2ug/kg/min continuous intravenous pump injection, addition of sufentanil by 10～20ug before skin incision and sternum splitting.
- Inhaled general anesthetics: sevoflurane and isoflurane can be inhaled discontinuously as requested，with MAC 0.7～0.
- Muscle relaxant: common vecuronium bromide and rocuronium bromide, etc.
- After the completion of tracheal intubation, the anaesthesia machine is connected immediately, and ETCO2 is examined, and the breathing sound of both lungs is auscultated to determine the position of endotracheal tube.
- Common parameters of mechanical ventilation: VT: 7～8 ml/kg, RR: 10～12 bpm; PaO2: 200 mmHg, PaCO2: 35～45 mmHg, FiO2: 80%.
The status related to adverse events is acquired according to the self-report of the patient or direct observation of clinicians or by non-induced query of the patient, and his/her clinical safety is evaluated (see Table 1).
The chief surgeon of thoracic surgery department, anesthetist to implement anesthetic management, nurse of anesthesiology department to carry out TEAS (having received specialized acupuncture training) as well as blood sampling personnel of clinical lab and data recording personnel are fixed to avoid bias from human operations. Specialized acupuncture training mainly includes selection of acupoints, TEAS operation standard and procedure (see Table 2).
Data collection and management
The data will be collected as primary and secondary endpoints, with above described method. All data will be saved safely in internal server of Shuguang Hospital, with complete confidentiality. The participants of this study will be cited with a code different from their real names. The data management program will be approved by the trial manager and other clinicians before the registration of the first participant.