Participants and research design
The research was a prospective, single-center, and randomized-controlled trial. This study was ethically approved by the Ethics Committee of the Affiliated Hospital of Jiaxing University (LS2021-KY-061), Jiaxing, China on April 16, 2021. The following principles summarized in the Declaration of Helsinki were performed. The registration of research protocol was made in the Chinese Clinical Trial Register (ChiCTR2100046254, links to registration documents: https://www.chictr.org.cn/edit.aspx?pid=126397&htm=4). The Chinese Clinical Trial was registered on May 12, 2021 (12/05/2021), and patients were enrolled on May 14, 2021 (14/05/2021). All patients who were screened and met the eligibility standards were invited to take part in the trial, and patients enrolled provided written informed consent. Patients were required to give consent on arrival at the operating room or if they were hospitalized at the night before the surgery. Inclusion standards were ASA grade 1 ~ 3, age 18–80 years, patients receiving general anesthesia for unilateral VATS, and no contraindications to peripheral regional anesthetic block. Exclusion standards were contraindication to local anesthesia, pre-existing infection at the block site, pre-existing chronic pain or cognitive dysfunction, and history of opioid abuse that would prevent patients from accurately participating in postoperative quality of recovery and analgesia assessment.
All patients were monitored in the operating room (OR) using standard ECG, noninvasive blood pressure, peripheral oxygen saturation, and dual frequency index (BIS). First heart rate and mean arterial pressure (MAP) were measured as baseline (minute 0). After placing the 22 gage intravenous (IV) line, a 15 mL/ kg/h isotonic saline IV infusion was performed among all patients under the same general anesthesia. Pre-oxygenation was employed to induce anesthesia for 3 minutes, and the intravenous injection of midazolam (0.05 mg/kg), sufentanil (0.5 µg/kg), propofol (2–3 mg/kg), and rocuronium (0.6 mg/kg) was made. The end-tidal carbon dioxide extent of 35–40 mmHg was kept with a double-lumen endotracheal catheter was adopted for positive-pressure ventilation, and a fiber-optic bronchoscope was used to determine the correct location. During operation, the anesthesia maintenance regimen was propofol (50–150 μg·kg-1·min-1) and remifentanil (0.1 μg-1·kg-1·min-1). An anesthesiologist was employed to titrate the minimum alveolar concentration of sevoflurane, and the BIS value of between 40 and 60 was kept. Volume control ventilation was applied with the coefficients below: tidal volume 6-8 ml/kg, respiratory rate 12–20 beats/min, and 2L gas with 70% oxygen and 30% air.
During anesthesia, the intravenous administration of 0.1μg/kg sufentanil was made when the heart rate or blood pressure was 20% higher than the basic value; the administration of 0.5 mg atropine was made when the heart rate was less than 50 beats/min, and the intravenous injection of ringer’s lactate solution of 250 ml or ephedrine of 0.1 mg·kg-1 was made when the blood pressure was lower than 20% of the elementary value.
The administration of granisetron 3mg was made 30 minutes before the surgery, so as to stop postoperative nausea and vomiting. All patients were sent to the postanesthesia care unit (PACU) after surgery. The administration of atropine of 0.01 mg/kg and neostigmine of 0.05 mg·kg-1 as made for reversing the muscle relaxation role of rocuronium as required. The patients were sent to the surgery ward when they met the PACU discharging standard.
In patients with one trochlear port, a single 3.0–4.0 cm incision was made in the 4th or 5th intercostal space of the anterior axillary line and a trochal port was insert the chest wall, then the surgery procedure was performed via the trochal port. A thoracic drainage tube was inserted through the incision before the skin of the 4th or 5th intercostal segments was closed.
Patient grouping and randomization
Eligible patients were recruited by surgeons and research nurses. Patients were fallen into four groups: group control (Group C), group R0.2%, R0.3%, and R0.4%, according to the ratio of 1:1:1:1 randomly. Random numbers were produced on computer and kept in sealed opaque envelopes. After the final part of the trial was randomized, the principal investigator (who would not receive any surgery) decided the four surgeons who would perform the surgery for balancing the number of VATS steps for every surgeon. The main investigator or research nurse informed the surgeon of patient assignment the day before surgery and the operating room team on the day of surgery. After induction of anesthesia, RIB was done by an anesthesiologist who has experience in more than 30 cases of RIB independently. The researcher responsible for the 48-hour postoperative follow-up was blind to the randomization group. In addition, during the preoperative follow-up, patients were instructed on how to apply a patient-stipulated intravenous analgesia (PCA) device for pain management and how to assess pain at rest and on movement applying the NRS scale.
Application of block intervention
After induction of anesthesia, RIB was conducted according to the past description . A high frequency linear ultrasonic probe (LOGIQ e ultrasound system, Deutschland GmbH & Co. KG, Solingen, Germany). The medial placement of oblique sagittal plane was made on the medial margin of the scapula. Ultrasound identified trapezius, intercostal, rhomboid, pleura, and lung markers. Under aseptic conditions, the insertion of an 80mm gauge 21 needle was conducted at the ultrasonic section T5-6. In the group R0.2%, the injection of a dose of 30 ml of 0.2% ropivacaine was performed in the fascial plane between the rhomboid and intercostal muscles; in the group R0.3%, the injection of a dose of 30 ml 0.3% ropivacaine was performed in the fascial plane between the rhomboid and intercostal muscles; and in the group R0.4%, the injection of a single dose of 30 ml 0.4% ropivacaine was performed in the fascial plane between the rhomboid and intercostal muscles. The diffusion of local anesthetic fluid under rhomboid muscle was observed by ultrasound.
Analgesic protocol and assessment of pain and sensorial block
In the PACU, all patients underwent patient-stipulated intravenous analgesia (PCIA): 150 μg sufentanil with a total of 150 mL, loading dose of 2 mL, background dose of 2 mL, and locking time of 15 min. Another blinded anesthesiologist made pain evaluation, about 30 min after being blocked with the 11-point NRS, ranging from 0 (no pain) to 10 (worst pain imaginable). In the surgical ward, the postoperative assessment of patients was made again at 0.5, 1, 3, 6, 12, 18, 24, 36, and 48 h. In case of the NRS mark of >3, the physician pressed the analgesia pump once, and evaluate pain after 15 min. If the NRS mark was >3 continuously, the physician pressed the analgesia pump again. Rescue analgesia was made on basis of the anesthesiologist’s estimate with parecoxib sodium 40 mg.
This research held the main results of the overallQoR-40 scores 24 hours after surgery between the four groups. There were a total of 40 questions for the assessment of five rehabilitation areas in this questionnaire: 12 items about physical comfort, 9 items about emotional state, 5 items about physical independence, 7 item about psychological support, and 7 item about pain . The secondary result methods were AUC the NRS for pain at rest and on movement over 48 hours, time of first postoperative analgesic request, postoperative 48-hour opioid dosage, and satisfaction mark of patients (1–10, where 10 is the highest). Except these methods, dosage of propofol and remifentanil, PACU duration, postoperative nausea and vomiting (PONV), and total number of patients with a postoperative complication were put into record.
The power exploration and sample size (PASS) 15.0 program (NCSS, LLC., Kaysville, UT, USA) was adopted to calculate the sample size of this research. Based on past researches, the 10-point diversities in QoR-40 marks between the group R0.2% and group R0.4% was considered clinically important [26, 27]. On basis of our preliminary research on 20 patients, the QoR-40 mark of group R0.2% was 164.7 ± 5.5, and the QoR-40 mark of the group R0.4% was 170.3 ± 5.9. Assuming α error=0.05 (two-tailed), β error=0.1 with a power of 0.90, at least 23 participants were required per group, considering the 20% dropout rate (on basis of a preliminary research); while increasing the sample scale, the research finally included 29 patients in every group.
SPSS version 25.0 (IBM Corp., Armonk, NY, USA) was adopted for data analysis. For every patient, the time interval with the NRS score was multiplied to calculate their AUC of NRS pain marks both on movement and at rest with GraphPad Prism version 7 (GraphPad Software Inc., San Diego, CA,USA). Continuous data was examined and tested for distribution with the Shapiro-Wilk test. One-way analysis of variance was adopted to explora normally distributed data for the comparison of group-wise diversities in the result coefficients (BMI, age, operation time, anesthesia time, remifentanil dosage, propofol dosage, preoperative QoR-40 mark, QoR-40 mark, physical comfort, emotional state, psychological support, physical independence, pain, the NRS mark curve (AUC) for pain at rest and on movement, time to first postoperative analgesic request, PACU duration, postoperative 48-hour total amount of opioids, satisfaction score of patients, and parecoxib sodium for injections). Normally distributed data are shown as mean ± standard deviation. The diversities among male/female, ASAI/II/III, total number of patients with a postoperative complication, operation procedure, and surgical incision (left chest/right chest) were compared with the chi-square test. Operation procedure and PONV scores were analyzed using Kruskal-Wallis test, and a five-point numerical scale (0=no symptom, 1=scarcely, 2=usually, 3=most of the time, 4=all the time) was adopted to assess PONV. P values <0.05 were regarded significant for the test outcomes displayed.