Patients and grouping
Our study was approved by the Ethics Committee of China-Japan Union Hospital of Jilin University (2016ks008) and was in accordance with good clinical practice and the guiding principles of the Helsinki Declaration. The written informed consents were obtained from all patients. The trial was registered prior to patient enrollment at clinicaltrials.gov (NCT03035916, principal investigator: Guoqing Zhao, Ruizhu Liu, Kai Li, date of registration: 01/27/2017).
Patients meeting the following inclusion criteria were enrolled: patients who were scheduled for open radical gastrectomy; patients who had no contraindication to local anesthetic, and patients whose American Society of Anesthesiologists’ (ASA) physical status I, II or III. Emergency patients and patients with preoperative infection, or patients with a history of immune disease, endocrine system disease, blood transfusion, or chemotherapy were excluded from this study.
Patients were randomly divided into two groups by a computerized random-number generator with 1:1 ratio for TAP group and control group. The pre-anesthetic interview was carried out by a single investigator to assess the eligibility of participants and to record the baseline data. Another anesthesiologist (not involved in study) who took the corresponding opaque envelope in the operating room performed the block and anesthesia induction, so he was unblinded to group allocation. A resident anesthetist who was blinded to randomization was responsible for collection of intraoperative data and blood. Postoperative data and blood were collected by another investigator who visited the participants at 1, 6, 12, 24, 48 h after surgery. All patients underwent surgery from the same operative team. The patients allocated to respective groups were administered as follows: TAP group: general anesthesia and ultrasonography-guided TAP block with 40 ml of 0.375% ropivacaine; Control group: standard general anesthesia (no sham intervention for TAP block).
No preoperative sedatives or analgesics were administered before the operation. Routine monitoring including electrocardiogram, invasive arterial blood pressure, pulse oximetry, and end-tidal carbon dioxide was established before anesthetic induction. All patients underwent standard general anesthesia induced by midazolam 0.02 mg/kg (Enhua Pharmaceutical Co., Ltd., Jiangsu, China), propofol 2.0–2.5 mg/kg (Fresenius Kabi Deutschland, Germany), sufentanil 0.3 μg/kg (Yichang Humanwell Pharmaceutical Co., Ltd., Yichang, China), and cis-Atracurium 0.15 mg/kg (Hengrui Pharmaceutical Co., Ltd., Jiangsu, China). In order to maintain general anesthesia, intravenous and inhaled volatile anaesthetics of nitrous oxide, sevoflurane (Maruishi Pharmaceutical Co., Ltd., Japan), sufentanil, and cis-Atracurium were used. During the operation, the MAC value was maintained within 1.2–1.5% by regulating the inhalation concentration of nitrous oxide and sevoflurane. Tidal volume and rate were adjusted to maintain an end-tidal PCO2 of 30–40 mmHg. When hemodynamic values increased more than 15% above pre-induction baseline values, an appropriate dose (0–10 μg) of sufentanil was used to intervene. Heart rate (HR) < 40 beats/min (bradycardia) was intervened with 0.5 mg atropine, and mean arterial blood pressure (MAP) < 60 mmHg (hypotension) was treated with 5 mg ephedrine. The body temperature was maintained between 36 °C and 37 °C during the operation.
TAP block was administered after anesthesia induction. In the TAP group, TAP block was performed bilaterally under ultrasound (SonoSite Portable M-Turbo, Sonosite Inc., Bothwell, UT, USA) guidance at 30 min before the surgical incision. The probe was placed in the midline of abdomen below the xiphoid and moved right laterally along the subcostal margin to the anterior axillary line. After the probe identified the plane between the rectus and transverse abdominal muscles, a 100-mm, 20-G Stimuplex block needle was guided within the plane to the point just inferior to the right costal margin such that the tip laid between the obliquus internus abdominis and transversus abdominis within the neurovascular fascial plane. After aspiration, to exclude vascular puncture, 1 mL test dose was injected to determine the flow resistance and confirm needle tip placement within the fascial plane. Then, 10 mL 0.375% ropivacaine was multi-point injected in this plane laterally along the subcostal margin. The probe was moved back to the anterior axillary line, and another 10 mL 0.375% ropivacaine was injected through the needle inferior to the costal margin within the TAP using an identical technique, making this two injected drug a continuous plane under the costal margin, from the medial margin of the rectus abdominis muscle to anterior axillary line. The left side of TAP block was conducted with the identical technique.
After extubation, patients were transferred to the post-anesthesia care unit (PACU), and all of them received morphine patient-controlled analgesia (PCA) with a standard dosing regimen: 2 mL/h continuous infusion (a bolus of 1 mL with a lock-time of 15 min) by using the electronics pump (Shanghai Bochuang, China).
The primary outcome was neuroendocrine mediators and cytokines at different time points of 48 h after operation. Venous blood samples were collected before anesthesia (baseline), immediately after surgery, and at 6, 24, and 48 h after surgery, and stored in pre-chilled tubes on ice and then centrifuged within 90 min. The separated plasma was stored at − 80 °C. Glucose (Glu) level was measured immediately after venous blood was collected using glucometer (ACCU- CHEK Active, Inc.). Plasma levels of norepinephrine (NE), epinephrine (E), C-reactive protein (CRP), cortisol (Cor), interleukin (IL)-6, and IL-10 were measured by micro enzyme-linked immunosorbent assays kits (R&D system, Inc.,USA).
The second outcomes included pain scores, hemodynamic variables and recovery characteristics during the first 2 postoperative days. Pain scores included VAS scores at rest and during movement (cough or rotating the body) in the first 2 postoperative days. The MAP and HR were continuously measured and recorded before anesthesia, during induction, tracheal intubation, incision, immediately after tracheal extubation, as well as at 6, 24, and 48 h postoperatively. The other recorded observations included additional sufentanil consumption, postoperative opioid requirement, and recovery profiles (duration of PACU, side effects such as nausea, sedation, and vomiting, time of first flatus, and hospital stays). Sedation was assessed by Ramsay score (2–4: satisfactory sedation, > 4: excessive sedation). Additionally, discontinuing PACU was determined by a standard score test (= 10: PACU should be discontinued). The study processes are shown in Additional file 1: Figure S1.
The minimum detectable difference of plasma cortisol concentration was estimated immediately after surgery between two groups. The mean and SD values of plasma cortisol were as follows: MTAP = 410 nmol/L, MControl = 521 nmol/L, STAP = 142 nmol/L, and SControl = 16.4 nmol/L. Based on sample size analysis performed using PASS 11.0 (NCSS Statistical Software, Kaysville, UT), with α = 0.05 and β = 0.2, a minimum sample of 25 cases in each group was required, respectively.
Statistical analyses were performed using SPSS 18.0 (Chicago, IL, USA). The normal distribution of data was evaluated using Shapiro-Wilk test. Data were expressed as mean (± SD) or percentages of the total number of patients (%). Comparisons of NE, E, Cor, Glu, cytokines, hemodynamic data, and VAS scores between groups were performed by repeated-measures analysis of variance. The differences for opioid consumption, time to first flatus, and time in PACU were analyzed using Student’s t test followed by 2-tailed Dunnett test. Categorical data were analyzed by using χ2 or Fisher exact test. P value < 0.05 was considered significant.